Simeprevir

Simeprevir
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, M.D. [2]

Disclaimer

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Overview

Simeprevir is a hepatitis C virus NS3/4A protease inhibitor that is FDA approved for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen. Common adverse reactions include pruritus, rash, nausea, hyperbilirubinemia, headache, insomnia, and fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

OLYSIO® is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen.

Limitations of Use:

• OLYSIO mono therapy is not recommended.

• OLYSIO efficacy in combination with peg interferon alfa and ribavirin (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. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.
• OLYSIO is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) due to substantial increases in simeprevir exposures, which have been associated with increased frequency of adverse reactions.
• OLYSIO is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO or other HCV protease inhibitors.

Dosage

OLYSIO Combination Treatment

Administer OLYSIO in combination with other antiviral drugs for the treatment of CHC infection. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information. OLYSIO monotherapy is not recommended. Administer OLYSIO in combination with either:

• Peg-IFN-alfa and RBV: Table 1 displays the recommended dosage regimen and treatment duration of OLYSIO in combination with Peg-IFN-alfa and RBV. Refer to Table 3 for treatment stopping rules for OLYSIO combination therapy with Peg-IFN-alfa and RBV; or
• Sofosbuvir: Table 2 displays the recommended dosage regimen and treatment duration of OLYSIO in combination with sofosbuvir.

The recommended dosage of OLYSIO is one capsule taken orally once daily with food. The capsule should be swallowed as a whole.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

Testing Prior to Initiation of OLYSIO in HCV Genotype 1a-Infected Patients

Prior to initiation of treatment with OLYSIO 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. Prior to initiation of treatment with OLYSIO with sofosbuvir, screening patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism is not strongly recommended but may be considered.

Discontinuation of Dosing

Use 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 ≥ 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 virology response at Weeks 4, 12, and 24.

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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 drugs used in combination with OLYSIO for the treatment of CHC infection are permanently discontinued for any reason, OLYSIO should also be discontinued.

Hepatic Impairment

No dosage recommendation can be made for patients with moderate hepatic impairment (Child-Pugh Class B) due to modest increases in simeprevir exposures. OLYSIO is not recommended for patients with severe hepatic impairment (Child-Pugh Class C) due to substantially higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity.

The safety and efficacy of OLYSIO have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). Do not administer OLYSIO in combination with Peg-IFN-alfa and RBV in patients with decompensated cirrhosis (moderate or severe hepatic impairment) [see Peg-IFN-alfa prescribing information]. The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients with moderate hepatic impairment.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Simeprevir in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Simeprevir in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Simeprevir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Simeprevir in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Simeprevir in pediatric patients.

Contraindications

There are no specific contraindications to simeprevir. However, as simeprevir should always be administered in combination with other antiviral drugs for the treatment of chronic [[hepatitis C]] infection, prescribers should consult the complete prescribing information for these drugs for a description of contraindications.

Warnings

Risk of Serious Adverse Reactions Associated With Combination Treatment. simeprevir should be used in combination with other antiviral drugs for the treatment of CHC infection. Therefore, 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 simeprevir combination treatment.

Photosensitivity

Photosensitivity reactions have been observed with simeprevir combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with simeprevir in combination with Peg-IFN-alfa and ribavirin. 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

Co-administration 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

Adverse Reactions

Clinical Trials Experience

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:

• Photosensitivity
• Rash

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-naïve 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 (14)]. 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-naïve or who had previously relapsed after Peg-IFN-alfa and RBV therapy (see TABLE 4).

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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.

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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.

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.

Postmarketing Experience

There is limited information regarding Simeprevir Postmarketing Experience in the drug label.

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. 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.

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.

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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 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

Pregnancy

OLYSIO must be administered in combination with other antiviral drugs. Refer to prescribing information of the drugs used in combination with OLYSIO for information regarding use in pregnancy.

Pregnancy Category C

Risk Summary

Adequate and well-controlled trials with OLYSIO have not been conducted in pregnant women. In animal reproduction studies with simeprevir, embryofetal developmental toxicity was observed at drug exposures higher than human exposure at the recommended clinical dose. OLYSIO should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method.

If OLYSIO is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on use in pregnancy.

Animal Data

Simeprevir showed no teratogenicity in rats and mice at exposures 0.5 times (in rats) and 6 times (in mice) the mean area under the plasma concentration time curve (AUC) in humans at the recommended dose of 150 mg once daily.

In a mouse embryofetal study at doses up to 1000 mg/kg, simeprevir resulted in early and late in utero fetal losses and early maternal deaths at an exposure approximately 6 times higher than the mean AUC in humans at the recommended 150 mg daily dose. Significantly decreased fetal weights and an increase in fetal skeletal variations were seen at exposures approximately 4 times higher than the mean AUC in humans at the recommended daily dose.

In a rat pre- and postnatal study, maternal animals were exposed to simeprevir during gestation and lactation at doses up to 1000 mg/kg/day. In pregnant rats, simeprevir resulted in early deaths at 1000 mg/kg/day corresponding to exposures similar to the mean AUC in humans at the recommended 150 mg once daily dose. Significant reduction in body weight gain was seen at an exposure 0.7 times the mean AUC in humans at the recommended 150 mg once daily dose. 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 a maternal exposure similar to the mean AUC in humans at the recommended 150 mg once daily dose. Subsequent survival, behavior and reproductive capacity were not affected.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Simeprevir in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Simeprevir during labor and delivery.

Nursing Mothers

Nursing Mothers

It is not known whether OLYSIO or its metabolites are present in human breast milk. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with OLYSIO, taking into account the importance of the therapy to the mother.

If OLYSIO is administered in a regimen containing RBV, the information for RBV with regard to nursing mothers also applies to this combination regimen.

Pediatric Use

The safety and efficacy of OLYSIO in pediatric patients have not been established.

Geriatic 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 dose adjustment of OLYSIO is required in geriatric patients.

Gender

There is no FDA guidance on the use of Simeprevir with respect to specific gender populations.

Race

Patients of East Asian ancestry exhibit higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients of East Asian ancestry.

Renal Impairment

No dose 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 dose adjustment of OLYSIO is required in patients with mild hepatic impairment (Child-Pugh Class A). The safety and efficacy of OLYSIO have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). No dosage recommendation can be given for patients with moderate hepatic impairment (Child-Pugh Class B) due to modest increases in simeprevir exposures. OLYSIO is not recommended for patients with severe hepatic impairment (Child-Pugh Class C) due to substantially higher simeprevir exposures.

In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients with moderate hepatic impairment.

Refer to the prescribing information for the antiviral drug(s) used in combination with OLYSIO regarding their use in patients with hepatic impairment. The combination of OLYSIO with Peg-IFN-alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment).

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Simeprevir in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Simeprevir in patients who are immunocompromised.

Administration and Monitoring

Administration

Oral

Monitoring

• 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 virology response (i.e., HCV RNA ≥ 25 IU/mL) are not likely to achieve a sustained virology response (SVR), discontinuation of treatment is recommended in these patients.

• 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.

• Discontinuation of OLYSIO should be considered if the rash becomes severePatients should be monitored until the rash has resolved.

• 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.

• 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.

• Clinical monitoring of patients is recommended when OLYSIO is co-administered with orally administered calcium channel blockers.

• Concomitant use of OLYSIO with simvastatin resulted in increased plasma concentrations of simvastatin. Titrate the simvastatin dose carefully and use the lowest necessary dose of simvastatin while monitoring for safety when co-administered with OLYSIO.

• 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.

• 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.

• 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.

IV Compatibility

There is limited information regarding the compatibility of Simeprevir and IV administrations.

Overdosage

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.

Pharmacology

Mechanism of Action

There is limited information regarding Simeprevir Mechanism of Action in the drug label.

Structure

There is limited information regarding Simeprevir Structure in the drug label.

Pharmacodynamics

Cardiac Electrophysiology

The effect of simeprevir at the recommended dose of 150 mg once daily and 350 mg (at 2.3 times the recommended dosage) once daily for 7 days on the QT interval was evaluated in a randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg once daily), 4-way cross-over study in 60 healthy subjects. No meaningful changes in QTc interval were observed at either the recommended dose of 150 mg once daily or the dose of 350 mg (2.3 times the recommended dosage) once daily.

Pharmacokinetics

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 HCV-infected subjects, the mean steady-state predose plasma concentration was 1936 ng/mL (standard deviation: 2640) and the mean steady-state AUC24 was 57469 ng.h/mL (standard deviation: 63571).

Absorption

Simeprevir is orally bioavailable. 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

Administration of simeprevir with food to healthy subjects increased the relative bioavailability (AUC) by 61% and 69% after a high-fat, high-caloric (928 kcal) and normal-caloric (533 kcal) breakfast, respectively, and delayed the absorption by 1 hour and 1.5 hours, respectively. Due to increased bioavailability, OLYSIO should be administered with food. The type of food does not affect exposure to simeprevir.

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 [see DRUG INTERACTIONS (7)].

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.

Nonclinical Toxicology

There is limited information regarding Simeprevir Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Simeprevir Clinical Studies in the drug label.

How Supplied

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) or a bottle of 7 capsules (emergency supply; NDC 59676-225-07).

Storage

Store OLYSIO capsules in the original bottle in order to protect from light at room temperature below 30°C (86°F).

Images

Drug Images

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Package and Label Display Panel

NDC 59676-225-28

28 Capsules

Olysio® (simeprevir) Capsules 150 mg

Each capsule contains simeprevir sodium equivalent to 150 mg simeprevir

Rx only

janssen

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Patient Counseling Information

OLYSIO® (oh li see oh) (simeprevir) Capsules

Read this Patient Information before you start taking OLYSIO and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

OLYSIO is used in combination with other antiviral medicines for treating chronic hepatitis C infection. When taking OLYSIO in combination with peginterferon alfa and ribavirin you should also read those Medication Guides. When taking OLYSIO in combination with sofosbuvir, you should also read its Patient Information leaflet.

What is the most important information I should know about OLYSIO?

If you are pregnant, or plan to become pregnant, talk with your healthcare provider before taking OLYSIO. It is not known if OLYSIO will harm your unborn baby. Also read the Medication Guides for peginterferon alfa and ribavirin if your healthcare provider prescribes these medications for you in combination with OLYSIO. Females must use an effective form of birth control during treatment with OLYSIO. Talk with your healthcare provider about birth control methods that you may use during treatment with OLYSIO. OLYSIO combination treatment may cause rashes and skin reactions to sunlight. These rashes and skin reactions to sunlight can be severe and you may need to be treated in a hospital. Rashes and skin reactions to sunlight are most common during the first 4 weeks of treatment, but can happen at any time during combination treatment with OLYSIO.

Use sunscreen, and wear a hat, sunglasses, and protective clothing when you will be exposed to sunlight during treatment with OLYSIO. Limit sunlight exposure during treatment with OLYSIO. Avoid use of tanning beds, sunlamps, or other types of light therapy during treatment with OLYSIO. Call your healthcare provider right away if you get any of the following symptoms: burning, redness, swelling or blisters on your skin mouth sores or ulcers red or inflamed eyes, like "pink eye" (conjunctivitis) You should not take OLYSIO alone. OLYSIO should be used together with other medicines to treat chronic hepatitis C infection.

What is OLYSIO?

OLYSIO is a prescription medicine used with other antiviral medicines to treat chronic (lasting a long time) hepatitis C infection in adults. OLYSIO should not be taken alone. It is not known if OLYSIO is safe and effective in children under 18 years of age.

Who should not take OLYSIO?

"WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?"

What should I tell my healthcare provider before taking OLYSIO?

Before taking OLYSIO, tell your healthcare provider if you:

have liver problems other than hepatitis C virus infection have ever taken any medicine to treat hepatitis C virus infection had a liver transplant are receiving phototherapy have any other medical condition are of East Asian descent are breastfeeding. It is not known if OLYSIO passes into your breast milk. You and your healthcare provider should decide if you will take OLYSIO or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

OLYSIO and other medicines may affect each other. This can cause you to have too much or not enough OLYSIO or other medicines in your body, which may affect the way OLYSIO or your other medicines work, or may cause side effects. Do not start taking a new medicine without telling your healthcare provider or pharmacist.

Especially tell your healthcare provider if you take any of the following medicines:

amiodarone (Cordarone®, Pacerone®), when taken by mouth amlodipine (Norvasc®), when taken by mouth atazanavir (Reyataz®) atorvastatin (Lipitor®, Caduet®) carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®) cisapride (Propulsid®, Propulsid Quicksolv®) clarithromycin (Biaxin®, Prevpac®) cobicistat-containing medicine (Stribild®) cyclosporine (Gengraf®, Neoral®, Sandimmune®) darunavir (Prezista®) delavirdine mesylate (Rescriptor®) dexamethasone, when taken by mouth or given by injection digoxin (Lanoxin®) diltiazem (Cardizem®, Dilacor XR®, Tiazac®), when taken by mouth disopyramide (Norpace®), when taken by mouth efavirenz (Sustiva®, Atripla®) erythromycin (E.E.S.®, Eryc®, Ery-Tab®, Erythrocin®, Erythrocin Stearate®), when taken by mouth or when given by injection etravirine (Intelence®) felodipine (Plendil®), when taken by mouth flecainide (Tambocor®), when taken by mouth fluconazole (Diflucan®), when taken by mouth or when given by injection fosamprenavir (Lexiva®) indinavir (Crixivan®) itraconazole (Sporanox®, Onmel®), when taken by mouth ketoconazole (Nizoral®), when taken by mouth lopinavir (Kaletra®) lovastatin (Advicor®, Altoprev®, Mevacor®) mexiletine (Mexitil®), when taken by mouth midazolam, when taken by mouth milk thistle (Silybum marianum) or products containing milk thistle nelfinavir (Viracept®) nevirapine (Viramune®, Viramune XR®) nicardipine (Cardene®), when taken by mouth nifedipine (Adalat CC®, Afeditab CR®, Procardia®), when taken by mouth nisoldipine (Sular®), when taken by mouth oxcarbazepine (Oxtellar XR™, Trileptal®) phenobarbital (Luminal®) phenytoin (Dilantin®, Phenytek®) pitavastatin (Livalo®) posaconazole (Noxafil®), when taken by mouth pravastatin (Pravachol®) propafenone (Rythmol SR®), when taken by mouth quinidine (Nuedexta®, Duraquin®, Quinaglute®), when taken by mouth rifabutin (Mycobutin®) rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®) rifapentine (Priftin®) ritonavir (Norvir®) rosuvastatin (Crestor®) saquinavir mesylate (Invirase®) sildenafil (Revatio®, Viagra®) simvastatin (Zocor®, Vytorin®, Simcor®) sirolimus (Rapamune®) St. John's wort (Hypericum perforatum) or products containing St. John's wort tadalafil (Adcirca®, Cialis®) telithromycin (Ketek®) tipranavir (Aptivus®) triazolam (Halcion®), when taken by mouth verapamil (Calan®, Covera-HS®, Isoptin®, Tarka®), when taken by mouth voriconazole (Vfend®), when taken by mouth or when given by injection This is not a complete list of medicines that could interact with OLYSIO. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take OLYSIO?

Take OLYSIO exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to. Do not stop taking OLYSIO unless your healthcare provider tells you to. If you think there is a reason to stop taking OLYSIO, talk to your healthcare provider before doing so. Take 1 OLYSIO capsule each day with food. Swallow OLYSIO capsules whole. If you miss a dose of OLYSIO and it is more than 12 hours until your next dose, take the missed dose as soon as possible with food. Take the next dose of OLYSIO at your regular time. If you miss a dose of OLYSIO and it is less than 12 hours until your next dose, skip the missed dose. Take the next dose of OLYSIO at your regular time. Do not take two doses of OLYSIO at the same time to make up for a missed dose. If you take too much OLYSIO, call your healthcare provider right away or go to the nearest hospital emergency room.

What are the possible side effects of OLYSIO?

See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?" The most common side effects of OLYSIO when used in combination with peginterferon alfa and ribavirin include:

skin rash. See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?" section of this leaflet. itching nausea The most common side effects of OLYSIO when used in combination with sofosbuvir include:

tiredness headache nausea Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of OLYSIO. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store OLYSIO?

Store OLYSIO at room temperature below 86°F (30°C). Store OLYSIO in the original bottle to protect it from light. Keep OLYSIO and all medicines out of the reach of children.

General information about the safe and effective use of OLYSIO

It is not known if treatment with OLYSIO will prevent you from infecting another person with the hepatitis C virus during your treatment. Talk with your healthcare provider about ways to prevent spreading the hepatitis C virus.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use OLYSIO for a condition for which it was not prescribed. Do not give your OLYSIO to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information about OLYSIO, talk with your pharmacist or healthcare provider. You can ask your pharmacist or healthcare provider for information about OLYSIO that is written for health professionals.

For more information about OLYSIO, go to www.OLYSIO.com or call 1-800-526-7736.

What are the ingredients in OLYSIO?

Active ingredient: simeprevir

Inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate, sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904).

This Patient Information has been approved by the U.S. Food and Drug Administration.

Precautions with Alcohol

Alcohol-Simeprevir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Simeprevir Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Simeprevir Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.