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Olysio

"The U.S. Food and Drug Administration today approved Olysio (simeprevir), a new therapy to treat chronic hepatitis C virus infection.

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Olysio

Side Effects
Interactions

SIDE EFFECTS

OLYSIO should be administered in combination with other antiviral drugs. Refer to the prescribing information of the antiviral drugs used in combination with OLYSIO for a description of adverse reactions associated with their use.

The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling:

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions when Used in Combination with Peg-IFN-Alfa and RBV

The safety profile of OLYSIO in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection who were treatment-na´ve or who had previously relapsed following interferon therapy with or without RBV is based on pooled data from three Phase 3 trials [see Clinical Studies]. 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 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 Receiving OLYSIO 150 mg Once Daily in Combination with Peg-IFN-alfa and RBV Compared to Subjects Receiving Placebo in Combination with Peg-IFN-alfa and RBV During the First 12 Weeks of Treatment in Subjects with CHC Infection*(Pooled Phase 3 Trials†)


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-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.

Dyspnea

During the 12 weeks of treatment with OLYSIO, dyspnea was reported in 12% of OLYSIO-treated subjects compared to 8% of placebo-treated subjects (all grades; pooled Phase 3 trials). All dyspnea events reported in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). There were no Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment with OLYSIO due to dyspnea. Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with OLYSIO.

Laboratory Abnormalities

There were no differences between treatment groups for the following laboratory parameters: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, or serum creatinine. Laboratory abnormalities that were observed at a higher incidence in OLYSIO-treated subjects than in placebo-treated subjects are listed in Table 5.

Table 5: Laboratory Abnormalities (WHO Worst Toxicity Grades 1 to 4) Observed at a Higher Incidence in OLYSIO-Treated Subjects (Pooled Phase 3 Trials*; First 12 Weeks of Treatment)

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

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.

Adverse Reactions when Used with Sofosbuvir

In the COSMOS trial, the most common ( > 10%) adverse reactions reported during 12 weeks treatment with OLYSIO in combination with sofosbuvir without RBV were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with OLYSIO in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported.

Read the Olysio (simeprevir hard gelatin capsules) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Potential For OLYSIO To Affect Other Drugs

Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Co-administration of OLYSIO with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs (see Table 6). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo.

Simeprevir inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters. Co-administration of OLYSIO with drugs that are substrates for OATP1B1/3 and P-gp transport may result in increased plasma concentrations of such drugs (see Table 6).

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
Antiarrhythmics
Digoxin* ↑ digoxin Concomitant use of OLYSIO with digoxin resulted in increased concentrations of digoxin due to inhibition of P-gp by simeprevir. Routine therapeutic drug monitoring of digoxin concentrations is acceptable.
Oral administration
Amiodarone
Disopyramide
Flecainide
Mexiletine
Propafenone
Quinidine
↑ antiarrhythmics Concomitant use of OLYSIO with these antiarrhythmics when given orally may result in mild increases in concentrations of these antiarrhythmics due to intestinal CYP3A4 inhibition by simeprevir. Therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when co-administered with OLYSIO.
Anticonvulsants
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
↓ simeprevir Concomitant use of OLYSIO with carbamazepine, oxcarbazepine, phenobarbital or phenytoin may result in significantly decreased plasma concentrations of simeprevir due to strong CYP3A induction by these anticonvulsants. This may result in loss of therapeutic effect of OLYSIO. Co-administration of OLYSIO with these anticonvulsants is not recommended.
Anti-infectives
Antibiotics (systemic administration):
Erythromycin
↑ simeprevir
↑ erythromycin
Concomitant use of OLYSIO with erythromycin resulted in significantly increased plasma concentrations of both erythromycin and simeprevir due to inhibition of CYP3A and P-gp by both erythromycin and simeprevir. Co-administration of OLYSIO with systemic erythromycin is not recommended.
Antibiotics (systemic administration):
Clarithromycin
Telithromycin
↑ simeprevir Concomitant use of OLYSIO with clarithromycin or telithromycin may result in increased plasma concentrations of simeprevir due to CYP3A inhibition by these antibiotics. Co-administration of OLYSIO with systemic clarithromycin or telithromycin is not recommended.
Antifungals (systemic administration):
Itraconazole
Ketoconazole
Posaconazole
↑ simeprevir Concomitant use of OLYSIO with systemic itraconazole, ketoconazole or posaconazole may result in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by these antifungals. Co-administration of OLYSIO with systemic itraconazole, ketoconazole or posaconazole is not recommended.
Antifungals (systemic administration):
Fluconazole
Voriconazole
↑ simeprevir Concomitant use of OLYSIO with systemic fluconazole or voriconazole may result in increased plasma concentrations of simeprevir due to mild to moderate CYP3A inhibition by these antifungals. Co-administration of OLYSIO with systemic fluconazole or voriconazole is not recommended.
Antimycobacterials:
Rifampin
Rifabutin
Rifapentine
↓ simeprevir
↔ rifampin, rifabutin, rifapentine
Concomitant use of OLYSIO with rifampin, rifabutin or rifapentine may result in significantly decreased plasma concentrations of simeprevir due to CYP3A4 induction by these antimycobacterials. This may result in loss of therapeutic effect of OLYSIO. Co-administration of OLYSIO with rifampin, rifabutin or rifapentine is not recommended.
Calcium Channel Blockers (oral administration)
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Nisoldipine
Verapamil
↑ calcium channel blockers Concomitant use of OLYSIO with orally administered calcium channel blockers may result in increased plasma concentrations of calcium channel blockers due to intestinal CYP3A4 and/or P-gp inhibition by simeprevir. Clinical monitoring of patients is recommended when OLYSIO is co-administered with orally administered calcium channel blockers.
Corticosteroids
Systemic
Dexamethasone
↓ simeprevir Concomitant use of OLYSIO with systemic dexamethasone may result in decreased plasma concentrations of simeprevir due to moderate induction of CYP3A4 by dexamethasone. This may result in loss of therapeutic effect of OLYSIO. Co-administration of OLYSIO with systemic dexamethasone is not recommended.
Gastrointestinal Products
Propulsive: Cisapride ↑ cisapride Cisapride has the potential to cause cardiac arrhythmias. Concomitant use of OLYSIO with cisapride may result in increased plasma concentrations of cisapride due to intestinal CYP3A4 inhibition by simeprevir. Co-administration of OLYSIO with cisapride is not recommended.
Herbal Products
Milk thistle (Silybum marianum) ↑ simeprevir Concomitant use of OLYSIO with milk thistle may result in increased plasma concentrations of simeprevir due to CYP3A inhibition by milk thistle. Co-administration of OLYSIO with milk thistle is not recommended.
St. John’s wort (Hypericum perforatum) ↓ simeprevir Concomitant use of OLYSIO with products containing St. John’s wort may result in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by St. John’s wort. This may result in loss of therapeutic effect of OLYSIO. Co-administration of OLYSIO with products containing St. John’s wort is not recommended.
HIV Products
Cobicistat-containing product (elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate) ↑ simeprevir Concomitant use of OLYSIO and a cobicistat-containing product (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) may result in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by cobicistat. Co-administration of OLYSIO with a cobicistat-containing product is not recommended.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Efavirenz ↓ simeprevir
↔ efavirenz
Concomitant use of OLYSIO with efavirenz resulted in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by efavirenz. This may result in loss of therapeutic effect of OLYSIO. Co-administration of OLYSIO with efavirenz is not recommended.
Other NNRTIs (Delavirdine, Etravirine, Nevirapine) ↑ or ↓ simeprevir Concomitant use of OLYSIO with delavirdine, etravirine or nevirapine may result in altered plasma concentrations of simeprevir due to CYP3A inhibition (delavirdine) or induction (etravirine and nevirapine) by these drugs. Co-administration of OLYSIO with delavirdine, etravirine or nevirapine is not recommended.
Protease Inhibitors (Ms): Darunavir/ritonavir*‡ ↑ simeprevir
↑ darunavir
Concomitant use of OLYSIO with darunavir/ritonavir resulted in increased plasma concentrations of simeprevir due to CYP3A inhibition by darunavir/ritonavir. Co-administration of darunavir/ritonavir and OLYSIO is not recommended.
Protease Inhibitors (PIs): Ritonavir # ↑ simeprevir Concomitant use of OLYSIO with ritonavir resulted in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by ritonavir. Co-administration of OLYSIO with ritonavir is not recommended.
Other ritonavir-boosted or unboosted HIV PIs, e.g., Atazanavir, Fosamprenavir, Lopinavir, Indinavir, Nelfinavir, Saquinavir, Tipranavir ↑ or ↓ simeprevir Concomitant use of OLYSIO with ritonavir-boosted or unboosted HIV PIs may result in altered plasma concentrations of simeprevir due to CYP3A inhibition or induction by these HIV PIs. Co-administration of OLYSIO with any HIV PI, with or without ritonavir is not recommended.
HMG CO-A Reductase Inhibitors
Rosuvastatin* ↑ rosuvastatin Concomitant use of OLYSIO with rosuvastatin resulted in increased plasma concentrations of rosuvastatin due to inhibition of OATP1B1 by simeprevir. Initiate rosuvastatin therapy with 5 mg once daily. The rosuvastatin dose should not exceed 10 mg daily when co-administered with OLYSIO.
Atorvastatin* ↑ atorvastatin Concomitant use of OLYSIO with atorvastatin resulted in increased plasma concentrations of atorvastatin due to inhibition of OATP1B1 and/or CYP3A4 by simeprevir. Use the lowest necessary dose of atorvastatin, but do not exceed a daily dose of 40 mg when co-administering with OLYSIO.
Simvastatin* ↑ simvastatin Concomitant use of OLYSIO with simvastatin resulted in increased plasma concentrations of simvastatin due to inhibition of OATP1B1 and/or CYP3A4 by simeprevir. Titrate the simvastatin dose carefully and use the lowest necessary dose of simvastatin while monitoring for safety when co-administered with OLYSIO.
Pitavastatin
Pravastatin
Lovastatin
↑ pitavastatin, pravastatin, lovastatin Concomitant use of OLYSIO with pitavastatin, pravastatin or lovastatin has not been studied. The dose of pitavastatin, pravastatin or lovastatin should be titrated carefully and the lowest necessary dose should be used while monitoring for safety when co-administered with OLYSIO.
Immunosuppressants
Cyclosporine* ↑ cyclosporine
↑ simeprevir§
Concomitant use of OLYSIO with cyclosporine resulted in significantly increased plasma concentrations of simeprevir due to inhibition of OATP1B1, P-gp and CYP3A by cyclosporine. It is not recommended to coadminister OLYSIO with cyclosporine.
Sirolimus ↑ or ↓ sirolimus Concomitant use of OLYSIO and sirolimus may result in mildly increased or decreased plasma concentrations of sirolimus. Routine monitoring of blood concentrations of sirolimus is acceptable.
Phosphodiesterase Type 5 (PDE-5) Inhibitors
Sildenafil
Tadalafil
Vardenafil
↑ PDE-5 inhibitors Concomitant use of OLYSIO with PDE-5 inhibitors may result in mild increases in concentrations of PDE-5 inhibitors due to intestinal CYP3A4 inhibition by simeprevir. No dose adjustment is required when OLYSIO is co-administered with doses of sildenafil, tadalafil or vardenafil indicated for the treatment of erectile dysfunction. 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.
Sedatives/Anxiolytics
Midazolam* (oral administration) ↑ midazolam Concomitant use of OLYSIO with orally administered midazolam resulted in increased plasma concentrations of midazolam due to mild inhibition of intestinal CYP3A4 by simeprevir. Caution is warranted when this drug, with a narrow therapeutic index, is co-administered with OLYSIO via the oral route.
Triazolam (oral administration) ↑ triazolam Concomitant use of OLYSIO with orally administered triazolam may result in mild increases in concentrations of triazolam due to intestinal CYP3A4 inhibition by simeprevir. Caution is warranted when this drug, with a narrow therapeutic index, is co-administered with OLYSIO via the oral route.
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, the corticosteroids budesonide, fluticasone, methylprednisolone, and prednisone, 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.

Last reviewed on RxList: 11/14/2014
This monograph has been modified to include the generic and brand name in many instances.

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