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Olysio

SIDE EFFECTS

OLYSIO should be administered with peginterferon alfa and ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin 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 Studies 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.

The safety profile of OLYSIO in combination with peginterferon alfa and ribavirin in patients with HCV genotype 1 infection who were treatment-na´ve or who had previously relapsed following interferon therapy with or without ribavirin is based on pooled data from three Phase 3 trials. These trials included a total of 1178 subjects who received OLYSIO or placebo in combination with 24 or 48 weeks of peginterferon alfa and ribavirin. 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 peginterferon alfa and ribavirin were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving OLYSIO in combination with peginterferon alfa and ribavirin versus 25% of subjects receiving placebo in combination with peginterferon alfa and ribavirin. Serious adverse reactions were reported in 2% of subjects receiving OLYSIO in combination with peginterferon alfa and ribavirin and in 3% of subjects receiving placebo in combination with peginterferon alfa and ribavirin. Discontinuation of OLYSIO or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving OLYSIO with peginterferon alfa and ribavirin and subjects receiving placebo with peginterferon alfa and ribavirin, 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 peginterferon alfa and ribavirin compared to subjects receiving placebo in combination with peginterferon alfa and ribavirin 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 peginterferon alfa and ribavirin therapy (see Table 3).

Table 3: Adverse Reactions (all Grades) that Occurred with at Least 3% Higher Frequency Among Subjects Receiving OLYSIO 150 mg Once Daily in Combination with Peginterferon alfa and Ribavirin Compared to Subjects Receiving Placebo in Combination with Peginterferon alfa and Ribavirin During the First 12 Weeks of Treatment (Pooled Phase 3 Trials; Intent-to-Treat Analysis)

Preferred Term or Grouped Term OLYSIO + Peginterferon alfa+ Ribavirin First 12 Weeks
N=781
% (n)
Placebo + Peginterferon alfa+ Ribavirin 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)
* Grouped term 'rash' includes the following preferred terms: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, urticaria, rash generalized, drug eruption, dermatitis allergic, dermatosis, vasculitic rash, toxic skin eruption, exfoliative rash, generalized erythema, dermatitis exfoliative, cutaneous vasculitis, photosensitivity reaction, polymorphic light eruption, solar dermatitis, photodermatosis, and sunburn.
† Grouped term 'pruritus' included the preferred terms pruritus and pruritus generalized.
‡ Grouped term 'dyspnea' includes the preferred terms dyspnea and dyspnea exertional.

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/placebo in combination with peginterferon alfa and ribavirin. 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/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/placebo in combination with peginterferon alfa and ribavirin. 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). 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. Treatment-emergent laboratory abnormalities that were observed at a higher incidence in OLYSIO-treated subjects than in placebo-treated subjects are listed in Table 4.

Table 4: Treatment-Emergent 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 Treatments; Intent-to-Treat Analysis)

Laboratory Parameter WHO Toxicity Range OLYSIO + Peginterferon alfa + Ribavirin
N=781
%
Placebo+ Peginterferon alfa + Ribavirin
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
* 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.

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

DRUG INTERACTIONS

[See also WARNING AND PRECAUTIONS and CLINICAL PHARMACOLOGY]

Potential For OLYSIO To Affect Other Drugs

Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.

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 5). 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 5).

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 5). Therefore, co-administration of OLYSIO with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended [see WARNING AND PRECAUTIONS].

Established And Other Potentially Significant Drug Interactions

Table 5 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 5. For information regarding the magnitude of interaction, see Tables 6 and 7 (see CLINICAL PHARMACOLOGY).

Table 5: 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.
Amiodarone Disopyramide Flecainide Mexiletine Propafenone Quinidine ↑ antiarrhythmics Concomitant use of OLYSIO with these antiarrhythmics may result in mild increases in concentrations of these antiarrhythmics due to intestinal CYP3A4 inhibition by simeprevir. Caution is warranted and therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when co-administered with OLYSIO.
Anticoagulants
Warfarin* ↔ warfarin No dose adjustment is required when OLYSIO is co-administered with warfarin. Routine monitoring of the international normalized ratio (INR) is acceptable.
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. It is not recommended to co-administer OLYSIO with these anticonvulsants.
Anti-infectives
Antibiotics: 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. It is not recommended to co-administer OLYSIO with erythromycin.
Antibiotics: 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. It is not recommended to co-administer OLYSIO with clarithromycin or telithromycin.
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. It is not recommended to co-administer OLYSIO with systemic itraconazole, ketoconazole or posaconazole.
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. It is not recommended to co-administer OLYSIO with systemic fluconazole or voriconazole.
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. It is not recommended to co-administer OLYSIO with rifampin, rifabutin or rifapentine.
Calcium Channel Blockers
Amlodipine Diltiazem Felodipine Nicardipine Nifedipine Nisoldipine Verapamil ↑calcium channel blockers Concomitant use of OLYSIO with calcium channel blockers may result in increased plasma concentrations of calcium channel blockers due to intestinal CYP3A4 and/or P-gp inhibition by simeprevir. Caution is warranted and clinical monitoring of patients is recommended when OLYSIO is co-administered with 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. It is not recommended to co-administer OLYSIO with systemic dexamethasone.
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. It is not recommended to co-administer OLYSIO with cisapride.
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. It is not recommended to co-administer OLYSIO with milk thistle.
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. It is not recommended to co-administer OLYSIO with products containing St. John's wort.
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. It is not recommended to co-administer OLYSIO with a cobicistat-containing product.
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. It is not recommended to co-administer OLYSIO with efavirenz.
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. It is not recommended to co-administer OLYSIO with delavirdine, etravirine or nevirapine.
Protease Inhibitors (PIs):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. It is not recommended to co-administer darunavir/ritonavir and OLYSIO.
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. It is not recommended to co-administer OLYSIO with ritonavir.
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. It is not recommended to co-administer OLYSIO with any HIV PI, with or without ritonavir.
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 No dose adjustment is required when OLYSIO is co-administered with cyclosporine. Routine monitoring of blood concentrations of cyclosporine is acceptable.
Tacrolimus* ↓tacrolimus No dose adjustment is required when OLYSIO is co-administered with tacrolimus. Routine monitoring of blood concentrations of tacrolimus is acceptable.
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 6 and 7].
† 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.

In addition to the drugs included in Table 5, 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, and tenofovir disoproxil fumarate.

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: 1/23/2014
This monograph has been modified to include the generic and brand name in many instances.

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