OLYSIO 150mg hard capsules - Ireland[爱尔兰药品]

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OLYSIO 150mg hard capsules

2015-04-18 18:05:11 来源: 作者: 【大中小】浏览:480次评论:0条

1. Name of the medicinal product

OLYSIO 150 mg hard capsules

2. Qualitative and quantitative composition

Each hard capsule contains simeprevir sodium equivalent to 150 mg of simeprevir.

Excipient with known effect: each capsule contains 78.4 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Hard capsule (capsule)

White gelatin capsule of approximately 22 mm in length, marked with “TMC435 150” in black ink.

4. Clinical particulars

4.1 Therapeutic indications

OLYSIO is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult patients (see sections 4.2, 4.4 and 5.1).

For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1.

4.2 Posology and method of administration

Treatment with OLYSIO should be initiated and monitored by a physician experienced in the management of CHC.

Posology

The recommended dosage of OLYSIO is one capsule of 150 mg once daily for 12 weeks, taken with food.

OLYSIO must not be administered as monotherapy. OLYSIO must be used in combination with other medicinal products for the treatment of CHC (see section 5.1). When considering OLYSIO combination treatment with peginterferon alfa and ribavirin in HCV genotype 1a patients, patients should be tested for the presence of virus with the NS3 Q80K polymorphism before starting treatment (see section 4.4).

Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with OLYSIO.

The recommended co-administered medicinal product(s) and treatment duration for OLYSIO combination therapy are provided in table 1.

Table 1: Recommended co-administered medicinal product(s) and treatment duration for OLYSIO combination therapy
Patient population	Treatment	Duration
Treatment-naïve and prior relapse¹ patients with HCV genotype 1 or 4
with or without cirrhosis, who are not co-infected with HIV without cirrhosis, who are co-infected with HIV	OLYSIO + peginterferon alfa + ribavirin²	24 weeks³ Treatment with OLYSIO must be initiated in combination with peginterferon alfa and ribavirin and administered for 12 weeks and then followed by an additional 12 weeks of peginterferon alfa and ribavirin.
with cirrhosis, who are co-infected with HIV	OLYSIO + peginterferon alfa + ribavirin²	48 weeks³ Treatment with OLYSIO must be initiated in combination with peginterferon alfa and ribavirin and administered for 12 weeks and then followed by an additional 36 weeks of peginterferon alfa and ribavirin.
Prior non-responder⁴ patients (including partial and null responders) with HCV genotype 1 or 4, with or without cirrhosis, with or without HIV co-infection	OLYSIO + peginterferon alfa + ribavirin²	48 weeks³ Treatment with OLYSIO must be initiated in combination with peginterferon alfa and ribavirin and administered for 12 weeks and then followed by an additional 36 weeks of peginterferon alfa and ribavirin.
Treatment-naïve, prior relapse¹ and prior non-responder⁴ patients (including partial and null responders) with HCV genotype 1 or 4, with or without cirrhosis, with or without HIV co-infection	OLYSIO + sofosbuvir (+/- ribavirin)⁵	12 weeks⁶ (see sections 4.4, 4.8 and 5.1)
¹ Relapse following prior treatment with interferon (pegylated or non-pegylated), with or without ribavirin (see section 5.1). ² When considering OLYSIO combination treatment with peginterferon alfa and ribavirin in HCV genotype 1a patients, testing for NS3 Q80K polymorphism should be performed before starting treatment (see section 4.4). ³ Recommended duration of treatment provided that patient does not meet a stopping rule (see table 2). ⁴ Non-response following prior treatment with interferon (pegylated or non-pegylated), with or without ribavirin (see section 5.1). ⁵ OLYSIO with sofosbuvir should only be used in patients who are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment. Ribavirin could be added based on a clinical assessment of each individual patient (see sections 4.4, 4.8 and 5.1). The recommended treatment duration is 12 weeks. A longer treatment duration (up to 24 weeks) of OLYSIO with sofosbuvir (with or without ribavirin) could be considered based on an individual basis (see sections 4.4, 4.8 and 5.1). ⁶ No stopping rules apply to the combination of OLYSIO with sofosbuvir.

Refer to table 2 for treatment stopping rules based on HCV RNA levels at weeks 4, 12 and 24 for patients receiving treatment with OLYSIO, peginterferon alfa and ribavirin.

Treatment discontinuation in patients with inadequate on-treatment virologic response

Use with peginterferon alfa and ribavrin

It is unlikely that patients with inadequate on-treatment virologic response will achieve a sustained virologic response (SVR), therefore discontinuation of treatment is recommended in these patients. The HCV RNA thresholds that trigger discontinuation of treatment (i.e., treatment stopping rules) are presented in table 2.

Table 2: Treatment stopping rules in patients receiving OLYSIO in combination with peginterferon alfa and ribavirin with inadequate on-treatment virologic response
HCV RNA	Action
Treatment week 4: ≥ 25 IU/ml	Discontinue OLYSIO, peginterferon alfa and ribavirin
Treatment week 12: ≥ 25 IU/ml¹	Discontinue peginterferon alfa and ribavirin (treatment with OLYSIO is complete at week 12)
Treatment week 24: ≥ 25 IU/ml¹	Discontinue peginterferon alfa and ribavirin
¹ Re-eva luation of HCV RNA is recommended in case of HCV RNA ≥ 25 IU/ml after previous undetectable HCV RNA to confirm HCV RNA levels prior to discontinuing HCV treatment.

Use with sofosbuvir

There are no virologic treatment stopping rules that apply to the combination of OLYSIO with sofosbuvir.

Dosage adjustment or interruption of OLYSIO treatment

To prevent treatment failure, the dose of OLYSIO must not be reduced or interrupted. If treatment with OLYSIO is discontinued because of adverse reactions or inadequate on-treatment virologic response, OLYSIO treatment must not be reinitiated.

Dosage adjustment or interruption of medicinal products used in combination with OLYSIO for the treatment of CHC

If adverse reactions, potentially related to the medicinal products that are used in combination with OLYSIO for the treatment of CHC, require dosage adjustment or interruption of the medicinal product(s), refer to the instructions outlined in the respective Summary of Product Characteristics for these medicinal products.

If the other medicinal products that are used in combination with OLYSIO for the treatment of CHC are permanently discontinued for any reason, OLYSIO must also be discontinued. When ribavirin has been added to the combination of OLYSIO and sofosbuvir, and ribavirin needs to be discontinued, consideration can be given to continue treatment of OLYSIO with sofosbuvir alone (see section 5.1).

Missed dose

If a dose of OLYSIO is missed, and the patient notices within 12 hours of the usual dosing time, the patient should take the missed dose of OLYSIO with food as soon as possible and then take the next dose of OLYSIO at the regularly scheduled time.

If a dose of OLYSIO is missed by more than 12 hours after the usual dosing time, the patient should not take the missed dose of OLYSIO and should resume dosing of OLYSIO with food at the regularly scheduled time.

Special populations

Elderly (over 65 years of age)

There are limited data on the safety and efficacy of OLYSIO in patients older than 65 years. There are no safety and efficacy data of OLYSIO in patients over the age of 75 years. No dose adjustment of OLYSIO is required in elderly patients (see section 5.2).

Renal impairment

No dose adjustment of OLYSIO is required in patients with mild or moderate renal impairment. Increased simeprevir exposures have been observed in individuals with severe renal impairment. OLYSIO has 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 haemodialysis. As exposure may be increased in HCV infected patients with severe renal impairment, caution is recommended when prescribing OLYSIO to these patients (see section 5.2).

Refer to the respective Summary of Product Characteristics of the medicinal products 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 or moderate hepatic impairment (Child-Pugh class A or B). Simeprevir exposure is significantly increased in subjects with severe hepatic impairment (Child-Pugh class C) and no dose recommendation can be given for those patients (see section 5.2). 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); therefore particular caution is recommended when prescribing OLYSIO to HCV infected patients with moderate or severe hepatic impairment.

Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with OLYSIO regarding their use in patients with decompensated cirrhosis (Child-Pugh class B or C).

Race

Given limited data, the potential risks and benefits of OLYSIO 150 mg should be carefully considered prior to use in East Asian patients (see section 5.2).

Paediatric population

The safety and efficacy of OLYSIO in children aged below 18 years have not yet been established. No data are available.

HCV/Human immunodeficiency virus type 1 (HIV-1) co-infection

No dose adjustment of OLYSIO is required in HCV/HIV-1 co-infected patients (see sections 4.8, 5.1 and 5.2).

OLYSIO in combination with peginterferon alfa and ribavirin: HCV/HIV-1 co-infected patients, irrespective of prior HCV treatment history, should be treated in the same way as HCV mono-infected patients, except for co-infected patients with cirrhosis who should receive 36 weeks of treatment with peginterferon alfa and ribavirin after completing 12 weeks of treatment with OLYSIO, peginterferon alfa and ribavirin (total treatment duration of 48 weeks).

Please refer to sections 4.4 and 4.5 for relevant interactions with antiretroviral agents.

Method of administration

OLYSIO must be taken orally once a day with food (see section 5.2). The capsule should be swallowed as a whole.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

General

The efficacy of OLYSIO has not been studied in patients with HCV genotypes 2, 3, 5 or 6; therefore OLYSIO should not be used in these patients (see section 5.1).

OLYSIO must not be administered as monotherapy and must be prescribed in combination with other medicinal products for the treatment of CHC.

Consult the Summary of Product Characteristics of the co-prescribed medicinal products before starting therapy with OLYSIO. Warnings and precautions related to these medicinal products also apply to their use in OLYSIO combination treatment.

There are no clinical data on the use of OLYSIO in re-treating patients who have failed an HCV NS3-4A protease inhibitor-based therapy (see sections 5.1 and 5.3).

Use of simeprevir in patients infected with HCV genotype 1a

Simeprevir efficacy in combination with peginterferon alfa and ribavirin is substantially reduced in patients infected with hepatitis C genotype 1a with the NS3 Q80K polymorphism at baseline compared to patients with hepatitis C genotype 1a without the Q80K polymorphism (see section 5.1). Testing for the presence of the Q80K polymorphism in patients with HCV genotype 1a is strongly recommended when considering therapy with OLYSIO in combination with peginterferon alfa and ribavirin. Alternative therapy should be considered for patients infected with HCV genotype 1a with the Q80K polymorphism or in cases where testing is not accessible.

Data are too limited to eva luate whether the presence of Q80K polymorphism in HCV genotype 1a patients reduces the efficacy of simeprevir when OLYSIO is used in combination with other direct acting antivirals against HCV (see section 5.1). Until confirmatory data becomes available, testing for the presence of the Q80K polymorphism should be considered before initiating OLYSIO in combination with sofosbuvir in patients infected with HCV genotype 1a.

Interferon-free therapy

Interferon-free regimens with OLYSIO have not been investigated in phase 3 studies (see section 5.1). The optimal regimen and treatment duration have not been established. Interferon-free therapy with OLYSIO should only be used in patients who are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment.

Co-administration with other direct acting antivirals against HCV

OLYSIO should only be co-administered with other direct acting antiviral medicinal products if the benefits are considered to outweigh the risks based upon available data. There are no data to support the co-administration of OLYSIO and telaprevir or boceprevir. These HCV protease inhibitors are anticipated to be cross-resistant, and co-administration is not recommended (see also section 4.5).

OLYSIO in combination with peginterferon alfa-2b

In the clinical studies, patients randomised to simeprevir in combination with peginterferon alfa-2b and ribavirin obtained numerically lower SVR12 rates and also experienced viral breakthrough and viral relapse more frequently than those treated with simeprevir in combination with peginterferon alfa-2a and ribavirin (see section 5.1).

Pregnancy and contraception

OLYSIO should only be used during pregnancy or in women of childbearing potential if the benefit justifies the risk. Female patients of childbearing potential must use an effective form of contraception (see section 4.6).

The contraindications and warnings regarding pregnancy and contraception requirements applicable to the co-administered medicinal products also apply to their use in OLYSIO combination treatment.

Ribavirin may cause birth defects and/or death of the exposed foetus. Therefore, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients (see section 4.6).

Photosensitivity

Photosensitivity reactions have been observed with OLYSIO combination treatment (see section 4.8). Patients should be informed of the risk of photosensitivity reactions and on the importance of applying appropriate sun protective measures during treatment with OLYSIO. Excess exposure to sun and use of tanning devices during treatment with OLYSIO should be avoided. If photosensitivity reactions occur, discontinuation of OLYSIO should be considered and patients should be monitored until the reaction has resolved.

Rash

Rash has been observed with OLYSIO combination treatment (see section 4.8). Patients with mild to moderate rashes should be monitored for possible progression of rash, including the development of mucosal signs or systemic symptoms. In case of severe rash, OLYSIO and other co-administered medicinal products for the treatment of CHC should be discontinued and the patients should be monitored until the symptoms have resolved.

Hepatic impairment

Simeprevir plasma exposure is significantly increased in subjects with severe hepatic impairment (Child-Pugh class C). 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) or in decompensated patients; therefore particular caution is recommended when prescribing OLYSIO to these patients (see sections 4.2 and 5.2).

Laboratory testing during treatment with OLYSIO, peginterferon alfa and ribavirin

HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated (see also guidelines for treatment duration and stopping rules; section 4.2). Use of a sensitive quantitative HCV RNA assay for monitoring HCV RNA levels during treatment is recommended.

Refer to the Summary of Product Characteristics of peginterferon alfa and ribavirin for baseline, on-treatment and post-treatment laboratory testing requirements including haematology, biochemistry (including hepatic enzymes and bilirubin), and pregnancy testing requirements.

Interactions with medicinal products

Co-administration of OLYSIO with substances that moderately or strongly induce or inhibit cytochrome P450 3A (CYP3A4) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively.

Please refer to section 4.5 for information on interactions with medicinal products.

Hepatitis B Virus (HBV) co-infection

The safety and efficacy of OLYSIO for the treatment of HCV infection in patients co-infected with HBV have not been studied.

Organ transplant patients

Co-administration of OLYSIO with ciclosporin is not recommended as this leads to significantly higher exposure of simeprevir based on interim data from an ongoing phase 2 study in HCV infected post-liver transplant patients (see section 4.5).

Excipient of OLYSIO capsules

OLYSIO capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products that affect simeprevir exposure

The primary enzyme involved in the biotransformation of simeprevir is CYP3A4 (see section 5.2) and clinically relevant effects of other medicinal products on simeprevir pharmacokinetics via CYP3A4 may occur. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A4 may significantly increase the plasma exposure of simeprevir, while co-administration with moderate or strong inducers of CYP3A4 may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see table 3). Therefore, co-administration of OLYSIO with substances that moderately or strongly inhibit or induce CYP3A4 is not recommended.

Hepatic uptake of simeprevir is mediated by OATP1B1. Inhibitors of OATP1B1 such as eltrombopag or gemfibrozil may result in mild increases in simeprevir plasma concentrations.

Medicinal products that are affected by the use of simeprevir

Simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity. Co-administration of OLYSIO with medicinal products that are primarily metabolised by CYP3A4 may result in increased plasma concentrations of such medicinal products (see table 3). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo.

Simeprevir inhibits OATP1B1 and P-gp transporters. Co-administration of OLYSIO with medicinal products that are substrates for OATP1B1 and P-gp transport may result in increased plasma concentrations of such medicinal products (see table 3).

Interaction table

Established and theoretical interactions between simeprevir and selected medicinal products are listed in table 3 (least square mean ratios with 90% confidence intervals (90% CI) are presented, increase is indicated as “↑”, decrease as “↓”, no change as “↔”). Interaction studies have been performed in healthy adults with the recommended dose of 150 mg simeprevir once daily unless otherwise noted.

Table 3: Interactions and dose recommendation with other medicinal products
Medicinal products by therapeutic areas	Effect on drug levels Least Squares Mean Ratio (90%CI)	Recommendation for co-administration
ANALEPTIC
Caffeine 150 mg	caffeine AUC 1.26 (1.21-1.32) ↑ caffeine C_max 1.12 (1.06-1.19) ↔ caffeine C_min not studied	No dose adjustment is required.
ANTIARRHYTHMICS
Digoxin 0.25 mg	digoxin AUC 1.39 (1.16-1.67) ↑ digoxin C_max 1.31 (1.14-1.51) ↑ digoxin C_min not studied (inhibition of P-gp transporter)	Concentrations of digoxin should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Amiodarone Disopyramide Flecainide Mexiletine Propafenone Quinidine	Not studied. Mild increases in concentrations of these antiarrhythmics may be expected when these medicinal products are administered orally. (intestinal CYP3A4 enzyme inhibition) Mild increases in simeprevir concentrations may occur due to inhibition of CYP3A4 by amiodarone.	Caution is warranted and therapeutic drug monitoring for these antiarrhythmics and/or clinical monitoring (ECG etc.) when orally administered are recommended.
ANTICOAGULANTS
Warfarin 10 mg	S-warfarin AUC 1.04 (1.00-1.07) ↔ S-warfarin C_max 1.00 (0.94-1.06) ↔ S-warfarin C_min not studied	No dose adjustment is required. However, it is recommended that the international normalised ratio (INR) be monitored.
ANTICONVULSANTS
Carbamazepine Oxcarbazepine Phenobarbital Phenytoin	Not studied. Significant decrease in plasma concentrations of simeprevir are expected. (strong CYP3A4 induction)	It is not recommended to co-administer OLYSIO with these anticonvulsants as co-administration may result in loss of therapeutic effect of OLYSIO.
ANTIDEPRESSANTS
Escitalopram 10 mg once daily	escitalopram AUC 1.00 (0.97-1.03) ↔ escitalopram C_max 1.03 (0.99-1.07) ↔ escitalopram C_min 1.00 (0.95-1.05) ↔ simeprevir AUC 0.75 (0.68-0.83) ↓ simeprevir C_max 0.80 (0.71-0.89) ↓ simeprevir C_min 0.68 (0.59-0.79) ↓	No dose adjustment is required.
ANTIHISTAMINES
Astemizole Terfenadine	Not studied. Astemizole and terfenadine have the potential for cardiac arrhythmias. Mild increases in concentrations of these antihistamines may be expected. (intestinal CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with astemizole or terfenadine.
ANTI-INFECTIVES
Antibiotics – macrolides (systemic administration)
Azithromycin	Not studied. Based on the elimination pathway of azithromycin, no drug interactions are expected between azithromycin and simeprevir.	No dose adjustment is required.
Erythromycin 500 mg three times a day	erythromycin AUC 1.90 (1.53-2.36) ↑ erythromycin C_max 1.59 (1.23-2.05) ↑ erythromycin C_min 3.08 (2.54-3.73) ↑ simeprevir AUC 7.47 (6.41-8.70) ↑ simeprevir C_max 4.53 (3.91-5.25) ↑ simeprevir C_min 12.74 (10.19-15.93) ↑ (inhibition of CYP3A4 enzymes and P-gp transporter by both erythromycin and simeprevir)	It is not recommended to co-administer OLYSIO with systemic erythromycin.
Clarithromycin Telithromycin	Not studied. Increased plasma concentrations of simeprevir are expected. (strong CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with clarithromycin or telithromycin.
Antifungals (systemic administration)
Itraconazole Ketoconazole* Posaconazole	Not studied. Significant increases in plasma concentrations of simeprevir are expected. (strong CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with systemic itraconazole, ketoconazole or posaconazole.
Fluconazole Voriconazole	Not studied. Significant increases in plasma concentrations of simeprevir are expected. (mild to moderate CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with systemic fluconazole or voriconazole.
Antimycobacterials
Bedaquiline	Not studied. No clinically relevant drug-drug interaction is expected.	No dose adjustment is required.
Rifampicin¹ 600 mg once daily	rifampicin AUC 1.00 (0.93-1.08) ↔ rifampicin C_max 0.92 (0.80-1.07) ↔ rifampicin C_min not studied 25-desacetyl-rifampicin AUC 1.24 (1.13-1.36) ↑ 25-desacetyl-rifampicin C_max 1.08 (0.98-1.19) ↔ 25-desacetyl-rifampicin C_min not studied simeprevir AUC 0.52 (0.41-0.67) ↓ simeprevir C_max 1.31 (1.03-1.66) ↑ simeprevir C_min 0.08 (0.06-0.11) ↓ (CYP3A4 enzyme induction)	It is not recommended to co-administer OLYSIO with rifampicin as co-administration may result in loss of therapeutic effect of OLYSIO.
Rifabutin Rifapentine	Not studied. Significant decreases in plasma concentrations of simeprevir are expected. (CYP3A4 enzyme induction)	It is not recommended to co-administer OLYSIO with rifabutin or rifapentine as co-administration may result in loss of therapeutic effect of OLYSIO.
ANTITUSSIVE
Dextromethorphan (DXM) 30 mg	DXM AUC 1.08 (0.87-1.35) ↑ DXM C_max 1.21 (0.93-1.57) ↑ DXM C_min not studied dextrorphan AUC 1.09 (1.03-1.15) ↔ dextrorphan C_max 1.03 (0.93-1.15) ↔ dextrorphan C_min not studied	No dose adjustment is required.
CALCIUM CHANNEL BLOCKERS (oral administration)
Amlodipine Bepridil Diltiazem Felodipine Nicardipine Nifedipine Nisoldipine Verapamil	Not studied. Increased plasma concentrations of orally administered calcium channel blockers may be expeced. (intestinal CYP3A4 enzyme and P-gp transporter inhibition) Increased simeprevir concentrations may occur due to mild inhibition of CYP3A4 by amlodipine and moderate inhibition of CYP3A4 by diltiazem and verapamil.	Caution is warranted and clinical monitoring of patients is recommended when these calcium channel blockers are given orally.
GLUCOCORTICOIDS
Dexamethasone (systemic)	Not studied. Decreased plasma concentrations of simeprevir are expected. (moderate CYP3A4 enzyme induction)	It is not recommended to co-administer OLYSIO with systemic dexamethasone as co-administration may result in loss of therapeutic effect of OLYSIO.
Budesonide Fluticasone Methylprednisolone Prednisone	Not studied. No clinically relevant drug-drug interaction is expected.	No dose adjustment is required.
GASTROINTESTINAL PRODUCTS
Antacid
e.g., Aluminium or Magnesium hydroxide, Calcium carbonate	Not studied. No clinically relevant drug-drug interaction is expected.	No dose adjustment is required.
H₂-receptor antagonists
e.g., Cimetidine, Nizatidine, Ranitidine	Not studied. No clinically relevant drug-drug interaction is expected.	No dose adjustment is required.
Propulsive
Cisapride	Not studied. Cisapride has the potential to cause cardiac arrhythmias. Increased concentrations of cisapride may be possible. (intestinal CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with cisapride.
Proton pump inhibitors
Omeprazole 40 mg	omeprazole AUC 1.21 (1.00-1.46) ↑ omeprazole C_max 1.14 (0.93-1.39) ↑ omeprazole C_min not studied	No dose adjustment is required.
Dexlansoprazole Esomeprazole Lansoprazole Pantoprazole Rabeprazole	Not studied. No clinically relevant drug drug-interaction is expected.	No dose adjustment is required.
HCV PRODUCTS
Antiviral
Daclatasvir 60 mg once daily	daclatasvir AUC 1.96 (1.84-2.10) ↑ daclatasvir C_max 1.50 (1.39-1.62) ↑ daclatasvir C_min 2.68 (2.42-2.98) ↑ simeprevir AUC 1.44 (1.32-1.56) ↑ simeprevir C_max 1.39 (1.27-1.52) ↑ simeprevir C_min 1.49 (1.33-1.67) ↑	No dose adjustment of daclatasvir or OLYSIO is required.
Sofosbuvir² 400 mg once daily	sofosbuvir AUC 3.16 (2.25-4.44) ↑ sofosbuvir C_max 1.91 (1.26-2.90) ↑ sofosbuvir C_min not studied GS-331007 AUC 1.09 (0.87-1.37) ↔ GS-331007 C_max 0.69 (0.52-0.93) ↓ GS-331007 C_min not studied simeprevir AUC 0.94 (0.67-1.33) ↔ simeprevir C_max 0.96 (0.71-1.30) ↔ simeprevir C_min not studied	Increase in sofosbuvir exposure observed in the pharmacokinetic substudy is not clinically relevant.
HERBAL PRODUCTS
Milk thistle (Silybum marianum)	Not studied. Increased plasma concentrations of simeprevir are expected. (CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with milk thistle.
St John's wort (Hypericum perforatum)	Not studied. Significantly decreased plasma concentrations of simeprevir are expected. (CYP3A4 enzyme induction)	It is not recommended to co-administer OLYSIO with products containing St John's wort as co-administration may result in loss of therapeutic effect of OLYSIO.
HIV PRODUCTS
Antiretroviral – CCR5 antagonist
Maraviroc	Not studied. No clinically relevant drug drug-interaction is expected.	No dose adjustment is required for either drug when OLYSIO is co-administered with maraviroc.
Antiretroviral – integrase inhibitor
Raltegravir 400 mg twice a day	raltegravir AUC 1.08 (0.85-1.38) ↑ raltegravir C_max 1.03 (0.78-1.36) ↔ raltegravir C_min 1.14 (0.97-1.36) ↑ simeprevir AUC 0.89 (0.81-0.98) ↔ simeprevir C_max 0.93 (0.85-1.02) ↔ simeprevir C_min 0.86 (0.75-0.98) ↓	No dose adjustment is required.
Antiretroviral – non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg once daily	efavirenz AUC 0.90 (0.85-0.95) ↔ efavirenz C_max 0.97 (0.89-1.06) ↔ efavirenz C_min 0.87 (0.81-0.93) ↔ simeprevir AUC 0.29 (0.26-0.33) ↓ simeprevir C_max 0.49 (0.44-0.54) ↓ simeprevir C_min 0.09 (0.08-0.12) ↓ (CYP3A4 enzyme induction)	It is not recommended to co-administer OLYSIO with efavirenz as co-administration may result in loss of therapeutic effect of OLYSIO.
Rilpivirine 25 mg once daily	rilpivirine AUC 1.12 (1.05-1.19) ↔ rilpivirine C_max 1.04 (0.95-1.13) ↔ rilpivirine C_min 1.25 (1.16-1.35) ↑ simeprevir AUC 1.06 (0.94-1.19) ↔ simeprevir C_max 1.10 (0.97-1.26) ↑ simeprevir C_min 0.96 (0.83-1.11) ↔	No dose adjustment is required.
Other NNRTIs (Delavirdine, Etravirine, Nevirapine)	Not studied. Altered plasma concentrations of simeprevir are expected. (CYP3A4 enzyme induction [etravirine or nevirapine] or inhibition [delavirdine])	It is not recommended to co-administer OLYSIO with delavirdine, etravirine or nevirapine.
Antiretroviral – nucleoside or nucleotide reverse transcriptase inhibitors (N(t)RTIs)
Tenofovir disoproxil fumarate 300 mg once daily	tenofovir AUC 1.18 (1.13-1.24) ↔ tenofovir C_max 1.19 (1.10-1.30) ↑ tenofovir C_min 1.24 (1.15-1.33) ↑ simeprevir AUC 0.86 (0.76-0.98) ↓ simeprevir C_max 0.85 (0.73-0.99) ↓ simeprevir C_min 0.93 (0.78-1.11) ↓	No dose adjustment is required.
Other NRTIs (Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Zidovudine)	Not studied. No clinically relevant drug drug interaction is expected.	No dose adjustment is required.
Antiretroviral – protease inhibitors (PIs)
Darunavir/ritonavir³ 800/100 mg once daily	darunavir AUC 1.18 (1.11-1.25) ↑ darunavir C_max 1.04 (0.99-1.10) ↔ darunavir C_min 1.31 (1.13-1.52) ↑ ritonavir AUC 1.32 (1.25-1.40) ↑ ritonavir C_max 1.23 (1.14-1.32) ↑ ritonavir C_min 1.44 (1.30-1.61) ↑ simeprevir AUC 2.59 (2.15-3.11) ↑* simeprevir C_max 1.79 (1.55-2.06) ↑* simeprevir C_min 4.58 (3.54-5.92) ↑* * darunavir/ritonavir + 50 mg simeprevir compared to 150 mg simeprevir alone. (strong CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with darunavir/ritonavir.
Ritonavir¹ 100 mg twice daily	simeprevir AUC 7.18 (5.63-9.15) ↑ simeprevir C_max 4.70 (3.84-5.76) ↑ simeprevir C_min 14.35 (10.29-20.01) ↑ (strong CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with ritonavir.
Other ritonavir-boosted or unboosted HIV PIs (e.g., Atazanavir, (Fos)amprenavir, Lopinavir, Indinavir, Nelfinavir, Saquinavir, Tipranavir)	Not studied. Altered plasma concentrations of simeprevir are expected. (CYP3A4 enzyme induction or inhibition)	It is not recommended to co-administer OLYSIO with any HIV PI, with or without ritonavir.
Cobicistat-containing medicinal products	Not studied. Significantly increased plasma concentrations of simeprevir are expected. (strong CYP3A4 enzyme inhibition)	It is not recommended to co-administer OLYSIO with cobicistat-containing medicinal products.
HMG CO-A REDUCTASE INHIBITORS
Rosuvastatin 10 mg	rosuvastatin AUC 2.81 (2.34-3.37) ↑ rosuvastatin C_max 3.17 (2.57-3.91) ↑ rosuvastatin C_min not studied (OATP1B1 transporter inhibition)	Titrate the rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety when co-administered with OLYSIO.
Pitavastatin Pravastatin	Not studied. Increased plasma concentrations of pitavastatin and pravastatin are expected. (OATP1B1 transporter inhibition)	Titrate the pitavastatin and pravastatin dose carefully and use the lowest necessary dose while monitoring for safety when co-administered with OLYSIO.
Atorvastatin 40 mg	atorvastatin AUC 2.12 (1.72-2.62) ↑ atorvastatin C_max 1.70 (1.42-2.04) ↑ atorvastatin C_min not studied 2-OH-atorvastatin AUC 2.29 (2.08-2.52) ↑ 2-OH-atorvastatin C_max 1.98 (1.70-2.31) ↑ 2-OH-atorvastatin C_min not studied (OATP1B1 transporter and/or CYP3A4 enzyme inhibition) Increased simeprevir concentrations may occur due to inhibition of OATP1B1 by atorvastatin.	Titrate the atorvastatin dose carefully and use the lowest necessary dose while monitoring for safety when co-administered with OLYSIO.
Simvastatin 40 mg	simvastatin AUC 1.51 (1.32-1.73) ↑ simvastatin C_max 1.46 (1.17-1.82) ↑ simvastatin C_min not studied simvastatin acid AUC 1.88 (1.63-2.17) ↑ simvastatin acid C_max 3.03 (2.49-3.69) ↑ simvastatin acid C_min not studied (OATP1B1 transporter and/or CYP3A4 enzyme inhibition)	Titrate the simvastatin dose carefully and use the lowest necessary dose while monitoring for safety when co-administered with OLYSIO.
Lovastatin	Not studied. Increased plasma concentrations of lovastatin are expected. (OATP1B1 transporter and/or CYP3A4 enzyme inhibition)	Titrate the lovastatin dose carefully and use the lowest necessary dose while monitoring for safety when co-administered with OLYSIO.
Fluvastatin	Not studied. No clinically relevant drug-drug interaction is expected.	No dose adjustment is required.
HORMONAL CONTRACEPTIVES
Ethinylestradiol and norethindrone 0.035 mg once daily/ 1 mg once daily	ethinylestradiol AUC 1.12 (1.05-1.20) ↔ ethinylestradiol C_max 1.18 (1.09-1.27) ↑ ethinylestradiol C_min 1.00 (0.89-1.13) ↔ norethindrone AUC 1.15 (1.08-1.22) ↔ norethindrone C_max 1.06 (0.99-1.14) ↔ norethindrone C_min 1.24 (1.13-1.35) ↑	No dose adjustment is required.
IMMUNOSUPPRESSANTS
Ciclosporin 100 mg patient individualised dose⁴	ciclosporin AUC 1.19 (1.13-1.26) ↑ ciclosporin C_max 1.16 (1.07-1.26) ↑ ciclosporin C_min not studied simeprevir AUC 5.81 (3.56-9.48) ↑⁵ simeprevir C_max 4.74 (3.12-7.18) ↑⁵ simeprevir C_min not studied⁵ (OATP1B1, P-gp and CYP3A inhibition by ciclosporin)	It is not recommended to co-administer OLYSIO with ciclosporin.
Tacrolimus 2 mg patient individualised dose⁴	tacrolimus AUC 0.83 (0.59-1.16) ↓ tacrolimus C_max 0.76 (0.65-0.90) ↓ tacrolimus C_min not studied simeprevir AUC 1.85 (1.18-2.91) ↑⁶ simeprevir C_max 1.79 (1.22-2.62) ↑⁶ simeprevir C_min not studied⁶ (OATP1B1 inhibition by tacrolimus)	No dose adjustment is required for either drug when co-administered with OLYSIO. Monitoring of blood concentrations of tacrolimus is recommended.
Sirolimus	Not studied. Mild increased or decreased plasma concentrations of sirolimus may occur.
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