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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 [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
- Hepatic Decompensation and Hepatic Failure [see WARNINGS AND PRECAUTIONS]
- Photosensitivity [see WARNINGS AND PRECAUTIONS]
- Rash [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions When Used With Sofosbuvir
In the COSMOS trial, the most common (greater than 10%) adverse reactions reported during 12 weeks treatment with OLYSIO in combination with sofosbuvir (without RBV) were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with OLYSIO in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported.
Adverse Reactions When Used In Combination With Peg-IFN-Alfa And RBV
The safety profile of OLYSIO in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection who were treatment-na´ve or who had previously relapsed following interferon therapy with or without RBV is based on pooled data from three Phase 3 trials (QUEST-1, QUEST-2 and PROMISE) [see Clinical Studies]. These trials included a total of 1178 subjects who received OLYSIO or placebo in combination with 24 or 48 weeks of Peg-IFN-alfa and RBV. Of the 1178 subjects, 781 subjects were randomized to receive OLYSIO 150 mg once daily for 12 weeks and 397 subjects were randomized to receive placebo once daily for 12 weeks.
In the pooled Phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with OLYSIO in combination with Peg-IFN-alfa and RBV were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving OLYSIO in combination with Peg-IFN-alfa and RBV versus 25% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Serious adverse reactions were reported in 2% of subjects receiving OLYSIO in combination with Peg-IFN-alfa and RBV and in 3% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Discontinuation of OLYSIO or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving OLYSIO with Peg-IFN-alfa and RBV and subjects receiving placebo with Peg-IFN-alfa and RBV, respectively.
The following table lists adverse reactions (all Grades) that occurred with at least 3% higher frequency among subjects with HCV genotype 1 infection receiving OLYSIO 150 mg once daily in combination with Peg-IFN-alfa and RBV, compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, during the first 12 weeks of treatment in the pooled Phase 3 trials in subjects who were treatment-na´ve or who had previously relapsed after Peg-IFN-alfa and RBV therapy (see Table 4).
Table 4: Adverse Reactions (all Grades) that Occurred
with at Least 3% Higher Frequency Among Subjects with HCV Genotype 1 Infection
Receiving OLYSIO 150 mg Once Daily in Combination with Peg-IFN-alfa and RBV
Compared to Subjects Receiving Placebo in Combination with Peg-IFN-alfa and RBV
During the First 12 Weeks of Treatment in Subjects with Chronic HCV Infection* (Pooled
Phase 3 Trials†)
|Adverse Reaction‡||OLYSIO 150 mg + Peg-IFN-alfa+ RBV First 12 Weeks
|Placebo + Peg-IFN-alfa+ RBV First 12 Weeks
|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-na´ve 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, rash (including photosensitivity reactions) was observed in 28% of OLYSIO-treated subjects compared to 20% of placebo-treated subjects during the 12 weeks of treatment with OLYSIO or placebo in combination with Peg-IFN-alfa and RBV. Fifty-six percent (56%) of rash events in the OLYSIO group occurred in the first 4 weeks, with 42% of cases occurring in the first 2 weeks. Most of the rash events in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or Grade 2). Severe (Grade 3) rash occurred in 1% of OLYSIO-treated subjects and in none of the placebo-treated subjects. There were no reports of life-threatening (Grade 4) rash. Discontinuation of OLYSIO or placebo due to rash occurred in 1% of OLYSIO-treated subjects, compared to less than 1% of placebo-treated subjects. The frequencies of rash and photosensitivity reactions were higher in subjects with higher simeprevir exposures.
All subjects enrolled in the Phase 3 trials were directed to use sun protection measures. In these trials, adverse reactions under the specific category of photosensitivity were reported in 5% of OLYSIO-treated subjects compared to 1% of placebo-treated subjects during the 12 weeks of treatment with OLYSIO or placebo in combination with Peg-IFN-alfa and RBV. Most photosensitivity reactions in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). Two OLYSIO-treated subjects experienced photosensitivity reactions which resulted in hospitalization. No life-threatening photosensitivity reactions were reported.
During the 12 weeks of treatment with OLYSIO, dyspnea was reported in 12% of OLYSIO-treated subjects compared to 8% of placebo-treated subjects (all grades; pooled Phase 3 trials). All dyspnea events reported in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). There were no Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment with OLYSIO due to dyspnea. Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with OLYSIO.
There were no differences between treatment groups for the following laboratory parameters: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, or serum creatinine. Laboratory abnormalities that were observed at a higher incidence in OLYSIO-treated subjects than in placebo-treated subjects are listed in Table 5.
Table 5: Laboratory Abnormalities (WHO Worst Toxicity
Grades 1 to 4) Observed at a Higher Incidence in OLYSIO-Treated Subjects
(Pooled Phase 3 Trials*; First 12 Weeks of Treatment)
|Laboratory Parameter||WHO Toxicity Range||OLYSIO 150 mg + Peg-IFN-alfa + RBV
|Placebo + Peg-IFN-alfa + RBV
|Grade 1||> 1.25 to ≤ 2.50 x ULN*||3||1|
|Grade 2||> 2.50 to ≤ 5.00 x ULN||< 1||0|
|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
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-na´ve subjects with chronic HCV genotype 1 infection (TIGER). The safety profile of OLYSIO in East Asian subjects was similar to that of the pooled Phase 3 population from global trials; however, a higher incidence of the laboratory abnormality hyperbilirubinemia was observed in patients receiving 150 mg OLYSIO plus Peg-IFN-alfa and RBV compared to patients receiving placebo plus Peg-IFN-alfa and RBV. Elevation of total bilirubin (all grades) was observed in 66% (99/151) of subjects treated with 150 mg OLYSIO plus Peg-IFN-alfa and RBV and in 26% (40/152) of subjects treated with placebo plus Peg-IFN-alfa and RBV. Bilirubin elevations were mainly Grade 1 or Grade 2. Grade 3 elevations in bilirubin were observed in 9% (13/151) of subjects treated with 150 mg OLYSIO plus Peg-IFN-alfa and RBV and in 1% (2/152) of subjects treated with placebo plus Peg-IFN-alfa and RBV. There were no Grade 4 elevations in bilirubin. The bilirubin elevations were not associated with increases in liver transaminases and were reversible after the end of treatment [see Use In Specific Populations and Clinical Studies].
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.
Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct-acting antiviral, including OLYSIO [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
hepatic decompensation, hepatic failure [see WARNINGS AND PRECAUTIONS].
Read the Olysio (simeprevir hard gelatin capsules) Side Effects Center for a complete guide to possible side effects
Potential For OLYSIO To Affect Other Drugs
Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Co-administration of OLYSIO with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs (see Table 6).
Simeprevir inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters. Co-administration of OLYSIO with drugs that are substrates for OATP1B1/3 and P-gp transport may result in increased plasma concentrations of such drugs (see Table 6).
Potential For Other Drugs To Affect OLYSIO
The primary enzyme involved in the biotransformation of simeprevir is CYP3A [see CLINICAL PHARMACOLOGY]. Clinically relevant effects of other drugs on simeprevir pharmacokinetics via CYP3A may occur. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir. Co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see Table 6). Therefore, co-administration of OLYSIO with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Established And Other Potentially Significant Drug Interactions
Table 6 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of OLYSIO and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with OLYSIO are also included in Table 6. For information regarding the magnitude of interaction, see Tables 7 and 8 [see CLINICAL PHARMACOLOGY].
Table 6: Established and Other Potentially Significant
Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on
Drug Interaction Studies or Predicted Interaction
|Concomitant Drug Class Drug Name||Effect on Concentration of Simeprevir or Concomitant Drug||Clinical Comment|
|Amiodarone||Effect on amiodarone, simeprevir, and sofosbuvir concentrations unknown||Co-administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended because it may result in serious symptomatic bradycardia. If co-administration is required, cardiac monitoring is recommended [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].|
|↑amiodarone||Caution is warranted and therapeutic drug monitoring of amiodarone, if available, is recommended for concomitant use of amiodarone with an OLYSIO-containing regimen that does not contain sofosbuvir.|
|Digoxin*||↑ digoxin||Routine therapeutic drug monitoring of digoxin concentrations is recommended.|
|Oral administration Disopyramide, Flecainide, Mexiletine, Propafenone, Quinidine||↑antiarrhythmics||Therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when co-administered with OLYSIO.|
|Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin||↓ simeprevir||Co-administration is not recommended.|
|Antibiotics (systemic administration): Erythromycin||↑ simeprevir
|Co-administration is not recommended.|
|Antibiotics (systemic administration): Clarithromycin, Telithromycin||↑ simeprevir||Co-administration is not recommended.|
|Antifungals (systemic administration): Itraconazole, Ketoconazole, Posaconazole||↑ simeprevir||Co-administration is not recommended.|
|Antifungals (systemic administration): Fluconazole, Voriconazole||↑simeprevir||Co-administration is not recommended.|
|Antimycobacterials: Rifampin , Rifabutin, Rifapentine||↓ simeprevir
↔ rifampin, rifabutin,
|Co-administration is not recommended.|
|Calcium Channel Blockers (oral administration)|
|Amlodipine, Diltiazem, Felodipine, Nicardipine, Nifedipine, Nisoldipine, Verapamil||↑calcium channel blockers||Clinical monitoring of patients is recommended when OLYSIO is co-administered with calcium channel blockers.|
|Systemic Dexamethasone||↓simeprevir||Co-administration is not recommended.|
|Propulsive: Cisapride||↑ cisapride||Co-administration is not recommended.|
|Milk thistle (Silybum marianum)||↑ simeprevir||Co-administration is not recommended.|
|St. John’s wort (Hypericum perforatum)||↓ simeprevir||Co-administration of OLYSIO with products containing St. John’s wort is not recommended.|
|Cobicistat-containing products||↑simeprevir||Co-administration is not recommended.|
|Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Efavirenz||↓ simeprevir
|Co-administration is not recommended.|
|Other NNRTIs Delavirdine Etravirine, Nevirapine||↑ simeprevir
|Co-administration is not recommended.|
|Protease Inhibitors (PIs):
|Co-administration is not recommended.|
|Protease Inhibitors (PIs): Ritonavir*#||↑simeprevir||Co-administration is not recommended.|
|Other ritonavir-boosted or unboosted HIV PIs (Atazanavir, Fosamprenavir, Lopinavir, Indinavir, Nelfinavir, Saquinavir, Tipranavir)||↑ or ↓ simeprevir||Co-administration of OLYSIO with any HIV PI, with or without ritonavir is not recommended.|
|HMG CO-A Reductase Inhibitors|
|Rosuvastatin*||↑ rosuvastatin||Initiate rosuvastatin therapy with 5 mg once daily. The rosuvastatin dose should not exceed 10 mg daily when co-administered with OLYSIO.|
|Atorvastatin*||↑ atorvastatin||Use the lowest necessary dose of atorvastatin, but do not exceed a daily dose of 40 mg when co-administering with OLYSIO.|
|Simvastatin*||↑simvastatin||Use the lowest necessary dose of simvastatin, titrate the simvastatin dose carefully, and monitor for safety when simvastatin is co-administered with OLYSIO.|
|Pitavastatin, Pravastatin, Lovastatin||↑pitavastatin, pravastatin, lovastatin||Use the lowest necessary dose of pitavastatin, pravastatin or lovastatin, titrate the dose carefully, and monitor for safety when co-administered with OLYSIO.|
|Co-administration is not recommended.|
|Sirolimus||↑ or ↓ sirolimus||Routine monitoring of blood concentrations of sirolimus is recommended.|
|Phosphodiesterase Type 5 (PDE-5) Inhibitors|
|Sildenafil, Tadalafil, Vardenafil||↑PDE-5 inhibitors||Dose adjustment of the PDE-5 inhibitor may be required when OLYSIO is co-administered with sildenafil or tadalafil administered chronically at doses used for the treatment of pulmonary arterial hypertension. Consider starting with the lowest dose of the PDE-5 inhibitor and increase as needed, with clinical monitoring as appropriate. No dose adjustment is required when OLYSIO is co-administered with doses of sildenafil, tadalafil or vardenafil indicated for the treatment of erectile dysfunction.|
|Midazolam* (oral administration)||↑ midazolam||Caution is warranted when midazolam, which has a narrow therapeutic index, is co-administered with OLYSIO.|
|Triazolam (oral administration)||↑ triazolam||Caution is warranted when triazolam, which has a narrow therapeutic index, is co-administered with OLYSIO.|
|The direction of the arrow (↑ = increase, ↓ =
decrease, ↔ = no change) indicates the direction of the change in PK.
* These interactions have been studied in healthy adults with the recommended dose of 150 mg simeprevir once daily unless otherwise noted [see CLINICAL PHARMACOLOGY, Tables 7 and 8].
† The dose of OLYSIO in this interaction study was 200 mg once daily both when given alone and when co-administered with rifampin 600 mg once daily.
‡ The dose of OLYSIO in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir, compared to 150 mg in the OLYSIO alone treatment group.
# The dose of OLYSIO in this interaction study was 200 mg once daily both when given alone and when co-administered in combination with ritonavir 100 mg given twice daily.
§ Studied in combination with an investigational drug and RBV in a Phase 2 trial in HCV-infected post-liver transplant patients.
Drugs Without Clinically Significant Interactions With OLYSIO
In addition to the drugs included in Table 6, the interaction between OLYSIO and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug [see CLINICAL PHARMACOLOGY]: caffeine, dextromethorphan, escitalopram, ethinyl estradiol/norethindrone, methadone, midazolam (intravenous administration), omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir disoproxil fumarate, and warfarin.
No clinically relevant drug-drug interaction is expected when OLYSIO is co-administered with antacids, azithromycin, bedaquiline, corticosteroids (budesonide, fluticasone, methylprednisolone, and prednisone), dolutegravir, fluvastatin, H2-receptor antagonists, the narcotic analgesics buprenorphine and naloxone, NRTIs (such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine), maraviroc, methylphenidate, and proton pump inhibitors.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/31/2016
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