Components:
Method of action:
Treatment option:
Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 14.03.2022
Attention! Information on this page is intended only for medical professionals! Information is collected in open sources and may contain significant errors! Be careful and double-check all the information on this page!
Dosage Forms And Strengths
OLYSIO is available as a white gelatin capsule marked with “TMC435 150” in black ink. Each capsule contains 150 mg simeprevir.
Storage And Handling
OLYSIO 150 mg capsules are white, marked with “TMC435 150” in black ink. The capsules are packaged into a bottle containing 28 capsules (NDC 59676-225-28).
Store OLYSIO capsules in the original bottle in order to protect from light at room temperature below 30°C (86°F).
Manufactured by: Janssen-Cilag SpA, Latina, Italy. Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP Titusville NJ 08560. Revised: May 2017
OLYSIO® is indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection :
- in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis
- in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis.
Limitations Of Use
- Efficacy of OLYSIO in combination with Peg-IFN-alfa and RBV is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism.
- OLYSIO is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO or other HCV protease inhibitors.
Testing Prior To The Initiation Of Therapy
Testing For HBV infection
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with OLYSIO.
Q80K Testing In HCV Genotype 1a-Infected Patients
OLYSIO in Combination with Sofosbuvir
In HCV genotype 1a-infected patients with compensated cirrhosis, screening for the presence of virus with the NS3 Q80K polymorphism may be considered prior to initiation of treatment with OLYSIO with sofosbuvir.
OLYSIO in Combination with Peg-IFN-alfa and RBV
Prior to initiation of treatment with OLYSIO in combination with Peg-IFN-alfa and RBV, screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.
Hepatic Laboratory Testing
Monitor liver chemistry tests before and during OLYSIO combination therapy.
OLYSIO Combination Treatment
Administer OLYSIO in combination with other antiviral drugs for the treatment of chronic HCV infection. OLYSIO monotherapy is not recommended. The recommended dosage of OLYSIO is one 150 mg capsule taken orally once daily with food. The capsule should be swallowed as a whole. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information.
OLYSIO can be taken in combination with sofosbuvir or in combination with Peg-IFN-alfa and RBV.
OLYSIO In Combination With Sofosbuvir
Table 1 displays the recommended treatment regimen and duration of OLYSIO in combination with sofosbuvir in patients with chronic HCV genotype 1 infection.
Table 1: Recommended Treatment Regimen and Duration for
OLYSIO and Sofosbuvir Combination Therapy in Patients with Chronic HCV Genotype
1 Infection
| Patient Population (HCV Genotype 1) | Treatment Regimen and Duration |
| Treatment-naive and treatment-experienced* patients: | |
| without cirrhosis | 12 weeks of OLYSIO + sofosbuvir |
| with compensated cirrhosis (Child-Pugh A) | 24 weeks of OLYSIO + sofosbuvir |
| * Treatment-experienced patients include prior relapsers, prior partial responders and prior null responders who failed prior IFN-based therapy. | |
OLYSIO In Combination With Peg-IFN-alfa And RBV
Table 2 displays the recommended treatment regimen and duration of OLYSIO in combination with Peg-IFN-alfa and RBV in mono-infected and HCV/HIV-1 co-infected patients with HCV genotype 1 or 4 infection. Refer to Table 3 for treatment stopping rules for OLYSIO combination therapy with Peg-IFN-alfa and RBV.
Table 2: Recommended Treatment Regimen and Duration
for OLYSIO, Peg-IFN-alfa, and RBV Combination Therapy in Patients with Chronic
HCV Genotype 1 or 4 Infection
| Patient Population (HCV Genotype 1 or 4) | Treatment Regimen and Duration |
| Treatment-naive patients and prior relapsers*: | |
| HCV mono-infected patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) | 12 weeks of OLYSIO + Peg-IFN-alfa + RBV followed by additional 12 weeks of Peg-IFN-alfa + RBV (total treatment duration of 24 weeks)† |
| HCV/HIV-1 co-infected patients without cirrhosis | |
| HCV/HIV-1 co-infected patients with compensated cirrhosis (Child-Pugh A) | 12 weeks of OLYSIO + Peg-IFN-alfa + RBV followed by additional 36 weeks of Peg-IFN-alfa + RBV (total treatment duration of 48 weeks)† |
| Prior non-responders (including partial‡ and null responders#): | |
| HCV/HIV-1 co-infected or HCV monoinfected patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) | 12 weeks of OLYSIO + Peg-IFN-alfa + RBV followed by additional 36 weeks of Peg-IFN-alfa + RBV (total treatment duration of 48 weeks)† |
| HIV = human immunodeficiency
virus. * Prior relapser: HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected during follow-up. † Recommended duration of treatment if patient does not meet stopping rules (see Table 3). ‡ Prior partial responder: prior on-treatment ≥ 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at end of prior IFN-based therapy. # Prior null responder: prior on-treatment < 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 during prior IFN-based therapy. |
|
Discontinuation Of Dosing
OLYSIO In Combination With Sofosbuvir
No treatment stopping rules apply to the combination of OLYSIO with sofosbuvir.
OLYSIO In Combination With Peg-IFN-alfa And RBV
During treatment, HCV RNA levels should be monitored as clinically indicated using a sensitive assay with a lower limit of quantification of at least 25 IU/mL. Because patients with an inadequate on-treatment virologic response (i.e., HCV RNA greater or equal to 25 IU/mL) are not likely to achieve a sustained virologic response (SVR), discontinuation of treatment is recommended in these patients. Table 3 presents treatment stopping rules for patients who experience an inadequate on-treatment virologic response at Weeks 4, 12, and 24.
Table 3: Treatment Stopping Rules in Patients
Receiving OLYSIO in Combination with Peg-IFN-alfa and RBV with Inadequate
On-Treatment Virologic Response
| Treatment Week | HCV RNA | Action |
| Week 4 | ≥ 25 IU/mL | Discontinue OLYSIO, Peg-IFN-alfa, and RBV |
| Week 12 | Discontinue Peg-IFN-alfa, and RBV (treatment with OLYSIO is complete at Week 12) | |
| Week 24 | Discontinue Peg-IFN-alfa, and RBV (treatment with OLYSIO is complete at Week 12) |
Dosage Adjustment Or Interruption
To prevent treatment failure, avoid reducing the dosage of OLYSIO or interrupting treatment. If treatment with OLYSIO is discontinued because of adverse reactions or inadequate on-treatment virologic response, OLYSIO treatment must not be reinitiated.
If adverse reactions potentially related to the antiviral drug(s) used in combination with OLYSIO occur, refer to the instructions outlined in their respective prescribing information for recommendations on dosage adjustment or interruption.
If any of the other antiviral drug(s) used in combination with OLYSIO for the treatment of chronic HCV infection are permanently discontinued for any reason, OLYSIO should also be discontinued.
Not Recommended In Patients With Moderate Or Severe Hepatic Impairment
OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C).
Because OLYSIO is used only in combination with other antiviral drugs (including Peg-IFN-alfa and RBV) for the treatment of chronic HCV infection, the contraindications to other drugs also apply to the combination regimen. Refer to the respective prescribing information for a list of contraindications.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
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 Co-administered With Sofosbuvir And Amiodarone
Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone was co-administered 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 co-administered OLYSIO and sofosbuvir:
- Counsel patients about the risk of serious symptomatic bradycardia.
- Cardiac monitoring in an in-patient setting for the first 48 hours of 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.
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.
OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C).
In clinical trials of OLYSIO, modest increases in bilirubin levels were observed without impacting hepatic function. 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. 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. 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. 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.
Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION).
Risk Of Hepatitis B Virus Reactivation In Patients Coinfected With HCV And HBV
Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of HBV infection.
Symptomatic Bradycardia When Used In Combination With Sofosbuvir And Amiodarone
Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems.
Pregnancy
Advise patients taking OLYSIO of the potential risk to the fetus. In addition, when OLYSIO is taken with RBV, advise patients to avoid pregnancy during treatment and within 6 months of stopping RBV and to notify their healthcare provider immediately in the event of a pregnancy.
Hepatic Decompensation And Failure
Inform patients to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to contact their healthcare provider immediately if such symptoms occur.
Photosensitivity
Advise patients of the risk of photosensitivity reactions related to OLYSIO combination treatment and that these reactions may be severe. Instruct patients to use effective sun protection measures to limit exposure to natural sunlight and to avoid artificial sunlight (tanning beds or phototherapy) during treatment with OLYSIO.
Advise patients to contact their healthcare provider immediately if they develop a photosensitivity reaction. Inform patients not to stop OLYSIO due to photosensitivity reactions unless instructed by their healthcare provider.
Rash
Advise patients of the risk of rash related to OLYSIO combination treatment and that rash may become severe. Advise patients to contact their healthcare provider immediately if they develop a rash. Inform patients not to stop OLYSIO due to rash unless instructed by their healthcare provider.
Administration
Advise patients to use OLYSIO only in combination with other antiviral drugs for the treatment of chronic HCV infection. Advise patients to discontinue OLYSIO if any of the other antiviral drugs used in combination with OLYSIO are permanently discontinued for any reason. Advise patients that the dose of OLYSIO must not be reduced or interrupted, as it may increase the possibility of treatment failure.
Advise patients to take OLYSIO every day at the regularly scheduled time with food. Inform patients that it is important not to miss or skip doses and to take OLYSIO for the duration that is recommended by the healthcare provider. Inform patients not to take more or less than the prescribed dose of OLYSIO at any one time.
Nonclinical Toxicology
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.
Use In Specific Populations
Pregnancy
Risk Summary
If OLYSIO is administered with RBV, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to prescribing information for RBV and for other drugs used in combination with OLYSIO for information on use in pregnancy.
No adequate human data are available to establish whether or not OLYSIO poses a risk to pregnancy outcomes. In animal reproduction studies with simeprevir, embryofetal developmental toxicity (including fetal loss) was observed in mice at simeprevir exposures greater than or equal to 1.9 times higher than exposure in humans at the recommended clinical dose while no adverse embryofetal developmental outcomes were observed in mice and rats at exposures similar to the exposure in humans at the recommended clinical dose. Given these findings, pregnant women should be advised of potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In embryofetal development studies in rats and mice, pregnant animals were administered simeprevir at doses up to 500 mg/kg/day (rats) and at 150, 500 and 1000 mg/kg/day (mice) on gestation days 6 to 17 (rats) and gestation days 6 to 15 (mice), resulting in late in utero fetal losses in mice at an exposure greater than or equal to 1.9 times higher than the exposure in humans at the recommended clinical dose. In addition, decreased fetal weights and an increase in fetal skeletal variations were observed in mice at exposures greater than or equal to 1.2 times higher than the exposure in humans at the recommended clinical dose. No adverse embryofetal developmental effects were observed in mice (at the lowest dose tested) or in rats (at up to the highest dose tested) at exposures similar to the exposure in humans at the recommended clinical dose.
In a rat pre-and post-natal development study, maternal animals were exposed to simeprevir from gestation day 6 to lactation/post-partum day 20 at doses up to 1000 mg/kg/day. At maternally toxic doses, the developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at maternal exposures similar to the exposure in humans at the recommended clinical dose. Subsequent survival, behavior and reproductive capacity of the offspring were not affected.
Lactation
Risk Summary
It is not known whether OLYSIO and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rats, simeprevir was detected in plasma of nursing pups, likely due to the presence of simeprevir in milk.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OLYSIO and any potential adverse effects on the breastfed child from OLYSIO or from the underlying maternal condition.
If OLYSIO is administered with RBV, the nursing mother's information for RBV also applies to this combination regimen. Refer to prescribing information for RBV and for other drugs used in combination with OLYSIO for more information on use during lactation.
Data
Animal Data
Although not measured directly, simeprevir was likely present in the milk of lactating rats in the pre-and post-natal development study, because systemic exposures (AUC) of simeprevir were observed in nursing pups on lactation/post-partum day 6 at concentrations approximately 10% of maternal simeprevir exposures.
Females And Males Of Reproductive Potential
If OLYSIO is administered with RBV, follow the recommendations for pregnancy testing and contraception within RBV's prescribing information. Refer to prescribing information for other drugs used in combination with OLYSIO for additional information on use in females and males of reproductive potential.
Infertility
There are no data on the effect of simeprevir on human fertility. Limited effects on male fertility were observed in animal studies. If OLYSIO is administered with RBV, the information for RBV with regard to infertility also applies to this combination regimen. In addition, refer to prescribing information for other drugs used in combination with OLYSIO for information on effects on fertility.
Pediatric Use
The safety and efficacy of OLYSIO in pediatric patients have not been established.
Geriatric Use
Clinical studies of OLYSIO did not include sufficient numbers of patients older than 65 years to determine whether they respond differently from younger patients. No dosage adjustment of OLYSIO is required in geriatric patients.
Race
Patients of East Asian ancestry exhibit higher simeprevir plasma exposures, but no dosage adjustment is required based on race.
Renal Impairment
No dosage adjustment of OLYSIO is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of OLYSIO have not been studied in HCV-infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end-stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir.
Refer to the prescribing information for the other antiviral drug(s) used in combination with OLYSIO regarding their use in patients with renal impairment.
Hepatic Impairment
No dosage adjustment of OLYSIO is required in patients with mild hepatic impairment (Child-Pugh A).
OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C). Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh B or C). In clinical trials of OLYSIO in combination with Peg-IFN-alfa and RBV, higher simeprevir exposures were associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy.
The safety and efficacy of OLYSIO have not been established in liver transplant patients. See the Peg-IFN-alfa prescribing information regarding its contraindication in patients with hepatic decompensation.
In vitro studies indicated that simeprevir is a substrate and mild inhibitor of CYP3A. Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. In vivo, simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.
In vitro, simeprevir is a substrate for P-gp, MRP2, BCRP, OATP1B1/3 and OATP2B1; simeprevir inhibits the uptake transporters OATP1B1/3 and NTCP and the efflux transporters P-gp/MDR1, MRP2, BCRP and BSEP and does not inhibit OCT2. The inhibitory effects of simeprevir on the bilirubin transporters OATP1B1/3 and MRP2 likely contribute to clinical observations of elevated bilirubin.
Simeprevir is transported into the liver by OATP1B1/3 where it undergoes metabolism by CYP3A. Based on results from in vivo studies, co-administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir, which may lead to loss of efficacy.
Drug interaction studies were performed in healthy adults with simeprevir (at the recommended dose of 150 mg once daily unless otherwise noted) and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax, AUC, and Cmin values of simeprevir are summarized in Table 9 (effect of other drugs on OLYSIO). The effect of co-administration of OLYSIO on the Cmax, AUC, and Cmin values of other drugs are summarized in Table 10 (effect of OLYSIO on other drugs). For information regarding clinical recommendations, see DRUG INTERACTIONS.
Table 9: Drug Interactions: Pharmacokinetic Parameters
for Simeprevir in the Presence of Co-administered Drugs
| Co-administered Drug | Dose (mg) and Schedule | N | Effect on * PK | LS Mean Ratio (90% CI) of Simeprevir PK Parameters with/without Drug | |||
| Drug | Simeprevir | Cmax | AUC | Cmin | |||
| Cyclosporine† | individualized dose* | 150 mg q.d. for 14 days | 9 | ↑ | 4.74 (3.12-7.18) |
5.81 (3.56-9.48) |
NA |
| Erythromycin | 500 mg t.i.d. for 7 days | 150 mg q.d. for 7 days | 24 | ↑ | 4.53 (3.91-5.25) |
7.47 (6.41-8.70) |
12.74 (10.19-15.93) |
| Escitalopram | 10 mg q.d. for 7 days | 150 mg q.d. for 7 days | 18 | ↓ | 0.80 (0.71-0.89) |
0.75 (0.68-0.83) |
0.68 (0.59-0.79) |
| Rifampin | 600 mg q.d. for 7 days | 200 mg q.d. for 7 days | 18 | ↓ | 1.31 (1.03-1.66) |
0.52 (0.41-0.67) |
0.08 (0.06-0.11) |
| Tacrolimus† | individualized dose‡ | 150 mg q.d. for 14 days | 11 | ↑ | 1.79 (1.22-2.62) |
1.85 (1.18-2.91) |
NA |
| Anti-HCV Drug | |||||||
| Sofosbuvir# | 400 mg q.d. | 150 mg q.d. | 21 | ↔ | 0.96 (0.71-1.30) |
0.94 (0.67-1.33) |
NA |
| Anti-HIV Drugs | |||||||
| Darunavir/Ritonavir§ | 800/100 mg q.d. for 7 days | 50 mg and 150 mg q.d. for 7 days | 25 | ↑ | 1.79 (1.55-2.06) |
2.59 (2.15-3.11) |
4.58 (3.54-5.92) |
| Efavirenz | 600 mg q.d. for 14 days | 150 mg q.d. for 14 days | 23 | ↓ | 0.49 (0.44-0.54) |
0.29 (0.26-0.33) |
0.09 (0.08-0.12) |
| Raltegravir | 400 mg b.i.d. for 7 days | 150 mg q.d. for 7 days | 24 | ↔ | 0.93 (0.85-1.02) |
0.89 (0.81-0.98) |
0.86 (0.75-0.98) |
| Rilpivirine | 25 mg q.d. for 11 days | 150 mg q.d. for 11 days | 21 | ↔ | 1.10 (0.97-1.26) |
1.06 (0.94-1.19) |
0.96 (0.83-1.11) |
| Ritonavir | 100 mg b.i.d. for 15 days | 200 mg q.d. for 7 days | 12 | ↑ | 4.70 (3.84-5.76) |
7.18 (5.63-9.15) |
14.35 (10.29-20.01) |
| Tenofovir disoproxil fumarate | 300 mg q.d. for 7 days | 150 mg q.d. for 7 days | 24 | ↓ | 0.85 (0.73-0.99) |
0.86 (0.76-0.98) |
0.93 (0.78-1.11) |
| CI = Confidence Interval; N =
number of subjects with data; NA = not available; PK = pharmacokinetics; LS =
least square; q.d. = once daily; b.i.d. = twice daily; t.i.d. = three times a
day * The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK (i.e., AUC). † Comparison based on historic controls. Interim data from a Phase 2 trial in combination with an investigational drug and RBV in HCV-infected post-liver transplant patients. ‡ Individualized dose at the discretion of the physician, according to local clinical practice. # Comparison based on historic controls. The interaction between simeprevir and sofosbuvir was evaluated in a pharmacokinetic substudy within a Phase 2 trial. §The dose of OLYSIO in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir compared to 150 mg once daily in the OLYSIO alone treatment group. |
|||||||
Table 10: Drug Interactions:
Pharmacokinetic Parameters for Co-administered Drugs in the Presence of OLYSIO
| Co-administered Drug | Dose (mg) and Schedule | N | Effect on * PK | LS Mean Ratio (90% CI) of Co-Administered Drug PK Parameters with/without OLYSIO | |||
| Drug | Simeprevir | Cmax | AUC | Cmin | |||
| Atorvastatin | 40 mg single dose | 150 mg q.d. for 10 days | 18 | ↑ | 1.70(1.42-2.04) | 2.12(1.72-2.62) | NA |
| 2-hydroxy-atorvastatin | ↑ | 1.98(1.70-2.31) | 2.29(2.08-2.52) | NA | |||
| Caffeine | 150 mg | 150 mg q.d. for 11 days | 16 | ↑ | 1.12 (1.06-1.19) |
1.26 (1.21-1.32) |
NA |
| Cyclosporine | 100 mg single dose | 150 mg q.d. for 7 days | 14 | ↑ | 1.16 (1.07-1.26) |
1.19 (1.13-1.26) |
NA |
| Dextromethorphan Dextrorphan | 30 mg | 150 mg q.d. for 11 days | 16 | ↔ | 1.21 (0.93-1.57) 1.03 (0.93-1.15) |
1.08 (0.87-1.35) 1.09 (1.03-1.15) |
NA NA |
| Digoxin | 0.25 mg single dose | 150 mg q.d. for 7 days | 16 | ↑ | 1.31 (1.14-1.51) |
1.39 (1.16-1.67) |
NA |
| Erythromycin | 500 mg t.i.d. for 7 days | 150 mg q.d. for 7 days | 24 | ↑ | 1.59 (1.23-2.05) |
1.90 (1.53-2.36) |
3.08 (2.54-3.73) |
| Escitalopram | 10 mg q.d. for 7 days | 150 mg q.d. for 7 days | 17 | ↔ | 1.03 (0.99-1.07) |
1.00 (0.97-1.03) |
1.00 (0.95-1.05) |
| Ethinyl estradiol (EE), co-administered with norethindrone (NE) | 0.035 mg q.d. EE + 1 mg q.d. NE for 21 days | 150 mg q.d. for 10 days | 18 | ↔ | 1.18 (1.09-1.27) |
1.12 (1.05-1.20) |
1.00 (0.89-1.13) |
| Midazolam (oral) | 0.075 mg/kg | 150 mg q.d. for 10 days | 16 | ↑ | 1.31 (1.19-1.45) |
1.45 (1.35-1.57) |
NA |
| Midazolam (i.v.) | 0.025 mg/kg | 150 mg q.d. for 11 days | 16 | ↑ | 0.78 (0.52-1.17) |
1.10 (0.95-1.26) |
NA |
| ? R(-) methadone | 30-150 mg q.d., individualized dose | 150 mg q.d. for 7 days | 12 | ↔ | 1.03 (0.97-1.09) |
0.99 (0.91-1.09) |
1.02 (0.93-1.12) |
| Norethindrone (NE), co-administered with EE | 0.035 mg q.d. EE + 1 mg q.d. NE for 21 days | 150 mg q.d. for 10 days | 18 | ↔ | 1.06 (0.99-1.14) |
1.15 (1.08-1.22) |
1.24 (1.13-1.35) |
| Omeprazole | 40 mg single dose | 150 mg q.d. for 11 days | 16 | ↑ | 1.14 (0.93-1.39) |
1.21 (1.00-1.46) |
NA |
| Rifampin 25-desacetyl-rifampin | 600 mg q.d. for 7 days | 200 mg q.d. for 7 days | 18 | ↔ | 0.92 (0.80-1.07) |
1.00 (0.93-1.08) |
NA |
| 17 | ↑ | 1.08 (0.98-1.19) |
1.24 (1.13-1.36) |
NA | |||
| Rosuvastatin | 10 mg single dose | 150 mg q.d. for 7 days | 16 | ↑ | 3.17 (2.57-3.91) |
2.81 (2.34-3.37) |
NA |
| Simvastatin Simvastatin acid | 40 mg single dose | 150 mg q.d. for 10 days | 18 | ↑ | 1.46 (1.17-1.82) |
1.51 (1.32-1.73) |
NA |
| ↑ | 3.03 (2.49-3.69) |
1.88 (1.63-2.17) |
NA | ||||
| Tacrolimus | 2 mg single dose | 150 mg q.d. for 7 days | 14 | ↓ | 0.76 (0.65-0.90) |
0.83 (0.59-1.16) |
NA |
| S-Warfarin | 10 mg single dose | 150 mg q.d. for 11 days | 16 | ↔ | 1.00 (0.94-1.06) |
1.04 (1.00-1.07) |
NA |
| Anti-HCV Drug | |||||||
| Sofosbuvir‡ | 400 mg q.d. | 150 mg q.d. | 22 | ↑ | 1.91 (1.26-2.90) |
3.16 (2.25-4.44) |
NA |
| GS-331007# | ↔ | 0.69 (0.52-0.93) |
1.09 (0.87-1.37) |
NA | |||
| Anti-HIV Drugs | |||||||
| Darunavir§ | 800 mg q.d. for 7 days | 50 mg q.d. for 7 days | 25 | ↑ | 1.04 (0.99-1.10) |
1.18 (1.11-1.25) |
1.31 (1.13-1.52) |
| Ritonavir§ | 100 mg q.d. for 7 days | ↑ | 1.23 (1.14-1.32) |
1.32 (1.25-1.40) |
1.44 (1.30-1.61) |
||
| Efavirenz | 600 mg q.d. for 14 days | 150 mg q.d. for 14 days | 23 | ↔ | 0.97 (0.89-1.06) |
0.90 (0.85-0.95) |
0.87 (0.81-0.93) |
| Raltegravir | 400 mg b.i.d. for 7 days | 150 mg q.d. for 7 days | 24 | ↑ | 1.03 (0.78-1.36) |
1.08 (0.85-1.38) |
1.14 (0.97-1.36) |
| Rilpivirine | 25 mg q.d. for 11 days | 150 mg q.d. for 11 days | 23 | ↔ | 1.04 (0.95-1.13) |
1.12 (1.05-1.19) |
1.25 (1.16-1.35) |
| Tenofovir disoproxil fumarate | 300 mg q.d. for 7 days | 150 mg q.d. for 7 days | 24 | ↔ | 1.19 (1.10-1.30) |
1.18 (1.13-1.24) |
1.24 (1.15-1.33) |
| CI = Confidence Interval; i.v.=
intravenous; N = number of subjects with data; NA = not available; PK =
pharmacokinetics; LS = least square; q.d. = once daily; b.i.d. = twice daily;
t.i.d. = three times a day * The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK (i.e., AUC). † The interaction between OLYSIO and the drug was evaluated in a pharmacokinetic study in opioid-dependent adults on stable methadone maintenance therapy. ‡ Comparison based on historic controls. The interaction between simeprevir and sofosbuvir was evaluated in a pharmacokinetic substudy within a Phase 2 trial. # Primary circulating metabolite of sofosbuvir. § The dose of OLYSIO in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir which is lower than the recommended 150 mg dose. |
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Risk Summary
If OLYSIO is administered with RBV, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to prescribing information for RBV and for other drugs used in combination with OLYSIO for information on use in pregnancy.
No adequate human data are available to establish whether or not OLYSIO poses a risk to pregnancy outcomes. In animal reproduction studies with simeprevir, embryofetal developmental toxicity (including fetal loss) was observed in mice at simeprevir exposures greater than or equal to 1.9 times higher than exposure in humans at the recommended clinical dose while no adverse embryofetal developmental outcomes were observed in mice and rats at exposures similar to the exposure in humans at the recommended clinical dose. Given these findings, pregnant women should be advised of potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In embryofetal development studies in rats and mice, pregnant animals were administered simeprevir at doses up to 500 mg/kg/day (rats) and at 150, 500 and 1000 mg/kg/day (mice) on gestation days 6 to 17 (rats) and gestation days 6 to 15 (mice), resulting in late in utero fetal losses in mice at an exposure greater than or equal to 1.9 times higher than the exposure in humans at the recommended clinical dose. In addition, decreased fetal weights and an increase in fetal skeletal variations were observed in mice at exposures greater than or equal to 1.2 times higher than the exposure in humans at the recommended clinical dose. No adverse embryofetal developmental effects were observed in mice (at the lowest dose tested) or in rats (at up to the highest dose tested) at exposures similar to the exposure in humans at the recommended clinical dose.
In a rat pre-and post-natal development study, maternal animals were exposed to simeprevir from gestation day 6 to lactation/post-partum day 20 at doses up to 1000 mg/kg/day. At maternally toxic doses, the developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at maternal exposures similar to the exposure in humans at the recommended clinical dose. Subsequent survival, behavior and reproductive capacity of the offspring were not affected.
Because OLYSIO is administered in combination with other antiviral drugs, refer to the prescribing information of the antiviral drugs used in combination with OLYSIO for a description of adverse reactions associated with their use.
The following serious and otherwise important adverse reactions are described below and in other sections of the labeling:
- Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone
- Hepatic Decompensation and Hepatic Failure
- Photosensitivity
- Rash
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
OLYSIO In Combination With Sofosbuvir
The safety profile of OLYSIO in combination with sofosbuvir in patients with HCV genotype 1 infection with compensated cirrhosis (Child-Pugh A) or without cirrhosis is based on pooled data from the Phase 2 COSMOS trial and the Phase 3 OPTIMIST-1 and OPTIMIST-2 trials which included 317 subjects who received OLYSIO with sofosbuvir (without RBV) for 12 or 24 weeks.
Table 4 lists adverse events (all grades) that occurred with at least 10% frequency among subjects receiving 12 or 24 weeks of treatment with OLYSIO 150 mg once daily in combination with sofosbuvir 400 mg once daily without RBV. The overall safety profile appeared similar among cirrhotic and non-cirrhotic subjects.
The majority of the adverse events reported were Grade 1 or 2 in severity. Grade 3 or 4 adverse events were reported in 4% and 13% of subjects receiving 12 or 24 weeks of OLYSIO with sofosbuvir, respectively. Serious adverse events were reported in 2% and 3% of subjects receiving 12 or 24 weeks of OLYSIO with sofosbuvir, respectively. One percent and 6% of subjects receiving 12 or 24 weeks of OLYSIO with sofosbuvir, respectively, discontinued treatment due to adverse events.
Table 4: Adverse Events (all Grades) that Occurred
≥ 10% Frequency Among Subjects Receiving 12 or 24 Weeks of OLYSIO in
Combination with Sofosbuvir±
| Adverse Events | 12 Weeks OLYSIO +Sofosbuvir N=286 % (n) |
24 Weeks OLYSIO +Sofosbuvir N=31 % (n) |
| Headache | 17 (49) | 23 (7) |
| Fatigue | 16 (47) | 32 (10) |
| Nausea | 14 (40) | 13 (4) |
| Rash (including photosensitivity) | 12 (34) | 16 (5) |
| Diarrhea | 6 (18) | 16 (5) |
| Dizziness | 3 (10) | 16 (5) |
| ± The 12 week group represents subjects pooled from COSMOS, OPTIMIST-1, and OPTIMIST-2 trials. The 24 week group represents subjects from COSMOS trial. |
Rash and Photosensitivity
In trials of OLYSIO in combination with sofosbuvir, rash (including photosensitivity reactions) was observed in 12% of OLYSIO-treated subjects receiving 12 weeks of treatment compared to 16% of OLYSIO-treated subjects receiving 24 weeks of treatment.
Most of the rash events in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). Among 317 subjects, Grade 3 rash was reported in one subject ( < 1%), leading to treatment discontinuation; none of the subjects experienced Grade 4 rash.
Most photosensitivity reactions were of mild severity (Grade 1); Grade 2 photosensitivity reactions were reported in 2 of 317 subjects ( < 1%). No Grade 3 or 4 photosensitivity reactions were reported and none of the subjects discontinued treatment due to photosensitivity reactions.
Laboratory Abnormalities
Among subjects who received OLYSIO in combination with sofosbuvir, the most common Grade 3 and 4 laboratory abnormalities were amylase and lipase elevations  (Table 5). Most elevations in amylase and lipase were transient and of mild or moderate severity. Amylase and lipase elevations were not associated with pancreatitis.
Table 5: Laboratory Abnormalities (WHO Worst Toxicity
Grades 1 to 4) in Amylase, Hyperbilirubinemia and Lipase in Subjects Receiving
12 or 24 Weeks of OLYSIO in Combination with Sofosbuvir±
| Laboratory Parameter | WHO Toxicity Range | 12 Weeks OLYSIO + Sofosbuvir N=286 % |
24 Weeks OLYSIO + Sofosbuvir N=31 % |
| Chemistry | |||
| Amylase* | |||
| Grade 1 | ≥ 1.1 to ≤ 1.5 x ULN† | 12 | 26 |
| Grade 2 | > 1.5 to ≤ 2.0 x ULN | 5 | 6 |
| Grade 3 | > 2.0 to ≤ 5.0 x ULN | 5 | 10 |
| Hyperbilirubinemia | |||
| Grade 1 | ≥ 1.1 to ≤ 1.5 x ULN | 12 | 16 |
| Grade 2 | > 1.5 to ≤ 3.0 x ULN | 3 | 3 |
| Grade 3 | > 3.0 to ≤ 5.0 x ULN | < 1 | 0 |
| Grade 4 | > 5.0 x ULN | 0 | 3 |
| Lipase | |||
| Grade 1 | ≥ 1.1 to ≤ 1.5 x ULN | 5 | 3 |
| Grade 2 | > 1.5 to ≤ 3.0 x ULN | 8 | 10 |
| Grade 3 | > 3.0 to ≤ 5.0 x ULN | < 1 | 3 |
| Grade 4 | > 5.0 x ULN | < 1 | 3 |
| ± The 12 week group represents subjects pooled from
COSMOS, OPTIMIST-1, and OPTIMIST-2 trials. The 24 week group represents
subjects from COSMOS trial. * No Grade 4 changes in amylase were observed. † ULN = Upper Limit of Normal |
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OLYSIO In Combination With Peg-IFN-alfa And RBV
The safety profile of OLYSIO in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection is based on pooled data from three Phase 3 trials (QUEST-1, QUEST-2 and PROMISE). These trials included a total of 1178 subjects who received OLYSIO or placebo in combination with 24 or 48 weeks of Peg-IFN-alfa and RBV. Of the 1178 subjects, 781 subjects were randomized to receive OLYSIO 150 mg once daily for 12 weeks and 397 subjects were randomized to receive placebo once daily for 12 weeks.
In the pooled Phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with OLYSIO in combination with Peg-IFN-alfa and RBV were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving OLYSIO in combination with Peg-IFN-alfa and RBV versus 25% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Serious adverse reactions were reported in 2% of subjects receiving OLYSIO in combination with Peg-IFN-alfa and RBV and in 3% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Discontinuation of OLYSIO or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving OLYSIO with Peg-IFN-alfa and RBV and subjects receiving placebo with Peg-IFN-alfa and RBV, respectively.
Table 6 lists adverse reactions (all Grades) that occurred with at least 3% higher frequency among subjects with HCV genotype 1 infection receiving OLYSIO 150 mg once daily in combination with Peg-IFN-alfa and RBV, compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, during the first 12 weeks of treatment in the pooled Phase 3 trials in subjects who were treatment-naïve or who had previously relapsed after Peg-IFN-alfa and RBV therapy.
Table 6: Adverse Reactions (all Grades) that occurred
≥ 3% Higher Frequency Among Subjects with HCV Genotype 1 Infection
Receiving OLYSIO Combination with Peg-IFN-alfa and RBV Compared to Subjects
Receiving Placebo in Combination with Peg-IFN-alfa and RBV During the First 12
Weeks of Treatment in Subjects with Chronic HCV Infection* (Pooled Phase 3†)
| Adverse Reaction‡ | OLYSIO 150 mg + Peg-IFN-alfa+ RBV First 12 Weeks N=781 % (n) |
Placebo + Peg-IFN-alfa+ RBV First 12 Weeks N=397 % (n) |
| Rash (including photosensitivity) | 28 (218) | 20 (79) |
| Pruritus | 22 (168) | 15 (58) |
| Nausea | 22 (173) | 18 (70) |
| Myalgia | 16 (126) | 13 (53) |
| Dyspnea | 12 (92) | 8 (30) |
| * Subjects were treatment-naïve or had previously
relapsed after Peg-IFN-alfa and RBV therapy. † Pooled Phase 3 trials: QUEST 1, QUEST 2, PROMISE. ‡ Adverse reactions that occurred at ≥ 3% higher frequency in the OLYSIO treatment group than in the placebo treatment group. |
Rash and Photosensitivity
In the Phase 3 clinical trials of OLYSIO or placebo in combination with Peg-IFN-alfa and RBV, rash (including photosensitivity reactions) was observed in 28% of OLYSIO-treated subjects compared to 20% of placebo-treated subjects during the 12 weeks of treatment with OLYSIO or placebo in combination with Peg-IFN-alfa and RBV. Fifty-six percent (56%) of rash events in the OLYSIO group occurred in the first 4 weeks, with 42% of cases occurring in the first 2 weeks. Most of the rash events in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). Severe (Grade 3) rash occurred in 1% of OLYSIO-treated subjects and in none of the placebo-treated subjects. There were no reports of life-threatening (Grade 4) rash. Discontinuation of OLYSIO or placebo due to rash occurred in 1% of OLYSIO-treated subjects, compared to less than 1% of placebo-treated subjects. The frequencies of rash and photosensitivity reactions were higher in subjects with higher simeprevir exposures.
All subjects enrolled in the Phase 3 trials were directed to use sun protection measures. In these trials, adverse reactions under the specific category of photosensitivity were reported in 5% of OLYSIO-treated subjects compared to 1% of placebo-treated subjects during the 12 weeks of treatment with OLYSIO or placebo in combination with Peg-IFN-alfa and RBV. Most photosensitivity reactions in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). Two OLYSIO-treated subjects experienced photosensitivity reactions which resulted in hospitalization. No life-threatening photosensitivity reactions were reported.
Dyspnea
During the 12 weeks of treatment with OLYSIO or placebo in combination with Peg-IFN-alfa and RBV, dyspnea was reported in 12% of OLYSIO-treated subjects compared to 8% of placebo-treated subjects (all grades; pooled Phase 3 trials). All dyspnea events reported in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). There were no Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment with OLYSIO due to dyspnea. Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with OLYSIO.
Laboratory Abnormalities
Among subjects who received OLYSIO or placebo plus Peg-IFN-alfa and RBV, there were no differences between treatment groups for the following laboratory parameters: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, or serum creatinine. Laboratory abnormalities that were observed at a higher incidence in OLYSIO-treated subjects than in placebo-treated subjects are listed in Table 7.
Table 7: Laboratory Abnormalities (WHO Worst Toxicity
Grades 1 to 4) Observed at a Higher Incidence in OLYSIO-Treated Subjects
(Pooled Phase 3*; First 12 Weeks of Treatment)
| Laboratory Parameter | WHO Toxicity Range | OLYSIO 150 mg + Peg-IFN-alfa + RBV N=781 % |
Placebo + Peg-IFN-alfa + RBV N=397 % |
| Chemistry | |||
| Alkaline phosphatase† | |||
| Grade 1 | > 1.25 to ≤ 2.50 x ULN‡ | 3 | 1 |
| Grade 2 | > 2.50 to ≤ 5.00 x ULN | < 1 | 0 |
| Hyperbilirubinemia | |||
| Grade 1 | > 1.1 to ≤ 1.5 x ULN | 27 | 15 |
| Grade 2 | > 1.5 to ≤ 2.5 x ULN | 18 | 9 |
| Grade 3 | > 2.5 to ≤ 5.0 x ULN | 4 | 2 |
| Grade 4 | > 5.0 x ULN | < 1 | 0 |
| * Pooled Phase 3 trials: QUEST 1, QUEST 2, PROMISE. † No Grade 3 or 4 changes in alkaline phosphatase were observed. ‡ ULN = Upper Limit of Normal |
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Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of OLYSIO. Bilirubin elevations were generally not associated with elevations in liver transaminases. The frequency of elevated bilirubin was higher in subjects with higher simeprevir exposures.
Adverse Reactions In HCV/HIV-1 Co-infection
OLYSIO in combination with Peg-IFN-alfa and RBV was studied in 106 subjects with HCV genotype 1/HIV-1 co-infection (C212). The safety profile in HCV/HIV co-infected subjects was generally comparable to HCV mono-infected subjects.
Adverse Reactions In HCV Genotype 4 Infection
OLYSIO in combination with Peg-IFN-alfa and RBV was studied in 107 subjects with HCV genotype 4 infection (RESTORE). The safety profile of OLYSIO in subjects with HCV genotype 4 infection was comparable to subjects with HCV genotype 1 infection.
Adverse Reactions In East Asian Subjects
OLYSIO in combination with Peg-IFN-alfa and RBV was studied in a Phase 3 trial conducted in China and South Korea in treatment-naïve subjects with chronic HCV genotype 1 infection (TIGER). The safety profile of OLYSIO in East Asian subjects was similar to that of the pooled Phase 3 population from global trials; however, a higher incidence of the laboratory abnormality hyperbilirubinemia was observed in patients receiving 150 mg OLYSIO plus Peg-IFN-alfa and RBV compared to patients receiving placebo plus Peg-IFN-alfa and RBV. Elevation of total bilirubin (all grades) was observed in 66% (99/151) of subjects treated with 150 mg OLYSIO plus Peg-IFN-alfa and RBV and in 26% (40/152) of subjects treated with placebo plus Peg-IFN-alfa and RBV. Bilirubin elevations were mainly Grade 1 or Grade 2. Grade 3 elevations in bilirubin were observed in 9% (13/151) of subjects treated with 150 mg OLYSIO plus Peg-IFN-alfa and RBV and in 1% (2/152) of subjects treated with placebo plus Peg-IFN-alfa and RBV. There were no Grade 4 elevations in bilirubin. The bilirubin elevations were not associated with increases in liver transaminases and were reversible after the end of treatment.
Postmarketing Experience
The following adverse reactions have been reported during post approval use of OLYSIO. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship between drug exposure and these adverse reactions.
Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with a sofosbuvir-containing regimen.
Hepatobiliary Disorders: hepatic decompensation, hepatic failure.
Human experience of overdose with OLYSIO is limited. There is no specific antidote for overdose with OLYSIO. In the event of an overdose, the patient's clinical status should be observed and the usual supportive measures employed.
Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir.
Cardiac Electrophysiology
In a thorough QT/QTc study in 60 healthy subjects, simeprevir 150 mg (recommended dose) and 350 mg (2.3 times the recommended dose) did not affect the QT/QTc interval.
The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma Cmax and AUC increased more than dose-proportionally after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once-daily dosing. Plasma exposure (AUC) of simeprevir in HCV-infected subjects was about 2-to 3-fold higher compared to that observed in HCV-uninfected subjects. Plasma Cmax and AUC of simeprevir were similar during co-administration of simeprevir with Peg-IFN-alfa and RBV compared with administration of simeprevir alone. In Phase 3 trials with Peg-IFN-alfa and RBV in HCV-infected subjects, the geometric mean steady-state pre-dose plasma concentration was 1009 ng/mL (geometric coefficient of variation [gCV] = 162%) and the geometric mean steady-state AUC24 was 39140 ng.h/mL (gCV = 98%).
Absorption
The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of OLYSIO in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post-dose.
In vitro studies with human Caco-2 cells indicated that simeprevir is a substrate of P-gp.
Effects of Food on Oral Absorption
Compared to intake without food, administration of simeprevir with food to healthy subjects increased the AUC by 61% after a high-fat, high-caloric breakfast (928 kcal) and by 69% after a normal-caloric breakfast (533 kcal), and delayed the absorption by 1 hour and 1.5 hours, respectively.
Distribution
Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3.
Metabolism
Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir.
Following a single oral administration of 200 mg (1.3 times the recommended dosage) 14C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation.
Elimination
Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose.
The terminal elimination half-life of simeprevir was 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects receiving 200 mg (1.3 times the recommended dosage) of simeprevir.
