Olysio

Instructions

Take with food (bioavailability improved)

Swallow capsule whole

Before taking simeprevir,

• tell your doctor and pharmacist if you are allergic to simeprevir, sulfa drugs, any other medications, or any of the ingredients in simeprevir capsules. Ask your pharmacist or check the manufacturer's patient information for a list of the ingredients.
• tell your doctor if you are taking any of the following medications: antifungal medications such as fluconazole (Diflucan), itraconazole (Onmel, Sporanox), ketoconazole (Nizoral), posaconazole (Noxafil), or voriconazole (Vfend); certain medications for HIV such as atazanavir (Reyataz), darunavir (Prezista), delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir (Kaletra), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), saquinavir (Invirase), or tipranavir (Aptivus); certain medications for seizures such as carbamazepine (Carbatrol, Epitol, Equetro, Tegretol), oxcarbazepine (Trileptal), phenobarbital, or phenytoin (Dilantin, Phenytek); cisapride (Propulsid) (not available in the U.S.); clarithromycin (Biaxin, in Prevpac); dexamethasone; erythromycin (E.E.S., Eryc, Ery-tab, others); medication containing cobicistat (Stribild); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); rifapentine (Priftin); or telithromycin (Ketek). Your doctor will probably tell you not to take simeprevir if you are taking one or more of these medications. Also tell your doctor if you have ever taken boceprevir (Victrelis) or telaprevir (Incivek).
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor XR, Tiazac), felodipine (Plendil), nicardipine (Cardene), nifedipine (Adalat, Procardia), nisoldipine (Sular), or verapamil (Calan, Covera HS, Isoptin); certain medications for high cholesterol such as atorvastatin (Lipitor, in Caduet), lovastatin (Altoprev, Mevacor, in Advicor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), or simvastatin (Zocor, in Simcor, in Vytorin); certain medications for irregular heartbeat such as amiodarone (Cordarone, Pacerone), disopyramide (Norpace), flecainide (Tambocor), mexiletine (Mexitil), propafenone (Rythmol SR), or quinidine; cyclosporine (Neoral, Sandimmune); digoxin (Lanoxin); midazolam taken by mouth; sildenafil (only Revatio brand used for lung disease); sirolimus (Rapamune); tacrolimus (Prograf); tadalafil (only Adcirca brand used for lung disease); triazolam (Halcion) taken by mouth; or warfarin (Coumadin). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with simeprevir, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor what herbal products you are taking, especially milk thistle or St. John's wort. You should not take milk thistle or St. John's wort during your treatment with simeprevir.
• tell your doctor if you have had a liver transplant, if you are receiving phototherapy, if you are of East Asian descent, and if you have or have ever had any type of liver disease other than hepatitis C.
• tell your doctor if you are pregnant, plan to become pregnant, or can possibly become pregnant. If you are male, tell your doctor if your partner is pregnant, plans to become pregnant, or can possibly become pregnant. Simeprevir must be taken with ribavirin which can seriously harm the fetus. You must use two methods of birth control to prevent pregnancy in you or your partner during treatment with these medications and for 6 months after your treatment. Talk to your doctor about which methods you should use; hormonal contraceptives (birth control pills, patches, implants, rings, or injections) may not work well in women who are taking these medications. You or your partner must be tested for pregnancy prior to treatment, every month during your treatment, and for 6 months after your treatment. If you or your partner becomes pregnant while taking these medications, call your doctor immediately.
• tell your doctor if you are breastfeeding.
• plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, a hat, and sunscreen. Also avoid the use of tanning beds, sunlamps, or other types of light therapy during your treatment. Simeprevir may make your skin sensitive to sunlight. Call your doctor right away if you experience a severe sunburn or burning, redness, swelling, or blisters on your skin.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

The recommended dose of simeprevir is one 150 mg capsule once daily with food for 12 weeks in combination with peginter-feron and ribavarin. It should be followed by 12 or 36 additional weeks of peginterferon and ribavirin depending on prior response. It can also be combined with sofosbuvir (Sovaldi) for 12 weeks.

Olysio is part of the drug class:

• Protease inhibitors

There is a risk of hepatitis B virus (HBV) becoming an active infection in those who have a current or previous infection with HBV and is treated with a certain antiviral medication (a direct-acting antiviral) to treat hepatitis C virus. Your healthcare provider will screen and monitor for HBV in those taking a direct-acting antiviral. Tell your healthcare provider if you have a history of hepatitis B infection or other liver problems before you are treated for hepatitis C. 

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Taking simeprevir together with sofosbuvir and amiodarone (a heart rhythm medication) may slow your heart rate which can lead to serious medical problems. Tell your doctor if you take amiodarone (Cordarone, Nexterone, Pacerone).

Other drugs may interact with simeprevir, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Chronic HCV Infection

Treatment of chronic HCV genotype 1 or genotype 4 infection in treatment-naive (previously untreated) or previously treated adults, including those with HIV coinfection.1 2 10 11 12 13 14 119

Must be used in conjunction with other antivirals;1 119 do not use alone.1 119

Usually used in multiple-drug regimen that includes simeprevir and sofosbuvir1 12 119 or multiple-drug regimen that includes simeprevir, peginterferon alfa, and ribavirin.1 10 11 13 14

Not recommended in patients in whom prior treatment with a regimen that included simeprevir or any other HCV protease inhibitor failed.1

Not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 (See Hepatic Impairment under Cautions.)

Efficacy of multiple-drug regimen of simeprevir, peginterferon alfa, and ribavirin for treatment of HCV genotype 1a infection is substantially reduced in patients with NS3 Q80K polymorphism at baseline compared with those without NS3 Q80K polymorphism.1 Screening for NS3 Q80K polymorphism at baseline strongly recommended;1 consider alternate therapy in those with NS3 Q80K polymorphism.1 (See General under Dosage and Administration.)

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Simeprevir Sodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	150 mg (of simeprevir)	Olysio	Janssen

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.

HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with Olysio. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with Olysio and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone was coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with Coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Coadministration of amiodarone with Olysio in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be coadministered Olysio and sofosbuvir:

• Counsel patients about the risk of serious symptomatic bradycardia.
• Cardiac monitoring in an in-patient setting for the first 48 hours of Coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking sofosbuvir in combination with Olysio who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone's long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with Olysio should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Adverse Reactions (6.2) and Drug Interactions (7.3)].

Hepatic Decompensation and Hepatic Failure

Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with Olysio in combination with Peg-IFN-alfa and RBV or in combination with sofosbuvir. Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made; and a causal relationship between treatment with Olysio and these events has not been established [see Adverse Reactions (6.2)].

Olysio is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C) [see Dosage and Administration (2.5) and Use in Specific Populations (8.8)].

In clinical trials of Olysio, modest increases in bilirubin levels were observed without impacting hepatic function [see Adverse Reactions (6.1)]. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during Olysio combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:

• Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
• Discontinue Olysio if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.

Risk of Serious Adverse Reactions Associated with Combination Treatment

Because Olysio is used in combination with other antiviral drugs for the treatment of chronic HCV infection, consult the prescribing information for these drugs before starting therapy with Olysio. Warnings and Precautions related to these drugs also apply to their use in Olysio combination treatment.

Photosensitivity

Photosensitivity reactions have been observed with Olysio combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with Olysio in combination with Peg-IFN-alfa and RBV [see Adverse Reactions (6.1)]. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.

Use sun protective measures and limit sun exposure during treatment with Olysio. Avoid use of tanning devices during treatment with Olysio. Discontinuation of Olysio should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue Olysio in the setting of a photosensitivity reaction, expert consultation is advised.

Rash

Rash has been observed with Olysio combination therapy [see Adverse Reactions (6.1)]. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of Olysio have been reported in subjects receiving Olysio in combination with Peg-IFN-alfa and RBV. Most of the rash events in Olysio-treated patients were of mild or moderate severity [see Adverse Reactions (6.1)]. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, Olysio should be discontinued. Patients should be monitored until the rash has resolved.

Sulfa Allergy

Olysio contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of Olysio.

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions

Coadministration of Olysio with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Simeprevir was not genotoxic in a series of in vitro and in vivo tests including the Ames test, the mammalian forward mutation assay in mouse lymphoma cells or the in vivo mammalian micronucleus test. Carcinogenicity studies with simeprevir have not been conducted.

If Olysio is administered in a combination regimen containing RBV, refer to the prescribing information for RBV for information on carcinogenesis and mutagenesis.

Impairment of Fertility

In a rat fertility study at doses up to 500 mg/kg/day, 3 male rats treated with simeprevir (2/24 rats at 50 mg/kg/day and 1/24 rats at 500 mg/kg/day) showed no motile sperm, small testes and epididymides, and resulted in infertility in 2 out of 3 of the male rats at exposures less than the exposure in humans at the recommended clinical dose.

If Olysio is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on impairment of fertility.

Animal Toxicology and/or Pharmacology

Cardiovascular toxicity consisting of acute endocardial and myocardial necrosis restricted to the left ventricular subendocardial area was seen in 2 out of 6 animals in a 2-week oral dog toxicity study at an exposure approximately 28 times the mean AUC in humans at the recommended daily dose of 150 mg. No cardiac findings were observed in a 6-month and a 9-month oral toxicity study at exposures, respectively, of 11 and 4 times the mean AUC in humans at the recommended daily dose of 150 mg.

If Olysio is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on animal toxicology.

Overview of Clinical Trials

The efficacy of Olysio in combination with sofosbuvir in subjects with HCV genotype 1 infection was evaluated in one Phase 2 trial (COSMOS) in prior null responders and treatment-naïve subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis, and in two Phase 3 trials in subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis (OPTIMIST-2 and OPTIMIST-1, respectively) who were HCV treatment-naïve or treatment-experienced (following prior treatment with IFN [pegylated or non-pegylated], with or without RBV) (see Table 14). Efficacy data from OPTIMIST-2, which evaluated Olysio in combination with sofosbuvir in subjects with compensated cirrhosis, are not shown because subjects in this trial received a shorter than recommended duration of therapy.

Table 14: Trials Conducted with Olysio in Combination with Sofosbuvir

Trial	Population	Relevant Study Arms (Number of Subjects Treated)
GT: genotype; TN: treatment-naïve; TE: treatment-experienced.
* Includes only null responders to prior Peg-IFN/RBV therapy. † Includes relapsers and non-responders to prior Peg-IFN-based therapy (with or without RBV), and IFN-intolerant subjects.
COSMOS (open-label)	GT 1, TN or TE*, with compensated cirrhosis or without cirrhosis	Olysio + sofosbuvir (12 weeks) (28) Olysio + sofosbuvir (24 weeks) (31)
OPTIMIST-1 (open-label)	GT 1, TN or TE†, without cirrhosis	Olysio + sofosbuvir (12 weeks) (155)
OPTIMIST-2 (open-label)	GT 1, TN or TE†, with compensated cirrhosis	Olysio + sofosbuvir (12 weeks) (103)

The efficacy of Olysio in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection was evaluated in three Phase 3 trials in treatment-naïve subjects (QUEST 1, QUEST 2 and TIGER), one Phase 3 trial in subjects who relapsed after prior interferon-based therapy (PROMISE), one Phase 2 trial in subjects who failed prior therapy with Peg-IFN and RBV (including prior relapsers, partial and null responders) (ASPIRE), and one Phase 3 trial in subjects with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naïve or failed previous HCV therapy with Peg-IFN and RBV (C212), as summarized in Table 15.

The efficacy of Olysio in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 4 infection was evaluated in one Phase 3 trial in treatment-naïve subjects or subjects who failed previous therapy with Peg-IFN and RBV (RESTORE) (see Table 15).

Table 15: Trials Conducted with Olysio in Combination with Peg-IFN-alfa and RBV

Trial	Population	Relevant Study Arms (Number of Subjects Treated)
GT: genotype; TN: treatment-naïve; TE: treatment-experienced, includes prior relapsers, partial responders and null responders following prior treatment with Peg-IFN and RBV.
* Includes only relapsers after prior IFN-based therapy.
QUEST-1 (double-blind)	GT 1, TN, with compensated cirrhosis or without cirrhosis	Olysio + Peg-IFN-alfa + RBV (264) Placebo (130)
QUEST-2 (double-blind)	GT 1, TN, with compensated cirrhosis or without cirrhosis	Olysio + Peg-IFN-alfa + RBV (257) Placebo (134)
TIGER (double-blind)	GT 1, TN, with compensated cirrhosis or without cirrhosis	Olysio + Peg-IFN-alfa + RBV (152) Placebo (152)
PROMISE (double-blind)	GT 1, TE*, with compensated cirrhosis or without cirrhosis	Olysio + Peg-IFN-alfa + RBV (260) Placebo (133)
ASPIRE (double-blind)	GT 1, TE, with compensated cirrhosis or without cirrhosis	Olysio + Peg-IFN-alfa + RBV (66) Placebo (66)
C212 (open-label)	GT 1, TN or TE, with compensated cirrhosis or without cirrhosis, HCV/HIV-1 co-infected	Olysio + Peg-IFN-alfa + RBV (106)
RESTORE (open-label)	GT 4, TN or TE, with compensated cirrhosis or without cirrhosis	Olysio + Peg-IFN-alfa + RBV (107)

Prior relapsers were subjects who had HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected during follow-up; prior partial responders were subjects with prior on-treatment greater than or equal to 2 log10 reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at the end of prior therapy with Peg-IFN and RBV; and null responders were subjects with prior on-treatment less than 2 log10 reduction in HCV RNA from baseline at Week 12 during prior therapy with Peg-IFN and RBV. These trials included subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis, HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with chronic HCV infection. In subjects who were treatment-naïve and prior relapsers, the overall duration of treatment with Peg-IFN-alfa and RBV in the Phase 3 trials was response-guided. In these subjects, the planned total duration of HCV treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy (RGT) criteria were met: HCV RNA lower than 25 IU/mL (detected or not detected) at Week 4 AND HCV RNA not detected at Week 12. Plasma HCV RNA levels were measured using the Roche COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System (25 IU/mL lower limit of quantification and 15 IU/mL limit of detection). Treatment stopping rules for HCV therapy were used to ensure that subjects with inadequate on-treatment virologic response discontinued treatment in a timely manner. In the Phase 3 trial C212 in HCV/HIV-1 co-infected subjects, the total duration of treatment with Peg-IFN-alfa and RBV in treatment-naïve and prior relapser subjects with compensated cirrhosis was not response-guided; these subjects received a fixed total duration of HCV treatment of 48 weeks. The total duration of treatment with Peg-IFN-alfa and RBV in non-cirrhotic HCV/HIV-1 co-infected treatment-naïve or prior relapser subjects was response-guided using the same criteria.

Olysio in Combination with Sofosbuvir

Adult Subjects with HCV Genotype 1 Infection

The efficacy of Olysio (150 mg once daily) in combination with sofosbuvir (400 mg once daily) in HCV genotype 1-infected treatment-naïve or treatment-experienced subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis was demonstrated in one Phase 2 trial (COSMOS) and one Phase 3 trial (OPTIMIST-1).

The COSMOS trial was an open-label, randomized Phase 2 trial to investigate the efficacy and safety of 12 or 24 weeks of Olysio (150 mg once daily) in combination with sofosbuvir (400 mg once daily) without or with RBV in HCV genotype 1-infected prior null responders with METAVIR fibrosis score F0–F2, or treatment-naïve subjects and prior null responders with METAVIR fibrosis score F3–F4 and compensated liver disease.

Results from treatment arms containing RBV in addition to Olysio and sofosbuvir in the COSMOS trial are not shown because efficacy was similar with or without RBV, and thus addition of RBV to Olysio and sofosbuvir is not recommended. In this trial, 28 subjects received 12 weeks of Olysio in combination with sofosbuvir and 31 subjects received 24 weeks of Olysio in combination with sofosbuvir. These 59 subjects had a median age of 57 years (range 27 to 68 years; with 2% above 65 years); 53% were male; 76% were White, and 24% Black or African American; 46% had a BMI greater than or equal to 30 kg/m2; the median baseline HCV RNA level was 6.75 log10 IU/mL; 19%, 31% and 22% had METAVIR fibrosis scores F0–F1, F2 and F3, respectively, and 29% had METAVIR fibrosis score F4 (cirrhosis); 75% had HCV genotype 1a of which 41% carried Q80K at baseline, and 25% had HCV genotype 1b; 14% had IL28B CC genotype, 64% IL28B CT genotype, and 22% IL28B TT genotype; 75% were prior null responders to Peg-IFN-alfa and RBV, and 25% were treatment-naïve.

OPTIMIST-1 was an open-label, randomized Phase 3 trial in HCV genotype 1-infected subjects without cirrhosis who were treatment-naïve or treatment-experienced (including prior relapsers, non-responders and IFN-intolerant subjects). Subjects were randomized to treatment arms of different durations. One hundred fifty-five subjects received 12 weeks of Olysio with sofosbuvir. The 155 subjects without cirrhosis receiving 12 weeks of Olysio with sofosbuvir had a median age of 56 years (range 19 to 70 years; with 7% above 65 years); 53% were male; 78% were White, 20% Black or African American, and 16% Hispanic; 37% had a BMI ≥ 30 kg/m2; the median baseline HCV RNA level was 6.83 log10 IU/mL; 75% had HCV genotype 1a of which 40% had Q80K polymorphism at baseline, and 25% had HCV genotype 1b; 28% had IL28B CC genotype, 55% IL28B CT genotype, and 17% IL28B TT genotype; 74% were treatment-naïve and 26% were treatment-experienced.

In the COSMOS and OPTIMIST-1 trials, SVR12 was achieved in 170/176 (97%) subjects without cirrhosis treated with 12 weeks Olysio in combination with sofosbuvir, as shown in Table 16. In the COSMOS trial, 10/10 (100%) subjects with compensated cirrhosis (Child-Pugh A) who received 24 weeks of Olysio with sofosbuvir achieved SVR12.

Table 16: Virologic Outcomes in Adults without Cirrhosis Receiving 12 Weeks of Olysio with Sofosbuvir (Pooled data from OPTIMIST-1 and COSMOS Trials)

Response Rates	Olysio+sofosbuvir* 12 weeks N=176 % (n/N)
SVR12: sustained virologic response 12 weeks after actual (OPTIMIST-1) or planned (COSMOS) EOT.
* 150 mg once daily Olysio for 12 weeks with 400 mg once daily sofosbuvir. † Viral relapse rates are calculated with a denominator of subjects with undetectable (or unconfirmed detectable) HCV RNA at EOT. In addition to five subjects with viral relapse, one subject failed to achieve SVR12 due to missing SVR12 data. No subjects experienced on-treatment virologic failure.
Overall SVR12	97 (170/176)
Outcome for subjects without SVR12
Viral relapse†	3 (5/175)

Among subjects without cirrhosis in OPTIMIST-1 who received 12 weeks of Olysio in combination with sofosbuvir, similar SVR12 rates were observed among subgroups, including: treatment-naïve and treatment-experienced subjects (112/115 [97%] and 38/40 [95%] respectively), subjects with HCV genotype 1a with and without NS3 Q80K polymorphism (44/46 [96%] and 68/70 [97%], respectively), genotype 1b (38/39 [97%]), and subjects with IL28B CC and non-CC genotypes (43/43 [100%] and 107/112 [96%], respectively).

Olysio in Combination with Peg-IFN-alfa and RBV

Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection

The efficacy of Olysio in treatment-naïve patients with HCV genotype 1 infection was demonstrated in two randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trials (QUEST 1 and QUEST 2). The designs of both trials were similar. All subjects received 12 weeks of once daily treatment with 150 mg Olysio or placebo, plus Peg-IFN-alfa-2a (QUEST 1 and QUEST 2) or Peg-IFN-alfa-2b (QUEST 2) and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa and RBV in accordance with the on-treatment protocol-defined RGT criteria. Subjects in the control groups received 48 weeks of Peg-IFN-alfa-2a or -2b and RBV.

In the pooled analysis for QUEST 1 and QUEST 2, demographics and baseline characteristics were balanced between both trials and between the Olysio and placebo treatment groups. In the pooled analysis of trials (QUEST 1 and QUEST 2), the 785 enrolled subjects had a median age of 47 years (range: 18 to 73 years; with 2% above 65 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) greater than or equal to 30 kg/m2; 78% had baseline HCV RNA levels greater than 800000 IU/mL; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype; 17% of the overall population and 34% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. In QUEST 1, all subjects received Peg-IFN-alfa-2a; in QUEST 2, 69% of the subjects received Peg-IFN-alfa-2a and 31% received Peg-IFN-alfa-2b.

Table 17 shows the response rates in treatment-naïve adult subjects with HCV genotype 1 infection. In the Olysio treatment group, SVR12 rates were lower in subjects with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.

Table 17: Virologic Outcomes in Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2 Trials)

Response Rate	Olysio + PR N=521 % (n/N)	Placebo + PR N=264 % (n/N)
Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
* On-treatment failure was defined as the proportion of subjects with confirmed HCV RNA detected at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough). † Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at actual EOT. Includes 4 Olysio-treated subjects who experienced relapse after SVR12.
Overall SVR12 (genotype 1a and 1b)	80 (419/521)	50 (132/264)
Genotype 1a	75 (191/254)	47 (62/131)
Without Q80K	84 (138/165)	43 (36/83)
With Q80K	58 (49/84)	52 (23/44)
Genotype 1b	85 (228/267)	53 (70/133)
Outcome for subjects without SVR12
On-treatment failure*	8 (42/521)	33 (87/264)
Viral relapse†	11 (51/470)	23 (39/172)

In the pooled analysis of QUEST 1 and QUEST 2, 88% (459/521) of Olysio-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 88% (405/459).

Seventy-nine percent (79%; 404/509) of Olysio-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404).

SVR12 rates were higher for the Olysio treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), METAVIR fibrosis score, and IL28B genotype. Table 18 shows the SVR rates by METAVIR fibrosis score.

Table 18: SVR12 Rates by METAVIR Fibrosis Score in Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2 Trials)

Subgroup	Olysio + PR % (n/N)	Placebo + PR % (n/N)
Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
F0–2	84 (317/378)	55 (106/192)
F3–4	68 (89/130)	36 (26/72)

SVR12 rates were higher for subjects receiving Olysio with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (88% and 78%, respectively) compared to subjects receiving placebo with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (62% and 42%, respectively) (QUEST 2).

Treatment-Naïve East Asian Subjects with HCV Genotype 1 Infection

TIGER was a Phase 3, randomized, double-blind, placebo-controlled trial in HCV genotype 1-infected treatment-naïve adult subjects from China and South Korea.

In this trial, 152 subjects received 12 weeks of once-daily treatment with 150 mg Olysio plus Peg-IFN-alfa-2a and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with protocol-defined RGT criteria; and 152 subjects received 12 weeks of placebo plus Peg-IFN-alfa-2a and RBV, followed by 36 weeks therapy with Peg-IFN-alfa-2a and RBV. These 304 subjects had a median age of 45 years (range: 18 to 68 years; with 2% above 65 years); 49% were male; all were East Asians (81% were enrolled in China, and 19% in South Korea); 3% had a body mass index (BMI) greater or equal to 30 kg/m2; 84% had baseline HCV RNA levels greater than 800000 IU/mL; 82% had METAVIR fibrosis score F0, F1 or F2, 12% METAVIR fibrosis score F3, and 6% METAVIR fibrosis score F4 (cirrhosis); 1% had HCV genotype 1a, and 99% HCV genotype 1b; less than 1% of the overall population had Q80K polymorphism at baseline; 79% had IL28B CC genotype, 20% IL28B CT genotype, and 1% IL28B TT genotype. Demographics and baseline characteristics were balanced across the Olysio 150 mg and placebo treatment groups.

SVR12 rates were 91% (138/152) in the Olysio 150 mg treatment group and 76% (115/152) in the placebo treatment group [see Adverse Reactions (6.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Adult Subjects with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy

The PROMISE trial was a randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trial in subjects with HCV genotype 1 infection who relapsed after prior IFN-based therapy. All subjects received 12 weeks of once daily treatment with 150 mg Olysio or placebo, plus Peg-IFN-alfa-2a and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Subjects in the control group received 48 weeks of Peg-IFN-alfa-2a and RBV.

Demographics and baseline characteristics were balanced between the Olysio and placebo treatment groups. The 393 subjects enrolled in the PROMISE trial had a median age of 52 years (range: 20 to 71 years; with 3% above 65 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI greater than or equal to 30 kg/m2; 84% had baseline HCV RNA levels greater than 800000 IU/mL; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype; 13% of the overall population and 31% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. The prior IFN-based HCV therapy was Peg-IFN-alfa-2a/RBV (68%) or Peg-IFN-alfa-2b/RBV (27%).

Table 19 shows the response rates for the Olysio and placebo treatment groups in adult subjects with HCV genotype 1 infection who relapsed after prior interferon-based therapy. In the Olysio treatment group, SVR12 rates were lower in subjects infected with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.

Table 19: Virologic Outcomes in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE Trial)

Response Rates	Olysio + PR N=260 % (n/N)	Placebo + PR N=133 % (n/N)
Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
* On-treatment failure was defined as the proportion of subjects with confirmed HCV RNA detected at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough). † Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at actual EOT and with at least one follow-up HCV RNA assessment. Includes 5 Olysio-treated subjects who experienced relapse after SVR12.
Overall SVR12 (genotype 1a and 1b)	79 (206/260)	37 (49/133)
Genotype 1a	70 (78/111)	28 (15/54)
Without Q80K	78 (62/79)	26 (9/34)
With Q80K	47 (14/30)	30 (6/20)
Genotype 1b	86 (128/149)	43 (34/79)
Outcome for subjects without SVR12
On-treatment failure*	3 (8/260)	27 (36/133)
Viral relapse†	18 (46/249)	48 (45/93)

In PROMISE, 93% (241/260) of Olysio-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 83% (200/241).

Seventy-seven percent (77%; 200/259) of Olysio-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200).

SVR12 rates were higher for the Olysio treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), prior HCV therapy, METAVIR fibrosis score, and IL28B genotype. Table 20 shows the SVR rates by METAVIR fibrosis score.

Table 20: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE Trial)

Subgroup	Olysio + PR % (n/N)	Placebo + PR % (n/N)
Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
F0–2	82 (137/167)	41 (40/98)
F3–4	73 (61/83)	24 (8/34)

The ASPIRE trial was a randomized, double-blind, placebo-controlled, Phase 2 trial in subjects with HCV genotype 1 infection, who failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders).

In this trial, 66 subjects received 12 weeks of 150 mg Olysio in combination with Peg-IFN-alfa-2a and RBV for 48 weeks, and 66 subjects received placebo in combination with Peg-IFN-alfa-2a and RBV for 48 weeks. These 132 subjects had a median age of 49 years (range: 20 to 66 years; with 1% above 65 years); 66% were male; 93% were White, 3% Black or African American, and 2% Asian; 27% had a BMI greater than or equal to 30 kg/m2; 85% had baseline HCV RNA levels greater than 800000 IU/mL; 64% had METAVIR fibrosis score F0, F1, or F2, 18% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 43% had HCV genotype 1a, and 57% HCV genotype 1b; 17% had IL28B CC genotype, 67% IL28B CT genotype, and 16% IL28B TT genotype (information available for 93 subjects); 27% of the overall population and 23% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. Forty percent (40%) of subjects were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with Peg-IFN-alfa and RBV. Demographics and baseline characteristics were balanced between the 12 weeks 150 mg Olysio and placebo treatment groups.

Table 21 shows the response rates for the 12 weeks of 150 mg Olysio and placebo treatment groups in prior relapsers, prior partial responders and prior null responders.

Table 21: Virologic Outcomes in Prior Partial and Null Responders with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy (ASPIRE Trial)

Response Rates	Olysio + PR N=66 % (n/N)	Placebo + PR N=66 % (n/N)
150 mg Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks; Placebo: placebo with Peg-IFN-alfa-2a and RBV for 48 weeks.
SVR24: sustained virologic response defined as undetectable HCV RNA 24 weeks after planned EOT.
* On-treatment virologic failure was defined as the proportion of subjects who met the protocol-specified treatment stopping rules (including stopping rule due to viral breakthrough) or who had HCV RNA detected at EOT (for subjects who completed therapy). † Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at EOT and with at least one follow-up HCV RNA assessment.
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)
Outcome for subjects without SVR24
On-treatment virologic failure*
Prior relapsers	8 (2/26)	22 (6/27)
Prior partial responders	22 (5/23)	78 (18/23)
Prior null responders	35 (6/17)	75 (12/16)
Viral relapse†
Prior relapsers	13 (3/23)	47 (9/19)
Prior partial responders	6 (1/17)	50 (2/4)
Prior null responders	18 (2/11)	25 (1/4)

SVR24 rates were higher in the Olysio-treated subjects compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, regardless of HCV geno/subtype, METAVIR fibrosis score, and IL28B genotype.

Subjects with HCV/HIV-1 Co-Infection

C212 was an open-label, single-arm Phase 3 trial in HIV-1 subjects co-infected with HCV genotype 1 who were treatment-naïve or failed prior HCV therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Non-cirrhotic treatment-naïve subjects or prior relapsers received 12 weeks of once-daily treatment with 150 mg Olysio plus Peg-IFN-alfa-2a and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Prior non-responder subjects (partial and null response) and all cirrhotic subjects (METAVIR fibrosis score F4) received 36 weeks of Peg-IFN-alfa-2a and RBV after the initial 12 weeks of Olysio in combination with Peg-IFN-alfa-2a and RBV.

The 106 enrolled subjects in the C212 trial had a median age of 48 years (range: 27 to 67 years; with 2% above 65 years); 85% were male; 82% were White, 14% Black or African American, 1% Asian, and 6% Hispanic; 12% had a BMI greater than or equal to 30 kg/m2; 86% had baseline HCV RNA levels greater than 800,000 IU/mL; 68% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 13% METAVIR fibrosis score F4; 82% had HCV genotype 1a, and 17% HCV genotype 1b; 28% of the overall population and 34% of the subjects with genotype 1a had Q80K polymorphism at baseline; 27% had IL28B CC genotype, 56% IL28B CT genotype, and 17% IL28B TT genotype; 50% (n=53) were HCV treatment-naïve subjects, 14% (n=15) prior relapsers, 9% (n=10) prior partial responders, and 26% (n=28) prior null responders. Eighty-eight percent (n=93) of the subjects were on highly active antiretroviral therapy (HAART), with nucleoside reverse transcriptase inhibitors and the integrase inhibitor raltegravir being the most commonly used HIV antiretroviral. HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (except rilpivirine) were prohibited from use in this study.

The median baseline HIV-1 RNA levels and CD4+ cell count in subjects not on HAART were 4.18 log10 copies/mL (range: 1.3–4.9 log10 copies/mL) and 677 × 106 cells/L (range: 489–1076 × 106 cells/L), respectively. The median baseline CD4+ cell count in subjects on HAART was 561 × 106 cells/mL (range: 275–1407 × 106 cells/mL).

Table 22 shows the response rates in treatment-naïve, prior relapsers, prior partial responders and null responders.

Table 22: Virologic Outcomes in Adult Subjects with HCV Genotype 1 Infection and HIV-1 Co-Infection (C212 Trial)

Response Rates	Treatment-Naïve Subjects N=53 % (n/N)	Prior Relapsers N=15 % (n/N)	Prior Partial Responders N=10 % (n/N)	Prior Null Responders N=28 % (n/N)
150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks.
SVR12: sustained virologic response 12 weeks after planned EOT.
* On-treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough). † Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT and with at least one follow-up HCV RNA assessment. Includes one prior null responder who experienced relapse after SVR12.
Overall SVR12 (genotype 1a and 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)
Outcome for subjects without SVR12
On-treatment failure*	9 (5/53)	0 (0/15)	20 (2/10)	39 (11/28)
Viral relapse†	10 (5/48)	13 (2/15)	0 (0/7)	12 (2/17)

Eighty-nine percent (n=54/61) of the Olysio-treated treatment-naïve subjects and prior relapsers without cirrhosis were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 87%.

Seventy-one percent (n=37/52), 93% (n=14/15), 80% (n=8/10) and 36% (n=10/28) of Olysio-treated treatment-naïve subjects, prior relapsers, prior partial responders and prior null responders had undetectable HCV RNA at week 4 (RVR). In these subjects the SVR12 rates were 89%, 93%, 75% and 90%, respectively.

Table 23 shows the SVR rates by METAVIR fibrosis scores.

Table 23: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection and HIV-1 co-Infection (C212 Trial)

Subgroup	Treatment-Naïve Subjects % (n/N)	Prior Relapsers % (n/N)	Prior Partial Responders % (n/N)	Prior Null Responders % (n/N)
150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks.
SVR12: sustained virologic response 12 weeks after planned EOT.
F0–2	89 (24/27)	78 (7/9)	50 (1/2)	57 (4/7)
F3–4	57 (4/7)	100 (2/2)	67 (2/3)	60 (6/10)

Two subjects had HIV virologic failure defined as confirmed HIV-1 RNA at least 200 copies/mL after previous less than 50 copies/mL; these failures occurred 36 and 48 weeks after end of Olysio treatment.

Adult Subjects with HCV Genotype 4 Infection

RESTORE was an open-label, single-arm Phase 3 trial in subjects with HCV genotype 4 infection who were treatment-naïve or failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Treatment-naïve subjects or prior relapsers received once-daily treatment with 150 mg Olysio plus Peg-IFN-alfa-2a and RBV for 12 weeks, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Prior non-responder subjects (partial and null response) received once-daily treatment with 150 mg Olysio plus Peg-IFN-alfa-2a and RBV for 12 weeks, followed by 36 weeks of Peg-IFN-alfa-2a and RBV.

The 107 enrolled subjects in the RESTORE trial with HCV genotype 4 had a median age of 49 years (range: 27 to 69 years; with 5% above 65 years); 79% were male; 72% were White, 28% Black or African American, and 7% Hispanic; 14% had a BMI greater than or equal to 30 kg/m2; 60% had baseline HCV RNA levels greater than 800,000 IU/mL; 57% had METAVIR fibrosis score F0, F1 or F2, 14% METAVIR fibrosis score F3, and 29% METAVIR fibrosis score F4; 42% had HCV genotype 4a, and 24% had HCV genotype 4d; 8% had IL28B CC genotype, 58% IL28B CT genotype, and 35% IL28B TT genotype; 33% (n=35) were treatment-naïve HCV subjects, 21% (n=22) prior relapsers, 9% (n=10) prior partial responders, and 37% (n=40) prior null responders.

Table 24 shows the response rates in treatment-naïve, prior relapsers, prior partial responders and null responders. Table 25 shows the SVR rates by METAVIR fibrosis scores.

Table 24: Virologic Outcomes in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)

Response Rates	Treatment-Naïve Subjects N=35 % (n/N)	Prior Relapsers N=22 % (n/N)	Prior Partial Responders N=10 % (n/N)	Prior Null Responders N=40 % (n/N)
150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks.
SVR12: sustained virologic response 12 weeks after planned EOT.
* On-treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough). † Viral relapse rates are calculated with a denominator of subjects with undetectable (or unconfirmed detectable) HCV RNA at actual EOT.
Overall SVR12	83 (29/35)	86 (19/22)	60 (6/10)	40 (16/40)
Outcome for subjects without SVR12
On-treatment failure*	9 (3/35)	9 (2/22)	20 (2/10)	45 (18/40)
Viral relapse†	9 (3/35)	5 (1/22)	20 (2/10)	15 (6/40)

Table 25: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)

Subgroup	Treatment-Naïve Subjects % (n/N)	Prior Relapsers % (n/N)	Prior Partial Responders % (n/N)	Prior Null Responders % (n/N)
150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks.
SVR12: sustained virologic response 12 weeks after planned EOT.
F0–2	85 (22/26)	91 (10/11)	100 (5/5)	47 (8/17)
F3–4	78 (7/9)	82 (9/11)	20 (1/5)	35 (7/20)

Take the missed dose as soon as you remember. If you are more than 12 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Applies to simeprevir: oral capsule

General

In clinical trials, most side effects reported in hepatitis C virus (HCV) genotype 1-infected patients with compensated cirrhosis (Child-Pugh A) or without cirrhosis using this drug with sofosbuvir (without ribavirin) for 12 or 24 weeks were grade 1 or 2 in severity; grade 3 or 4 side effects were reported in 4% and 13% of patients receiving this therapy for 12 and 24 weeks, respectively. Serious side effects were reported in 2% (12 weeks therapy) and 3% (24 weeks therapy) of patients, respectively. The most common side effects reported in patients using this drug plus sofosbuvir for 12 or 24 weeks were fatigue, headache, rash (including photosensitivity reaction), diarrhea, dizziness, nausea, constipation, and pruritus. Therapy was discontinued due to side effects in 1% (12 weeks therapy) and 6% (24 weeks therapy) of patients, respectively.

In clinical trials, most side effects reported in HCV genotype 1-infected patients using this drug with peginterferon alfa and ribavirin for 12 weeks were grade 1 to 2 in severity; grade 3 or 4 side effects were reported in up to 23% of patients using this drug with peginterferon alfa and ribavirin and in up to 25% using placebo with peginterferon alfa and ribavirin. Serious side effects were reported in up to 2% of patients using this drug with peginterferon alfa and ribavirin and in up to 3% using placebo with peginterferon alfa and ribavirin. During the first 12 weeks of therapy with this drug plus peginterferon alfa and ribavirin, the most common side effects were rash (including photosensitivity), nausea, pruritus, myalgia, dyspnea, increased blood bilirubin, and photosensitivity reaction. This drug was discontinued due to side effects in up to 2% of patients using this drug with peginterferon alfa and ribavirin.

The manufacturer product information for coadministered HCV antiviral drugs should be consulted for associated side effects.[Ref]

Hepatic

Very common (10% or more): Increased blood bilirubin (term included increased conjugated bilirubin, increased blood bilirubin, increased unconjugated blood bilirubin, hyperbilirubinemia; up to 66%)
Postmarketing reports: Hepatic decompensation, hepatic failure[Ref]

Grade 1, 2, and 3 hyperbilirubinemia were reported in 12%, 3%, and less than 1% of patients using this drug plus sofosbuvir for 12 weeks, respectively. Grade 1, 2, and 4 hyperbilirubinemia were reported in 16%, 3%, and 3% of patients using this drug plus sofosbuvir for 24 weeks, respectively. In 1 trial, increased bilirubin was reported in no patients using this drug plus sofosbuvir (without ribavirin) for 12 weeks versus 9.3% of patients using this drug plus sofosbuvir and ribavirin for 12 weeks.

During the 12 weeks of therapy with this drug plus peginterferon alfa and ribavirin, grade 1, 2, 3, and 4 hyperbilirubinemia were reported in 26.7%, 18.3%, 4.1%, and 0.4% of patients, respectively. Bilirubin elevations were mostly mild to moderate in severity, and included elevation of both direct and indirect bilirubin. Bilirubin elevations occurred soon after therapy started, peaked by the second week, and reversed quickly after this drug was stopped. In general, bilirubin elevations (direct and indirect) were not associated with liver transaminase elevations. The incidence of increased bilirubin was higher in patients with increased simeprevir exposures (e.g., patients with severe liver dysfunction); such bilirubin increases were not associated with any adverse liver safety finding.

Compared to a pooled phase 3 population from global trials, East Asian patients using this drug with peginterferon alfa and ribavirin had a higher incidence of hyperbilirubinemia; elevated total bilirubin (all grades) was reported in up to 66% of patients. Bilirubin elevations were primarily grade 1 or 2; grade 3 bilirubin elevations were reported in up to 9% of patients. Bilirubin elevations were not associated with liver transaminase elevations and were reversible after therapy ended.

Hepatic decompensation and hepatic failure (including fatalities) have been reported with this drug coadministered with peginterferon alfa and ribavirin or with sofosbuvir. Most reports occurred in patients with advanced and/or decompensated cirrhosis.[Ref]

Dermatologic

In trials of this drug plus sofosbuvir, rash (including photosensitivity reactions) was reported in 12% and 16% of patients receiving therapy for 12 and 24 weeks, respectively; pruritus was reported in 8.4% (12 weeks therapy) and 3.2% (24 weeks therapy) of patients. Most rash events were of mild or moderate severity (grade 1 or 2); most photosensitivity reactions were of mild severity (grade 1). Grade 3 rash was reported in 1 patient; therapy was discontinued. In 1 trial, rash was reported in 10.7% of patients using this drug plus sofosbuvir (without ribavirin) for 12 weeks versus 20.4% of patients using this drug plus sofosbuvir and ribavirin for 12 weeks.

Photosensitivity reactions (all grades) were reported in 3.1% (12 weeks therapy) and 6.5% (24 weeks therapy) of patients using this drug plus sofosbuvir. Most photosensitivity reactions were of mild severity (grade 1); grade 2 photosensitivity reactions were reported in 2 patients (12 weeks therapy). In 1 trial, photosensitivity reactions were reported in 7.1% of patients using this drug plus sofosbuvir (without ribavirin) for 12 weeks versus 5.6% of patients using this drug plus sofosbuvir and ribavirin for 12 weeks.

In trials of this drug plus peginterferon alfa and ribavirin, rash (including photosensitivity reactions) and pruritus were reported in up to 28% and 21.9% of patients, respectively, during the 12 weeks with this drug. Fifty-six percent (56%) of rash events occurred in the first 4 weeks; 42% in the first 2 weeks. Most rash and pruritus events were of mild or moderate severity (grade 1 or 2); severe rash and pruritus (grade 3) were reported in up to 1% and 0.1% of patients, respectively. This drug was discontinued due to rash and pruritus in up to 1% and 0.1% of patients, respectively. The frequencies of rash and photosensitivity reactions were higher in those with higher simeprevir (the active ingredient contained in Olysio) exposures.

All trial subjects were directed to use sun protection measures. In these trials, photosensitivity (specifically) was reported in 5% of patients during the 12 weeks of therapy with this drug plus peginterferon alfa and ribavirin. Most photosensitivity reactions were of mild or moderate severity (grade 1 or 2). Photosensitivity reactions requiring hospitalization occurred in 2 patients.[Ref]

Very common (10% or more): Rash (including photosensitivity; term included rash, erythema, eczema, maculopapular rash, macular rash, dermatitis, papular rash, skin exfoliation, pruritic rash, erythematous rash, urticaria, generalized rash, drug eruption, allergic dermatitis, dermatosis, vasculitic rash, toxic skin eruption, exfoliative rash, generalized erythema, exfoliative dermatitis, cutaneous vasculitis, photosensitivity reaction, polymorphic light eruption, solar dermatitis, photodermatosis, sunburn, blister, macule, erythema of eyelid, palmar erythema, papule, pityriasis rosea, follicular rash, morbilliform rash, pustular rash, scrotal erythema, skin irritation, skin reaction, umbilical erythema; up to 28%), pruritus (term included pruritus, generalized pruritus, eyelids pruritus, prurigo; up to 22%)
Common (1% to 10%): Photosensitivity reaction[Ref]

Other

During the 12 weeks of therapy with this drug plus peginterferon alfa and ribavirin, grade 1 and 2 alkaline phosphatase elevations were reported in 3.3% and 0.1% of patients, respectively.

Very common (10% or more): Fatigue (up to 32%)
Common (1% to 10%): Increased alkaline phosphatase

Gastrointestinal

Grade 1, 2, and 3 amylase elevations were reported in 11.9%, 5.2%, and 4.5% of patients using this drug plus sofosbuvir for 12 weeks, respectively. Grade 1, 2, and 3 amylase elevations were reported in 25.8%, 6.5%, and 9.7% of patients using this drug plus sofosbuvir for 24 weeks, respectively.

Grade 1, 2, 3, and 4 lipase elevations were reported in 4.5%, 7.7%, 0.3%, and 0.3% of patients using this drug plus sofosbuvir for 12 weeks, respectively. Grade 1, 2, 3, and 4 lipase elevations were reported in 3.2%, 9.7%, 3.2%, and 3.2% of patients using this drug plus sofosbuvir for 24 weeks, respectively.

Most amylase and lipase elevations were transient and of mild or moderate severity; such elevations were not associated with pancreatitis.[Ref]

Very common (10% or more): Elevated amylase (up to 26%), nausea (up to 22%), diarrhea (up to 16%)
Common (1% to 10%): Constipation, elevated lipase[Ref]

Nervous system

Very common (10% or more): Headache (up to 23%), dizziness (up to 16%)

Musculoskeletal

Very common (10% or more): Myalgia (up to 16%)[Ref]

Psychiatric

Very common (10% or more): Insomnia (14%)

Hematologic

Anemia was reported in 13% of patients using this drug with sofosbuvir and ribavirin and 0% using this drug with sofosbuvir.

A higher incidence of anemia was reported in patients with advanced fibrosis using this drug plus peginterferon alfa and ribavirin.

Very common (10% or more): Anemia (up to 13%)

Respiratory

Very common (10% or more): Dyspnea (term included dyspnea, exertional dyspnea; up to 12%)[Ref]

During the 12 weeks of therapy with this drug plus peginterferon alfa and ribavirin, dyspnea was reported in 12% of patients. All dyspnea events were of mild or moderate severity (grade 1 or 2). Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks. In patients older than 45 years, dyspnea was reported in 16.4% of patients using this drug compared to 9.1% using placebo with peginterferon alfa and ribavirin.[Ref]

Cardiovascular

Bradycardia has been reported when this drug was used with sofosbuvir and concomitant amiodarone. Serious symptomatic bradycardia has been reported in patients taking amiodarone who started therapy with a regimen containing sofosbuvir.

Postmarketing reports: Symptomatic bradycardia (including cases requiring pacemaker intervention)

Some side effects of Olysio may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

LactMed: If the mother requires this drug, it is not a reason to discontinue breastfeeding; some experts recommend against breastfeeding when this drug is used with ribavirin. -According to some authorities: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: -This drug has not been studied in nursing mothers receiving treatment for hepatitis C virus infection. -Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug. -The effects in the nursing infant are unknown; potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered. -The manufacturer product information for coadministered hepatitis C virus antiviral drugs (especially ribavirin and peginterferon alfa) should be consulted.