Sovriad - instructions for use, doses, side effects, contraindications

Active substanceSymeprevirSymeprevir

Similar drugsTo uncover

capsules inwards

Janssen-Sylag International N.V. Belgium

Dosage form: & nbspcapsules

Composition:

1 capsule contains: active ingredient - sodium simeprevir 154.40 mg (in terms of simeprivir 150.00 mg); auxiliary substances: sodium lauryl sulfate 1.25 mg, magnesium stearate 2.50 mg, silicon dioxide colloid 0.75 mg, croscarmellose sodium 12.50 mg, lactose monohydrate 78.40 mg; shell: titanium dioxide, gelatin; composition of ink: shellac, iron oxide, black, propylene glycol.

Description:

Hard gelatin capsules in the size "0" with a white body with an inscription in black ink "ТМС435 150" and a white cap. The contents of capsules are white or almost white powder.

Pharmacotherapeutic group:antiviral agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.14 Symeprevir

Pharmacodynamics:

Mechanism of action

Symeprivir is an inhibitor of the hepatitis C virus protease NS3 / 4A, which plays a key role in the replication of the virus. According to the results of a biochemical blood test simeprevir inhibited the proteolytic activity of recombinant hepatitis C virus proteases of genotypes 1a and lbNS3 / 4A with a median of Ki of 0.5 and 1.4 nmol / L, respectively.

Pharmacokinetics:

The pharmacokinetic properties of simeprevir were evaluated in adult healthy volunteers and in adult patients infected with the hepatitis C virus.The Cmax values in the plasma and the area under the concentration-time curve (AUC) after repeated administration of the drug at doses from 75 mg to 200 mg once a day increased more than in proportion to the dose; After repeated administration of the drug, its accumulation was observed. The equilibrium state was achieved after 7 days of administration once a day. The concentration of simeprevir in plasma (AUC) in patients infected with the hepatitis C virus was 2-3 times higher than the corresponding signs in healthy volunteers. The Cmax and AUC values of the simeprevir in plasma, when combined with peginterferon alfa and ribavirin, and in monotherapy with simeprevenram were similar.

Suction

The average value of bioavailability of simeprevir after a single dose of 150 mg orally during a meal is 62%. Maximum plasma concentrations (C max) are usually reached 4-6 hours after taking the drug. Studies in vitro on the culture of human cells Caco-2 showed that simeprevir is a substrate of P-glycoprotein.

Effect of food intake on the bioavailability of simeprevir

Compared to fasting with the intake of simeprevir during meals in healthy volunteers, the AUC increased by 61%after a high-calorie breakfast with a high fat content (928 kcal) and 69% after breakfast with a normal caloric content (533 kcal), while an increase in the suction time by 1 and 1.5 hours, respectively. Distribution

Simeprevir binds to a considerable extent to plasma proteins (> 99.9%), mainly with albumin and to a lesser extent with ss-acid glnkoirotein. In patients with impaired renal or hepatic function, no significant changes in binding to plasma proteins have been recorded. In animals simeprevir largely enters the intestinal and liver tissues (the ratio of liver and blood in rats is 29: 1).

Metabolism

Symeperivir is metabolized in the liver. According to the results of in vitro studies on microsomes of human liver simeprevir predominantly subjected to oxidative metabolism by means of the isoenzyme CYP3A of the liver. It is also impossible to exclude the participation of CYP2C8 and 2C19 isoenzymes.

Information on the effects of inhibitors or inducers of CYP isoenzymes on the pharmacokinetics of simeprevir, as well as information on the inhibitory potential of simeprevir for CYP isoenzymes in the section "Interaction with other drugs".

After a single dose of 200 mg of 14C-spmpecivir in a healthy volunteer, most of the radioactive material in the plasma (up to 98%) was an unchanged drug, and only a small part was metabolites (none of which was a significant metabolite). The metabolites identified in the stool were formed as a result of the oxidation of a macropylenic or aromatic group or both groups, as well as as a result of O-demethylation followed by oxidation.

Excretion

The withdrawal of simeprevir occurs with bile. Kidneys play a minor role in the excretion of the drug. After a single intake of 14C of simeprevir in a dose of 200 mg in healthy volunteers, an average of 91% of radioactive substances were secreted through the intestine, <1% of the dose given was excreted by the kidneys. Unchanged simeprevir in feces averaged 31% of the dose.

The period of semi-exposure of simeprevir with a dose of 200 mg in healthy volunteers was 10-13 hours, and in patients infected with hepatitis C virus-41 hours,

Special patient groups Children (under 18 years of age)

Studies to study the pharmacokinetics of simeprevir in children ns were conducted.

Elderly patients

There is a limited amount of data on the use of the drug Sovrirad® in patients older than 65 years. Based on the population analysis of pharmacokinetics in patients infected with the hepatitis C virus, patients who received simeprevir, age (18-73 years) had no clinically significant effect on the pharmacokinetics of simeprevir. In elderly patients, dose adjustment is not required.

Patients with impaired renal function The excretion of simeprevir by the kidneys is negligible.

Compared to patients without chronic hepatitis C with normal renal function (classified using the MDRD formula for calculating the glomerular filtration rate, the estimated glomerular filtration rate is> 80 ml / min), the mean values of AUC of the simeprevir in the equilibrium state are patients without chronic hepatitis C and with impaired renal function of a serious degree (glomerular filtration rate less than 30 ml / min) were 62% higher. Based on the studied and expected changes in the concentration of simeprevir in blood plasma, there is no need to correct the dose of Sovriad® in patients with mild, moderate and severe renal dysfunction.The efficacy and safety of the Sovriad® drug has not been studied in patients with chronic hepatitis C, with severe dysfunction or end-stage renal failure, including patients requiring hemodialysis.

Based on the results of a population analysis of pharmacokinetics in patients with impaired renal function of mild or moderate degree, with the treatment of the drug Sovriad® at a dose of 150 mg I once a day, the clearance of creatinine did not affect the parameters of the pharmacokinetics of simeprevir. Thus, clinically significant effects of mild or moderate renal dysfunction on the concentration of simeprevir are not expected. Because the simeprevir is largely associated with plasma proteins, it is unlikely to remove a significant amount of this drug through hemodialysis.

Information on the therapy with peginterferon alfa and ribavirin in patients with impaired renal function is given in the appropriate instructions for use.

Patients with hepatic impairment

Symeprevir is metabolized primarily in the liver.

The concentration of simeprevir in blood plasma in patients with hepatitis C was 2-3 times higher than that of healthy volunteers.

Compared with healthy volunteers with normal liver function in patients without hepatitis C with impaired liver function of moderate degree (class B on the Child-Pyo scale), the mean value of the SYUPEVIR AUC in the equilibrium state was 2.4 times higher, while in patients without hepatitis C with impaired hepatic function of a serious degree (class C but

scale Child-Pyo) it was higher by 5.2 times. Correction of dose of the drug Sovrirad® is not required

in patients with mild liver function disorder (Child-Pugh class A). In patients with hepatitis C with impaired liver function of moderate or severe degree (classes C and B on the Child-Pyo scale), the safety and effectiveness of simsprevir have not been studied. In clinical trials, an increase in the concentration of simeprevir in the blood caused an increase in the incidence of side effects, including rash and photosensitivity. For patients with impaired liver function of moderate or severe degree, there are no recommendations for correcting the dose of simsprevir. The potential benefits and risks of using Sovriad® should be carefully evaluated before use in patients with a moderate or severe liver dysfunction.

Based on the population analysis of pharmacokinetics in patients with hepatitis C who received the drug Sovriad, the stage of liver fibrosis did not have a clinically significant effect on the pharmacokinetics of simsprevir.

Information on the therapy with peginterferon alfa and ribavrinin is given in the relevant instructions for use.

Other patient groups

Dose adjustments are not required depending on sex, body weight or body mass index. Based on the population analysis of pharmacokinetics in patients infected with the hepatitis C virus in patients who received the medication Sovriad, these characteristics do not have a clinically significant effect on the pharmacokinetics of simsprevir.

Patients with co-infection BIP-I-1

Parameters of pharmacokinetics of simsprevir in patients with hepatitis C of genotype 1 with HIV-1 coinfection or without it were comparable.

Race

According to the results of studies in patients without hepatitis C and in patients with hepatitis C, the concentrations of simeprevir in blood plasma in Mongoloid race were higher compared to those in patients of the Caucasoid race. In the Phase 3 studies, when taking Sovriad® 150 mg once a dayday, the average concentration of simeprevir in patients of the Mongoloid race was 3.4 times higher than in all other patients. In clinical trials, higher concentrations of simeprevir in the blood caused an increase in the incidence of side effects, including rash and photosensitivity. The available safety data are not sufficient to provide any recommendations for patients of East-Asian origin.

The potential benefits and risks of using Sovriad® should be carefully evaluated before use in patients of East Asian origin.

Population pharmacokinetic analysis showed that the concentrations of simeprevir in blood plasma were comparable in patients of the European race with hepatitis C and patients of the Negroid race with hepatitis C.

Indications:

Treatment of chronic hepatitis C of genotype 1 in combination with peginterferon alfa and ribavrin in adult patients with compensated liver disease (including cirrhosis

liver), previously untreated or in whom previous treatment (based on interferon (pegylated or nspkgilirovannogo) with ribavirin or without it) wasineffective.

The drug Sovrirad® can not be used as a monotherapy.

Contraindications:

increased sensitivity to simeprevir or any auxiliary component of the drug
children under 18 years of age
pregnancy, including the pregnancy of a female partner of a man undergoing treatment with Sovrnad® in combination with peginterferon alfa and ribavirin
lactation period
lactase deficiency
lactose intolerance
glucose-galactose malabsorption
simultaneous reception with drugs that are moderate or powerful inducers or inhibitors of the isoenzyme CYP3A: anticonvulsants (carbamazepine, oxcarbzaspin, phenobarbital, phyiotonel), blockers Hi-gistaminovyh receptors (astemizole, terfenadine), antibiotics (erythromycin, clarithromycin, telithromycin), antifungal drugs for oral administration (itraconazole, kstoconazole, posaconazole, fluconazole, voriconazole), antituberculous drugs (rnfampicin, rifabutin, rifapentin), glucocorticosteroid preparations (dexamegazone for systemic use), prokinstiki (cisapride), herbal preparations (milk thistle (Silybum marianum), St. John's wort (Hypericum perforatum), drugs for the treatment of HIV infection (drugs containing cobicetate, non-nucleoside reverse transcriptase inhibitors: efavirenz, delavirdip, etravirine, nevirapine; protease inhibitors: a combination of darunavir / ritonavir, rigonavir, atazanavir, fosamprnavir, amprenavnir, lopinavir, indinavir, nelfinavir, saquinavr, tinranavir), immunosuppressants (ciclosporin)
contra-indications to therapy with peginterferon alfa and ribavirin are also applicable to combined therapy with medication Sodriad®: renal dysfunction (creatinine clearance less than 50 ml / min), decompensated cirrhosis of the liver, poor liver function of middle and severe degree (Child and Child classes B and C -Pyo). A complete list of contraindications for the therapy with peginterferon alfa and ribavirin is given in the relevant instructions for use.

Carefully:

in patients with impaired renal function of a serious degree (creatinine clearance less than 30 ml / min)
in elderly patients (age over 65)
with simultaneous administration with drugs metabolized primarily by isoenzyme CYP3A4, as well as with drugs that are substrates of P-glycoprotein: antiarrhythmic drugs (amiodarone, dsopyramide, flecainide, lidocaine (systematically), mexiletine, propafenone, хннпдин), blockers of "slow" calcium channels (amlodipine, beprideil, diltiazem, felodiinin, nicardipii, nifednin, nisoldipinn, verapamnl), sedatives / anchyolytics (midazolam, triazolam).

Pregnancy and lactation:

Pregnancy and contraceptive requirements

Comprehensive controlled clinical trials of simeprevir in pregnant women have been conducted. Studies in animals demonstrated the effect of simeprevir on reproductive function.

Application of the drug Sovriad in combination with peginterferon alfa and ribavirin is contraindicated during pregnancy, including during pregnancy of a female partner of a male receiving treatment, due to the fact that significant teratogenic and / or death-causing effects were observed with ribavirin. Care must be taken to prevent pregnancy in women undergoing treatment, as well as in female partners of men undergoing therapy.Patients who are fertile and patients with fertile partners should start taking ribavirin Only if they use a combination of two effective contraceptives throughout the treatment, and also within 6 months after its termination.

Lactation

Information on application during lactation is given in the relevant instructions for the use of peginterferon alfa and ribavirin.

It is not known whether simeprevir and its metabolites with human breast milk. When used in rats during lactation simeprevir was detected in the plasma of breast-fed rats, which was probably due to the excretion of simeprevir with breast milk. Because of the possible adverse effect of the drug Sovrirad® on infants, it is necessary to decide whether to stop breastfeeding or to opt-in / refuse therapy with the drug Sovriad * taking into account the benefits of breastfeeding for the baby and the positive effects of therapy in the mother.

Preclinical research data

There are currently no data on the effects of simeprevir on fertility in humans. During studies in animals, no effects on fertility were found.

In studies in rats and mice at doses of 0.5 times (in rats) and in 6 times (in mice) exceeding the average recommended daily dose (150 mg), there was no teratogenicity of the simeprevir.

In embryo-fetal studies in mice at doses up to 1000 mg / kg, simeprevir caused early and late death of embryos in utero, as well as early maternal mortality with doses, approximately 6 times the recommended daily dose. A significant reduction in fetal weight and an increase in the number of bone changes was observed with the administration of doses approximately 4 times the recommended daily dose.

In pre- and postnatal studies, rats took simeprevir in doses up to 1000 mg / kg / day during gestation and lactation. In pregnant rats simeprevir called early mortality when taken in a dose of 1000 mg / kg / day. A significant reduction in the rate of weight gain was observed with doses from 500 mg / kg / day. In the development of offspring of rats receiving doses of simeprevir during pregnancy or lactation, approximately equal to the recommended daily dose, there was a decrease in body weight and negative effects on growth (physical retardation and decrease in body size) and development (decreased motor activity).The subsequent survival, behavior and ability to reproduce the offspring did not change.

Dosing and Administration:

The recommended dose of Sovriad * is one capsule (150 mg) orally 1 once a day with meals. The type of food does not affect the pharmacokinetic parameters of the simeprevir. Capsules should be swallowed whole.

The drug Sovrnad can not be used as a monotherapy.

Sovrirad should be used in combination with peginterferon alfa and ribavirin. Information on the route of administration and doses of peginterferon alfa and ribavirin is given in the relevant instructions for use.

The recommended duration of therapy with the drug Sovriad in combination with peginterferon alpha and ribavirin is indicated in the table 1.

Group of Patients	Method of administration and duration of therapy
Patients with hepatitis C of genotype 1, who had not previously received therapy or had a history of relapse:
- without co-infection with HIV, with cirrhosis of the liver or without cirrhosis	*12 weeks of treatment with the drug Sovriad in combination with peginterferon alfa and ribavirin, then an additional 12 weeks of therapy with peginterferon alfa and ribavirin (the total duration of treatment is 2 <1 week)**²
- with HIV co-infection, without cirrhosis
- with HIV co-infection and liver cirrhosis	*12 weeks of treatment with Sovriad in combination with peginterferon alfa and ribavirin, followed by an additional 36 weeks of therapy with peginterferon alfa and ribavirin (the total duration of treatment is <18 weeks)**²
Patients with hepatitis C of genotype 1 whose previous therapy was ineffective³ (including no response or partial response), with cirrhosis of the liver or without cirrhosis, with HIV coinfection or without HIV co-infection	*12 weeks of treatment with Sovnarn in combination with peginterferon alfa and ribavirin, then an additional 36 weeks of peginterferon alfa and ribavirin therapy (the total duration of treatment is '18 weeks)**²
'Recurrence after previous therapy with interferon (unliped or unpaired) with or without ribavirin ² The recommended duration of therapy, provided that no withdrawal of therapy is required ³Etcdisruptive therapy with interferon (pegylated or unpegilated) with or without ribavirin

Rules for the abolition of therapy in patients receiving treatment with the drug Sovriad in

combinations with peginterferon alfa and ribavirin, are described in the table 2.

Table 2. Rules for discontinuation of therapy in patients taking the drug Sovriad * in combination with naginterferon alpha and ribavirin, from inadequate virological response to.

RNA level of hepatitis C virus	11Announcement procedure
4th week of therapy: at least 25 IU / ml	Cancel Sovriad, peginterferon alfa and ribavirin
12th week of therapy: not less than 25 IU / ml	Cancel peginterferon alfa and ribavirin
24th week of therapy: at least 25 IU / ml	Cancel peginterferon alfa and ribavirin
¹ If the hepatitis C virus RNA level is less than 25 IU / ml after the previously detected unrecoverable level, it is recommended to re-determine the level of hepatitis C virus RNA in order to confirm the values obtained before deciding to abolish therapy.

Discontinuation of therapy in patients with insufficient virologic response during treatment

Achieving a stable virologic response (SVR) in patients with an insufficient virologic response during treatment is unlikely. PTherefore, in such patients it is recommended to cancel treatment.Table 2 presents the threshold values of HCV RNA levels, which are the basis for the abolition of therapy in patients taking Sovriad '' 'in combination with peginterferon alfa and ribavirin.

In the event that peginterferon alfa or ribavirin is discontinued for any reason, therapy with the drug Sodriad® should also be canceled.

Correction of dose or suspension of therapy

To prevent ineffectiveness of therapy, it is not allowed to reduce the dose or suspend therapy with the drug Sovriad *. In the event of cancellation of therapy with the drug SORMRAD® due to the occurrence of unwanted reactions or an inadequate virologic response, resumption of therapy with this drug is not allowed.

If unwanted reactions potentially associated with peginterferon alfa or rnbavirin develop and require dose adjustment or suspension of therapy with any of these drugs, the directions in the appropriate medication should be followed.

Dose skip

If the delay in taking the drug Sovrirad® was less than 12 hours, then the missed dose should be taken as soon as possible with the beggar, and resume the usual dosing regimen.

If the delay in taking Medriad® drug was more than 12 hours, then the missed dose should not be taken; the next dose is taken at the usual time.

Special patient groups Children and adolescents (under 18 years of age)

The safety and efficacy of the drug Sovriad® in children and adolescents has been studied.

Elderly patients (over 65 years of age)

Data on the safety and efficacy of the drug Sorrow * in patients over 65 years of age are limited. Dose adjustments in elderly patients are not required.

Impaired renal function

Correction of the dose of the drug Sovriad * in patients with mild and moderate renal dysfunction is not required. The safety and efficacy of the drug Sovriad * in patients with impaired renal function of severe degree (creatinine clearance less than 30 ml / min) or terminal stage of renal failure, including patients on hemodialysis, has not been studied.Simenrevir is characterized by a high degree of binding to blood plasma proteins. Thus, hemodialysis with a high degree of probability does not lead to a significant withdrawal of simeprevir.

Information on the use of pegingerferon alfa and ribavirin in patients with impaired renal function is given in the relevant instructions for use.

Impaired liver function

It is not possible to provide any recommendations for dose adjustment in patients with moderate or severe liver dysfunction (Child-Pugh class B or C) due to higher concentrations of the symptomovirus in the blood. In clinical trials, increasing the concentration of simeprevir in the blood in these patients caused an increase in the incidence of side effects, including rash and photosensitivity. The efficacy and safety of the Sovriad * drug has not been studied in patients with hepatitis C and with poor liver function of medium and severe degree (Child B or C grade Child-Pyo). The use of a combination of peginterferon alfa and ribavirin is contraindicated in patients with decompensated liver cirrhosis (dysfunction of moderate and severe liver function).The potential benefit and risk of using Sovriad * should be carefully evaluated before use in patients with impaired liver function of moderate to severe severity.

Co-infection with human immunodeficiency virus type 1 (HIV-1)

In patients with hepatitis C and coinfection with HIV-1, dosage adjustment of the drug Sovrirad® is not required.

In the case of using Sovriad * in combination with peginterferon alfa and ribavirip, patients with co-infection with hepatitis C and HIV-1, regardless of the result of previous therapy for hepatitis C, should undergo treatment of the same duration as patients without co-infection. If a patient with co-infection has cirrhosis, then after 12 weeks of treatment with Sovriad® plus peginterferon alfa and ribavirin, continue therapy with peginterferon alfa and ribavirip for 36 weeks (the total duration of treatment is 48 weeks).

Race

In patients of East Asian origin, higher concentrations of simeprevir in the blood plasma are found. In clinical trials, higher concentrations of simeprevir in the blood caused an increase in the incidence of side effects, including rash and photosensitivity.The available safety data are not sufficient to provide any recommendations for patients of East Asian origin. The potential benefits and risks of using Sovriad® should be carefully evaluated before use in patients of East Asian origin.

Side effects:

The medicinal preparation of Sorrow should be used in combination with peginterferon alfa and ribavirin. Unwanted reactions observed with therapy peginterferon alpha and ribavirin, are described in the respective instructions for use.

The overall safety profile of the drug for combination Sovriad drug when used in combination with peginterferoiom alpha and ribavirin of patients with hepatitis C genotype 1Previously untreated therapy inefficiency or previous treatment by interferon with or without ribavirin, based on an aggregate data from two clinical trials IIb phase (studies of C205 and C206) and 3 clinical trials of phase III (studies of C208, C216 and HPC3007). Consolidated data from Phase II and Phase III studies included information on I486 patients taking simeprevir in combination with peginterferoea alfa and ribavirin (of which 924 patients were taking simeprevir in a dose of 150 mg I once a day for 12 weeks), and 540 patients receiving a placebo with peginterferon alfa and ribavirin.

The table below lists the undesirable reactions of at least moderate severity (ie, the degree> 2), registered with patients during 12-week therapy with medication Sovriad in a dose of 150 mg 1 time per day or placebo in combination with peginterferoioma alpha and ribavirin according to the combined data from phase III studies (studies C208, C216 and HPC3007). These side effects are listed in accordance with the system-organ classes and frequency. No other side effects have been reported in the remaining clinical trials.

In summary safety data from phase III studies, the majority of reported adverse reactions during a 12-week therapy with the drug Sovriad were severely related to grade 1 or 2. Side effects of grade 3 or 4 were reported in 2.8% of patients receiving medication Sovriad in combination with peginterferoea alfa and ribavirin, and in 0.5% of patients from placebo groups with peginterfero alfa and ribavirin.Serious side effects were reported in 0.3% of patients who received simeprevir, while there were no such reactions in placebo groups with peginterferoal alpha and ribavirin. The withdrawal of the drug Sovriad * or placebo due to adverse reactions was required in 0.9% and 0.3% of patients who received simeprevir with peginterferoea alfa and ribavirin or placebo with peginterferon alfa and ribavirin, respectively.

The safety profile of the drug Sovrirad® is comparable in patients with hepatitis C of genotype 4 (N = 107) and genotype 1.

Table. Side effects of at least moderate severity (i.e., degrees 2-4¹), registered in adult patients with hepatitis C of genotype 1 (based on the results of Phase III studies C208, C216 and HPC3007, the first 12 weeks of therapy, and the analysis according to the prescribed treatment).

System of organs	Sovriad^® + peginterferon alfa + ribavirin N = 781; n (%)	Placebo + peginterferon alfa + ribavirin N = 397; n (%)
From the gastrointestinal tract
Constipation²	2 (0.3%)	2 (0.5%)
From the liver and biliary tract
Increased level of bilirubin in the blood³	42 (5.4%)	9 (2.3%)
From the skin and subcutaneous tissue
Rash⁴	59 (7.6%)	15 (3.8%)
Itching⁵	24 (3.1%)	3 (0.8%)
Photosensitivity reaction⁶	6 (0.8%)	0 (0.0%)
On the part of the respiratory system, the organs of the thorax and the mediastinum
Dyspnea⁷	92 (12%)	30 (8%)

¹ - in accordance with the WHO toxicity assessment scale.
² - The group term "constipation" includes the preferred term constipation.
³ - The group term "increase in bilirubin level in the blood" includes the following preferred terms: increasing the level of conjugated bilirubin, increasing the level of bilirubin in the blood, increasing the level of unconjugated bilirubin and hyperbilirubinemia.
⁴ - the group term "rash" includes the following preferred terms: blister, medicinal dermatitis, erythema, erythema eyelids, exfoliative rash, generalized edema, macula, palmar erythema, papule, pink lichen, mild polymorphic rashes, rash, erythematous rash, follicular rash, generalized rash , macular rash, maculopapular rash, korepodobnaya rash, papular rash, itching rash, pustular rash, erythema of scrotum, skin peeling, skin irritation, skin reaction, toxic skin rashes, umbilical cord Erythema and vasculitic rash.
⁵ - The group term "pruritus" includes the following preferred terms: itchy eyelids, prurigo, pruritus and generalized pruritus.
⁶- The group term "photosensitivity reaction" includes the followingpreferred terms: photodermatosis, photosensitivity reaction, solar dermatitis and sunburn.
⁷ - The group term "dyspnea" includes the preferred term dyspnoea and shortness of breath during physical exertion.

Rashes and itching

For 12 weeks of treatment with the drug Sovrirad®, rashes and pruritus were recorded in 21.8% and 21.9% of enemprevir-treated patients compared to 16.6% and 14.6% of patients in the placebo group with peginterferon alfa and ribavirin , respectively. Most of the manifestations of rash and itching in patients taking the drug Sovriad® were light or medium-heavy (grades 1 or 2). A rash or itching of grade 3 was recorded in 0.5% and 0.1% of patients who received simeprevir, respectively. No reports of rash or itching of grade 4 are reported. The termination of therapy with the drug Sodriad® due to rash or pruritus was required in 0.8% and 0.1% of patients who used simervsir, compared with 0.3% and 0% of patients in the placebo group with peginterferon alfa and ribavirin, respectively.

Shortness of breath

During 12 weeks of therapy, dyspnea was noted in 12% of patients in the group receiving the drug Sovriad * compared with 8 % of patients in the placebo group. All cases of dyspnea in patients who received the drug Sovriad '⁵⁴', were of mild or moderate severity (1st and 2nd degree). Dyspnea of grade 3 or 4 did not occur. In addition, no patient stopped treatment due to dyspnea. 61% of all dyspnea cases were noted during the first 4 weeks of therapy with the drug Sovriad *.

Increased bilirubin concentration

Over the course of 12 weeks of therapy with the drug Sovriad^L an increase in the concentration of bilirubin in the blood was recorded in 7.4% of patients who received simvsvnr in comparison with 2,8% of patients treated with placebo with peginterferon alfa and rpbavirin. An increase in the concentration of bilirubin in blood of grade 3 or 4 was recorded in 2% and 0.3% of patients taking Medriad *, respectively (according to the results of Phase II studies). Discontinuation of therapy with epremeprovir due to increased bilirubin concentration in the blood was rarely required (0,1%; n =1). The increase in direct and indirect bilirubin was predominantly mild or of moderate severity and was reversible. Increases in bilirubin concentrations were usually accompanied by an increase in the level of liver transaminases and were due to a decrease in the elimination of bilirubin due to inhibition of the transport proteins of GAAT1B1 gayatocytes MRP2 under the influence of the simeirevnra.These changes are not considered clinically significant.

Photosensitivity reactions

During the 12-week therapy with the drug Sovriad *, photosensitivity reactions were registered in 4.7% of patients from the group of simepsvir in comparison with 0,8% of patients in the placebo group with peginterferon alfa and rpbavirin. Most photosensitivity reactions in patients taking the drug Sovriad * were light or of medium severity (grades 1 or 2); In 0.1% of enemprevir-treated patients, grade 3 reaction data were recorded. Photosensitivity reactions of degree 4 were not observed. None of the patients did not stop therapy due to the appearance of photosensitivity reactions.

Deviations from laboratory indicators

Differences in the level of hemoglobin or the number of neutrophils and platelets between the groups are not recorded. The deviations in the course of therapy from laboratory parameters that were registered with greater frequency with the treatment of the drug Sovriad * in comparison with the combination of placebo with peginterferon alfa and ribavirin are given in the table below.

Table 4.The deviations in the course of treatment from laboratory indicators (with the highest degree of toxicity on the WHO scale from 1 to 4), registered with a higher frequency during therapy with the drug Sovrirad^® (based on the results of phase III studies C208, C216 and HPC3007, the first 12 weeks of therapy, the analysis according to the prescribed treatment)

Laboratory indicators	Range for appropriate degree of toxicity by WHO	Sovriad^®+ peginterferon alfa + ribavirin N = 781 n (%)	Placebo + peginterferon alfa + ribavirin N = 397 n (%)
Blood chemistry
Alkaline phosphatase
Degree 1	from ≥1.25 to ≤2.50 VGN	26 (3.3%)	5 (1.3%)
Degree 2	from> 2.50 to ≤5.00 VGN	1 (0.1%)	0 (0%)
Hyperbilirubinemia
Degree 1	from ≥1.1 to ≤1.5 VGN	208 (26.7%)	61 (15.4%)
Degree 2	from> 1.5 to ≤2.5 VGN	143 (18.3%)	36 (9.1%)
Degree 3	from> 2.5 to ≤5.0 VGN	32 (4.1%)	6 (1.5%)
Degree 4	from> 5.0 VGN	3 (0.4%)	0 (0%)

VGN = upper limit of normal
No deviations from alkaline phosphatase level 3 or 4

Additional information on special patient groups Patients with HIV-1 coinfection

Safety profile of medicinal product in combination with peginterferon alfa and ribavirin in patients with hepatitis C of genotype I with codification of HIV-1 (N = 106) and without it comparable.

Overdose:

Symptoms

Information on the overdose of simeprevir in humans is limited. With a single admission of simeprevir in doses up to 600 mg or with repeated intake in doses up to 400 mg once a day for 5 days in healthy adult volunteers, and at a dose of 200 mg once a day for 4 weeks in adult patients with hepatitis With this drug, as a rule, was transferred well.

Treatment

The specific antidote is unknown. In case of an overdose, supportive therapy and patient monitoring are recommended.

Simeprswire is characterized by a high degree of binding to blood plasma proteins, therefore hemodialysis with a high degree of probability will not lead to significant excretion of simeprevir.

Interaction:

The main isoenzyme involved in the metabolism of simeprevir is CYP3A. Thus, it is possible to develop isoenzyme mediated CYP3A clinically significant effects of other drugs on the pharmacokinetics of simeprevir.

Symeprivir does not induce the action of isozymes CYP1A2 or ZA4 in human hepatocytes. Based on research results in vitro simeprevir is a moderate inhibitor of isozyme activity CYP2A6, 2C8 and 2D6 (values IC50 > 32 μg / ml) and a weak inhibitor of isoenzymes CYP2C19 and ЗЛ (values of 1С₅o> 64 μg / ml). Symeprevir is not a clinically significant inhibitor of the enzymatic activity of cathusine A (IC50 > 37 μg / ml).

According to the study in vitro Symeprevir is a substrate of transport proteins of drugs, including P-glycoprotein, MRP2, BCRP, OATP1B1, OATP2B1 and OATPIB3. Simeprevir inhibits the transport proteins of the capture of OATP1B1 and NTCP, as well as transport proteins of active excretion from the cell P-glycoprotein / MDRI, MRP2 and I3SEP. The proteins OATP1BI and MRP2 participate in the transport of bilirubin to hepatocytes and back. Combined use of simerevir with potent or moderate isoenzyme inhibitors CYP3A can lead to a significant increase in the concentration of simeprevir in the plasma, while a joint application with powerful or moderate isoenzyme inducers CYP3A can significantly reduce the concentration of simeprevir in the plasma and lead to a loss of its effectiveness. Thus, it is not recommended to use the medication Sovrirad® together with substances that are potent or moderate inhibitors or inducers of isoenzyme activity CYP3A.

Simeprevir is a weak inhibitor of isozyme activity CYP1A2 and SA4 in the intestine, while the effect on isoenzyme activity CYP3A4 in the liver is absent. The joint use of the drug Sovrirad® with preparations metabolized predominantly by isoenzyme CYP3.A4, can lead to an increase in the concentration of these drugs in the plasma.

The combined use of the drug Sovrirad® with preparations that are substrates of transport proteins OATP1131 and P-glycoprotein can lead to an increase in the concentration of such drugs in plasma.

The table below provides information on known and theoretically proposed interactions between simeprevir and other drugs (average values of changes in pharmacokinetic parameters calculated by least squares are presented at 90% confidence interval, the increase is indicated by the symbol "↑", the decrease is"↓", the absence of changes -" <-> ", if the interaction was not evaluated -" n / o. ") Information on the interaction of peginterferon alfa and ribavirin with other drugs is given in the relevant instructions for use.

A medicinal preparation used together with simeprevir	The dose of the drug used in conjunction with simeprevir	A medicinal preparation for which the change in pharmacokinetic parameters	C_max	AUC	C_min
Psychostimulating agents
Caffeine¹	150 mg	caffeine	↔1.12 (1.06-1.19)	↑1.26 (1.21-1.32)	but
	When the combined use of simeprevir with caffeine, dose adjustment is not required.
Antiarrhythmic drugs
Digoxin¹	0.25 mg	digoxin	↑ 1.31 (1.14-1.51)	↑ 1.39 (1.16-1.67)	but
	The simultaneous use of simeprevir with digoxin leads to an increase in digoxin concentration due to the inhibition of P-glycoprotein by simeprevir. When combined with simeprevir, it is necessary to monitor digoxin concentrations, taking into account the obtained values of the change in pharmacokinetic parameters, when titrating the dose of digoxin in order to obtain the desired clinical effect.
Amiodarone, Dysopyramide, Flecainide, Lidocaine (systematically), Mexiletin, Propafenone, Quinidine	The simultaneous use of simeprevir with these antiarrhythmic drugs can lead to a moderate increase in their concentrations due to inhibition of the isoenzyme СUR3А4 in the intestine under the influence of simeprevir.In such cases, care must be taken. In addition, in the case of joint use of these drugs with simeprevir, a therapeutic (if available) and / or drug monitoring (eg, ECG) is recommended.
Indirect anticoagulants
Warfarin¹	10 mg	S-warfarin	↔1.00 (0.94-1.06)	↔1.04 (1.00-1.07)	but
	With the simultaneous use of simeprevir with warfarin, dose adjustment is not required. Nevertheless, monitoring of INR is recommended.
Anticonvulsants
Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin	With the simultaneous use of simeprevir with carbamazepine, oxcarbazepine, phenobarbital or phenytoin, a significant decrease in the concentration of simeprevir in the plasma is possible due to the powerful inducing action of these anticonvulsants on the isoenzyme SUR3A. This may lead to a decrease in the therapeutic effect of simeprevir. The combined use of simeprevir with these anticonvulsants is not recommended.
Antidepressants
Escitalopram¹	10 mg 1 time / day	escitalopram	↔1.03 (0.99-1.07)	↔1.00 (0.97-1.03)	↔1.00 (0.95-1.05)
		simeprevir	↓ 0.80 (0.71-0.89)	↓0.75 (0.68-0.83)	↓0.68 90.59-0.79)
	Joint use of simeprevir with escitalopram leads to a decrease in the concentration of simeprevir in plasma.This decrease is not regarded as clinically significant. Correction of the dose of both drugs in the joint use of simeprevir and escitalopram is not required
Blockers H₁-gistaminovyh receptors
Astemizole, Terfenadine	Astemizole and terfenadine are potentially capable of causing arrhythmia. The combined use of simeprevir with astemizole and terfenadine may result in a slight increase in the concentration of these antihistamines due to inhibition of the isoenzyme CUR3A4 in the intestine by the action of simeprevir. The combined use of simeprevir with astemizole or terfenadine is not recommended.
Preparations for the prevention and treatment of infections
Antibiotics (systemic application)
Azithromycin	With the joint use of simeprevir with azithromycin, dose adjustment is not required.
Erythromycin¹	500 mg 3 times / day	erythromycin	↑ 1.59 (1.23-2.05)	↑ 1.90 (1.53-2.36)	↑ 3.08 (2.54-3.73)
		simeprevir	↑ 4.53 (3.91-5.25)	↑ 7.47 (6.41-8.70)	↑ 12.74 (10.19-15.93)
	The combined use of simeprevir with erythromycin results in a significant increase in the concentrations of both erythromycin and simeprevir in the plasma due to inhibition of the activity of the isoenzyme CUR3A and P-glycoprotein and erythromycin, and simeprevir.When systemic therapy with erythromycin is not recommended for joint use with simeprevir.
Clarithromycin, Telithromycin	The combined use of simeprevir with clarithromycin or telithromycin may lead to an increase in the concentration of the simeprevir in the plasma due to inhibition of the isoenzyme CUR3A under the action of these antibiotics. The combined use of simeprevir with clarithromycin or telithromycin is not recommended.
Antifungal drugs (systemic use)
Itraconazole, Ketoconazole, Posaconazole	Systemic use of itraconazole, ketoconazole or posaconazole in conjunction with simeprevir may lead to a significant increase in plasma concentration of the simeprivir due to the potent inhibitory effect of these antifungals against the activity of the CYP3A isoenzyme. The combined use of simeprevir with itraconazole, ketoconazole or posaconazole (for systemic therapy) is not recommended.
Fluconazole, Voriconazole	The simultaneous use of simeprevir with voriconazole or fluconazole (with their systemic application) may lead to an increase in the concentrations of simeprevir in the plasma due to a weak ormoderate inhibition of the activity of the CYP3A isoenzyme under the action of these antifungal agents. The combined use of simeprevir with voriconazole or fluconazole is not recommended.
Anti-TB drugs
Bedakvilin	When the combined use of simeprevir with bedakvilinom correction of the dose is not required.
Rifampicin^1,2	600 mg 1 time / day	rifampin	↔0.92 (0.80-1.07)	↔1.00 (0.93-1.08)	but
		25-Deacetyl-riampine	↔1.08 (0.98-1.19)	↑ 1.24 (1.13-1.36)	but
		simeprevir	↑ 1.31 (1.03-1.66)	↓ 0.52 (0.41-0.67)	↓ 0.08 (0.06-0.11)
	The simultaneous use of simeprevir with rifampicin / rifampin leads to a significant decrease in the concentration of simeprevir in plasma due to the induction of activity of the isoenzyme CYP3A4 under the action of rifampicin. This can lead to a loss of the therapeutic effect of simeprevir. The combined use of simeprevir with rifampicin is not recommended.
Rifabutin, Rifapentin	The simultaneous use of simeprevir with rifabutin or rifapentin can lead to a significant decrease in the concentrations of simeprevir in plasma due to the induction of the activity of the CYP3A4 isoenzyme under the action of these drugs. As a consequence, the loss of the therapeutic effect of simeprevir is possible. The combined use of simeprevir with rifabutin or rifapentin is not recommended.
Opioid cough opioids
Dextromethorphan¹	30 mg	dextromethorphan	↑ 1.21 (0.93-1.57)	↑ 1.08 (0.87-1.35)	but
		dextrofane	↔1.03 (0.93-1.15)	↔1.09 (1.03-1.15)	but
	With the simultaneous use of simeprevir with dextromethorphan, dose adjustment is not required.
Blockers of slow calcium channels
Amlodipine, Bepridil, Diltiazem, Felodipine, Nicaradipin, Nifedipine, Nisoldipin, Verapamil	With the simultaneous use of simeprevir with slow calcium channel blockers, an increase in the concentration of slow calcium channel blockers in plasma can be caused by inhibition of the CYP3A4 isoenzyme in the intestine and / or P-glycoprotein by the action of simeprevir. In the case of simultaneous use of simeprevir with slow calcium channel blockers (when administered orally), it is recommended that precautions be taken, as well as clinical monitoring of patients.
Glucocorticosteroid agents
Dexamethasone (systemic application)	Symeperivir therapy in combination with systemic administration of dexamethasone can lead to a decrease in plasma concentrations of the simeprevir as a result of a moderate inducing effect of dexamethasone on the activity of cytochrome P450 3A4. This can lead to a loss of the therapeutic effect of simeprevir.Joint use of simeprevir with dexamethasone (systemic) is not recommended
Budesonide, Fluticasone, Methylprednisolone, Prednisone	When combined use of simeprevir with budesonide, fluticasone, methylprednisolone, or prednisone, dose adjustment is not required
Preparations for the treatment of digestive diseases
Antacid preparations
Aluminum or Magnesium hydroxide, Calcium carbonate etc.	In the case of joint use of simeprevir with antacids, clinically significant interaction is not expected. When the combined use of simeprevir with antacids, dose adjustment is not required
The antagonists of H₂-gistaminovyh receptors
Cimetidine, Nisatidine, Ranitidine etc.	In the case of simultaneous application of simeprevir with H antagonists₂-gistaminovyh receptors clinically significant interaction is not expected. When combined use of simeprevir with H antagonists₂-gistamine receptor dosage correction is not required.
Prokinetics
Cisapride	Cisapride is potentially capable of causing arrhythmia. With the simultaneous use of simeprevir with cisapride, an increase in the concentration of cisapride in plasma is possible as a result of inhibition of the isoenzyme CUR3A4 in the intestine by the action of simeprevir.The combined use of simeprevir with cisapride is not recommended.
Proton pump inhibitors
Omeprazole¹	40 mg	omeprazole	↑1.14 (0.93-1.39)	↑1.21 (1.00-1.46)	but
	The combined use of simeprevir with omeprazole results in an increased concentration of omeprazole in plasma. However, no clinically significant increase in concentration is expected. Correction of the dose in the case of the use of simeprevir with omeprazole is not required.
Other proton pump inhibitors, for example, Dexlensoprazole, Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole	With the simultaneous use of simeprevir with proton pump inhibitors, no clinically significant interaction is expected. In the case of simultaneous application of simeprevir with proton pump inhibitors, dose adjustment is not required.
Preparations for the treatment of hepatitis C
Antiviral drugs
Sofosbuvir³	400 mg 1 time / day	sophosbuvier	↑1.91 (1.26-2.90)	↑3.16 (2.25-4.44)	but
		GS-331007	↓0.69 (0.52-0.93)	↔1.09 (0.87-1.37)	but
		simeprevir	↔0.96 (0.71-1.30)	↔0.94 (0.67-1.33)	but
	The combined use of simeprevir with cofosbuvir resulted in an increase in the concentration of cofosbuvir in the plasma without any change from the level of its nucleotide metabolite GS-331007 or simeprevir. The increase in concentration of sophosbuvira is not clinically significantdue to the low and persistent concentration of these substances for a short period of time relative to the total concentration of drug-related compounds.
Herbal preparations
Milk thistle (Silybum marianum)	The simultaneous use of simeprevir with preparations of milk thistle can lead to an increase in the concentration of the simeprevir in the plasma due to inhibition of the isoenzyme CUP3A under the action of this herbal preparation. The combined use of simeprevir with thyme spotted is not recommended.
Hypericum perforatum (Hypericum perforatum)	The simultaneous use of simeprevir with preparations containing St. John's Wort perfume can lead to a significant decrease in the concentration of simeprevir in the plasma as a result of the inducing effect of St. John's Wort on the activity of the isoenzyme СUR3A. This can lead to a loss of the therapeutic effect of simeprevir. The combined use of simeprevir with preparations containing St. John's wort is not recommended.
Preparations for the treatment of HIV infection
Preparations containing a cobicystate (elvitegravir / cobicystate / emtricitabine / tenofovir disoproxil fumarate)	The combined use of simeprevir and drugs containing the co-cystitis (elvitegravir / cobicystate / emtricitabine / tenofovir dizoproxil fumarate) can lead to a significant increase in the concentration of simeprevir in the plasma due to the potent inhibitory effect of the co-bicystate against the isoenzyme CUR3A. The combined use of simeprevir with a co-bicystate is not recommended.
Antiretroviral drugs are the antagonists of the chemokine 5 receptor (CCR5)
Maraviroc	The combined use of simeprevir with maraviroc is not expected to result in a clinically significant interaction. In the case of simultaneous administration of simeprevir with maraviroc, dose adjustment of these drugs is not required.
Antiretroviral drugs - integrase inhibitors
Raltegravir¹	400 mg 2 times / day	raltegravir	↔1.03 (0.78-1.36)	↑1.08 (0.85-1.38)	↑1.14 (0.97-1.36)
		simeprevir	↔0.93 (0.85-1.02)	↔0.89 (0.81-0.98)	↓0.96 (0.75-0.98)
	With the simultaneous use of simeprevir with raltegravir, dose adjustments of both drugs are not required.
Antiretroviral drugs are non-nucleoside reverse transcriptase inhibitors
efavirenz¹	600 mg 1 time / day	efavirenz	↔0.97 (0.89-1.02)	↔0.90 (0.85-0.95)	↔0.87 (0.08-0.12)
		simeprevir	↓0.49 (0.44-0.54)	↓0.29 (0.26-0.33)	↓0.09 (0.08-0.12)
	with the simultaneous use of simeprevir with efavirenz, a significant decrease in the concentration of simeprevir in the plasma was observed due to the inducing effect of efavirenz on the activity of the isoenzyme sup3a.this can lead to a loss of the therapeutic effect of simeprevir. simultaneous use of simeprevir and efavirenz is not recommended.
rilpivirine¹	25 mg 1 time / day	rilpivirine	↔1.04 90.95-1.13)	↔1.12 (1.05-1.19)	↑1.25 (1.16-1.35)
		simeprevir	↑1.10 (0.97-1.26)	↔1.06 (0.94-1.19)	↔0.96 (0.83-1.11)
	in the case of simultaneous application of simeprevir with rilpivirin, dose adjustment of both drugs is not required.
other non-nucleoside reverse transcriptase inhibitors (delavirdine, etravirine, nevirapine)	the combined use of simeprevir with delavirdine, etravirine, or nevirapine may result in a change in the concentration of simeprevir in plasma due to inhibition (delavirdine) or induction (etravirine and nevirapine) activity of the isoenzyme sup3a under the action of these drugs. simultaneous use of simeprevir with delavirdine, etravirine or nevirapine is not recommended.
antiretroviral drugs - nucleoside or nucleotide reverse transcriptase inhibitors
tenofovir disoproxyl fumarate¹	30 mg 1 time / day	tenofovir	↑1.19 (1.10-1.30)	↔1.18 (1.13-1.24)	↑1.24 (1.15-1.33)
		simeprevir	↓0.85 (0.73-0.99)	↓0.86 (0.76-0.98)	↓0.93 (0.78-1.11)
	in the case of the simultaneous use of simeprevir with tenofovir disoproxil fumarate, dose adjustment of both drugs is not required.
other nucleoside or nucleotide reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine)	with the simultaneous use of simeprevir with these drugs, clinically significant interaction is not expected, since these nucleoside or nucleotide reverse transcriptase inhibitors and simeprevir are characterized by different ways of elimination. correction of the dose of simeprevir in the case of joint application with these drugs is not required.
antiretroviral drugs - protease inhibitors
darunavir / ritonavir^1,4	^{800 mg / 100 mg 1 time / day}	darunavir	↔1.04 (0.99-1.10)	↑1.18 (1.11-1.25)	↑1.31 (1.13-1.52)
		simeprevir	↑1.79 (1.55-2.06)	↑2.59 (2.15-3.11)	↑4.58 (3.54-5.92)
	the simultaneous use of simeprevir with the darunavir / ritonavir combination resulted in an increase in the concentration of the simeprevir in the plasma due to inhibition of the activity of the isoenzyme sup3a under the action of the darunavir / ritonavir combination. The simultaneous use of darunavir / ritonavir with simeprevir is not recommended.
ritonavir^1,2	100 mg 2 times / day	simeprevir	↑4.70 (3.84-5.76)	↑7.18 (6.63-9.15)	↑14.35 (10.29-20.01)
	with the simultaneous use of simeprevir with ritonavir, there was a significant increase in plasma concentrations of simeprevir due to the possible inhibitory effect of ritonavir in relation toactivity of the isoenzyme sup3a. simultaneous use of simeprevir and ritonavir is not recommended.
other protease inhibitors with or without ritonavir, eg atazanavir, fosamprenavir, amprenavir, lopinavir, indinavir, nelfinavir, saquinavir, tipranavir	the simultaneous use of simeprevir and protease inhibitors with or without ritonavir enhancement may lead to a change in the concentrations of simeprevir in the plasma due to the inhibitory or inducing effect of these drugs with respect to the activity of the isoenzyme sup3a. the combined use of simeprevir with any HIV protease inhibitor in combination with or without ritonavir is not recommended.
inhibitors of GMG-co-reductase
rosuvastatin¹	10 mg	rosuvastine	↑3.17 (2.57-3.91)	↑2.81(2.34-3.37)	but
	with the simultaneous use of simeprevir with rosuvastatin, an increase in rosuvastatin concentration in plasma was observed due to the inhibitory effect of simeprovir against oatp1b1 activity. in the case of simultaneous application with simeprevir, careful titration of the dose of rosuvastatin with the minimum required dose should be used when monitoring safety.
pituastatin, pravastatin	the combined use of simeprevir with Pitavastatin or Pravastatin may lead to an increase in the concentrations of Pitavastatin or Pravastatin in plasma due to the inhibition of oatp1b1 by the action of simeprevir. in the case of simultaneous use with simeprevir, careful titration of the dose of Pitavastatin and Pravastatin should be made using the minimum required dose on the background of safety monitoring.
atorvastatin¹	40 mg	atorvastatin	↑1.70 (1.42-2.04)	↑2.12 (1.72-2.62)	but
		2-hydroxy-atorvastatin	↑1.98 (1.70-2.31)	↑2.29 (2.08-2.52)	but
	the simultaneous use of simeprevir with atorvastatin resulted in an increase in the concentration of atorvastatin in plasma due to the inhibitory effect of simeprevir in relation to the activity of oatp1b1 and / or the isoenzyme of sup3a4. in the case of simultaneous use with simeprevir, careful titration of the dose of atorvastatin should be performed using the minimum required dose on the background of safety monitoring.
simvastatin¹	40 mg	simvastatin	↑1.46 (1.17-1.82)	↑1.51 (1.32-1.73)	but
		simvastatin acid	↑3.03 (2.49-3.69)	↑1.88 (1.63-2.17)	but
	the simultaneous use of simeprevir with simvastatin resulted in an increase in the concentration of simvastatin in plasma due to the inhibitory effect of simeprevir in relation to the activity of oatp1b1 and / or the isoenzyme cyp3a4.in the case of simultaneous use with simeprevir, careful titration of the dose of simvastatin should be made using the minimum necessary dose on the background of safety monitoring.
lovastatin	the simultaneous use of simeprevir with lovastatin resulted in an increase in the concentration of lovastatin in plasma due to the inhibitory effect of simeprevir in relation to the activity of oatp1b1 and / or the isoenzyme cyp3a4. in the case of simultaneous use with simeprevir, careful titration of the dose of lovastatin should be made using the minimum required dose on the background of safety monitoring.
fluvastatin	with the simultaneous use of simeprevir with fluvastatin, clinically significant interaction is not expected. in the case of simultaneous application of simeprevir with fluvastatin, dose adjustment is not required.
hormonal contraceptive drugs
ethinyl estradiol¹,norethindrone¹	0.035 mg 1 time / day	ethinyl estradiol	↑1.18 (1.09-1.27)	↔1.12 (1.05-1.20)	↔1.00 (0.89-1.13)
	1 mg 1 time / day	norethindrone	↔1.06 (0.99-1.14)	↔1.15 (1.08-1.220	↑1.24 (1.13-1.35)
	with the simultaneous use of simeprevir with contraceptive medications based on estrogen and / or progesterone, dose adjustment is not required. due to significant teratogenic and / or death-leading embryo effectsribavirin during the therapy with this drug should use two effective methods of contraception.
immunosuppressants
ciclosporin¹	100 mg	ciclosporin	↑1.16 (1.07-1.26)	↑1.19 (1.13-1.36)	but
	with the simultaneous use of simeprevir with cyclosporin, dose adjustment is not required. it is recommended to monitor the concentration of cyclosporine in the blood.
tacrolimus¹	2 mg	tacrolimus	↓0.76 ()0.65-0.90)	↓0.83 (0.59-1.16)	but
	with the simultaneous use of simeprevir with tacrolimus, dose adjustment is not required. it is recommended that the concentration of tacrolimus in the blood be monitored.
sirolimus	with the simultaneous use of simeprevir with sirolimus, a slight increase or decrease in the concentrations of sirolimus in the plasma is possible. it is recommended to monitor the concentration of sirolimus in the blood.
narcotic analgesics
methadone⁵	30-150 mg 1 time / day, individual dose selection	r (-) methadone	↔1.03 (0.97-1.09)	↔0.99(0.91-1.09)	↔1.02 (0.93-1.12)
	with the simultaneous use of simeprevir with methadone, dose adjustment is not required.
buprenorphine, naloxone	with the simultaneous use of simeprevir with buprenorphine or naloxone, dose adjustment is not required.
inhibitors of phosphodiesterase type 5
sildenafil, tadalafil, vardenafil	when simpevir is used together with phosphodiesterase type 5 inhibitors, it is possible to have a mildincrease in the concentration of inhibitors of fde-5 due to inhibition of the isoenzyme of cyp3а4 intestines under the action of simeprevir. with the simultaneous use of simeprevir with sildenafil, vardenafil or tadalafil (intended for the treatment of erectile dysfunction), dose adjustment is not required. it may be necessary to adjust the dose of the inhibitor fde-5 in the case of the simultaneous use of simeprevir with sildenafil or tadalafil, prescribed for a long term for the therapy of pulmonary arterial hypertension. should consider the possibility of initiating therapy with an inhibitor of FED-5 at a minimal dose, after which it should be increased as needed against a background of appropriate clinical monitoring.
sedatives / anxiolytics
midazolam¹	0.075 mg / kg orally	midazolam	↑1.31 (1.19-1.45)	↑1.45 (1.35-1.57)	but
	0.025 mg / kg intravenously	midazolam	↓0.78 (0.52-1.17)	↑1.10 (0.95-1.26)	but
	with the simultaneous use of simeprevir with midazolam taken internally, an increase in midazolam plasma concentration was observed as a result of the weak inhibitory effect of the simeprevir against the activity of the isoenzyme cyp3a4 of the intestine. In the case of intravenous administration of midazolam, the effect on plasma concentration was absent, since simeprevir does not inhibit the activity of the isoenzyme of cyp3a4 of the liver. Due to the narrow therapeutic range of midazolam, when taken in conjunction with simeprevir, care must be taken.
triazolam	with the simultaneous use of simeprevir with triazolam taken orally, a slight increase in the concentration of triazolam is possible, due to the inhibition of the activity of the isoenzyme cyp3a4 in the intestine by the action of simeprevir. Due to the narrow therapeutic range of triazolam, when taken together with simeprevir, care must be taken.
psychostimulants
methylphenidate	with the simultaneous use of simeprevir with methylphenidate, dose adjustment is not required.

the direction of the arrow (↑ - increase, ↓ - decrease, ↔ - no change) for each pharmacokinetic parameter has a 90% confidence interval for the average geometric value within (↔), below (↓) or above (↑) of the range 0.80-1.25.

¹ - the interaction between simeprevir and this drug was evaluated in a study of pharmacokinetics in healthy adult volunteers. all other interactions between drugs are of a calculated nature.

² - this interaction study was conducted using a dose exceeding the recommended dose of simeprevir, in order to evaluate the maximum effect on the co-administered drug. these recommendations for dosing are applicable to the recommended dose of simeprivir, which is 150 mg 1 time / day.

³ - the comparison is based on the previously obtained control values. the interaction between simeprevir and this drug was evaluated in a preliminary study of pharmacokinetics in a phase II study in 22 hepatitis C infected patients. safety and effectiveness of simeprevir in combination with sophosbuvir is not established.

⁴ - the dose of simeprevir in this study of interaction between drugs was 50 mg when combined with darunavir / ritonavir, while in the monotherapy group of simeprevir it was 150 mg.

⁵ - the interaction between simeprevir and this drug was evaluated in a pharmacokinetic study in opioid-dependent adult patients receiving stable methadone maintenance therapy at a stable dose.

Special instructions:

Not allowed the use of the drug Sovrirad® as a monotherapy. Symeprevir it is necessary to appoint in combination with peginterferon alfa and ribavirin. Therefore, before starting therapy, you should read the instructions for the use of peginterferon alfa and ribavirin.

The specific instructions described for peginterferon alfa and ribavirin will also be applied to combination therapy with simeprevir.

Pregnancy and the requirements for contraception

Since the drug Sovrirad® is intended for use in combination with peginterferon alfa and ribavirin, the guidelines for pregnancy and contraceptive requirements for all drugs that make up this combination apply to combination therapy.

Ribavirin is capable of causing malformations and / or fetal death in the period of intrauterine development. Therefore, extreme care must be taken to avoid pregnancy in women receiving treatment and in partners undergoing treatment for men. See also the instructions for use of ribavirin.

Capable of giving birth to women and their partners,as well as men undergoing treatment with their partners during therapy and during the period specified in the instructions for the use of ribavirin, after its termination should use a combination of 2 effective methods of contraception.

Measurement of laboratory parameters during therapy with Sovriad in combination with peginterferon alfa and ribavirin

RNA levels of hepatitis C virus should be assessed at 4 and 12 weeks according to clinical indications. To monitor the level of hepatitis C virus RNA during therapy, it is recommended to use a sensitive quantitative analysis of hepatitis C virus RNA.

The requirements for the initial, as well as the results of a general clinical blood test, a biochemical blood test (including liver enzyme and bilirubin assays), and pregnancy tests are given in the instructions for the use of peginterferon alfa and ribavirin.

Application the patients after ineffectiveness of previous therapy with direct antiviral drugs against viral hepatitis C Safety and efficacy of simeprevir in patients after ineffectiveness of previous therapy with simeprevir orother direct antiviral drugs for the treatment of hepatitis C have not been studied.

Use in patients with other genotypes of the hepatitis C virus

Currently, there is insufficient clinical data to support the use of the drug Sovriad * in patients with hepatitis C genotypes 2, 3, 5 or 6, so the drug Sovrirad® should not be used in such patients.

Interactions with drugs

Joint use of the medication Sodriad® with drugs that provide strong or moderate inducing or inhibitory action against isoenzyme CYP3A, is not recommended, as this can lead to a significant reduction or increase in the concentration of simeprevir.

Joint use with other antiviral drugs for direct action for the treatment of hepatitis C

Data on the joint use of the drug Sovriad with telaprevir or bocepswir is absent. It is assumed that these protease inhibitors of the hepatitis C virus may exhibit cross-resistance. In this regard, their joint application is not recommended.

Use in combination with peginterferon alfa-2b

In clinical trials in patients taking simepsvir in combination with peginterferon alfa-2b and ribavirin, HC012 values were slightly lower, with increased viral load and recurrence of viremia more likely than in patients receiving simeprevir therapy in combination with peginterferon alfa-2but also ribavirin.

Co-fusion with the hepatitis B virus

The safety and efficacy of simeprevir in the treatment of hepatitis C in patients co-infected with hepatitis B virus has not been studied.

Organ transplantation

The safety and efficacy of simeprevir in patients after organ transplantation has not been studied.

The combined use of the drug Sovrirad® with cyclosporine is not recommended, so the concentration of simeprevir can be significantly increased.

Photosensitivity

Photosensitivity reactions (which were predominantly mild or moderate) were observed in patients receiving treatment with the drug Sovrirad® in combination with peginterferon alfa and ribavirin.

Suitable sun protection agents should be used during therapy with Sovrirad ® in combination with peginterferon alfa and ribavrinin.The use of tanning enhancers, as well as prolonged exposure to direct sunlight, is contraindicated during treatment with Sovrirad® in combination with peginterferon alfa and ribavrin. In the case of photosensitivity reactions, it is necessary to consider the desirability of abolishing therapy with Sovrirad® and to carefully monitor patients until the photosensitivity reactions disappear.

Rash

The rash was observed in patients undergoing Srirad® therapy in combination with peginterferon alfa and ribavirin. The rash most often appeared in the first 4 weeks of therapy, but its appearance is possible at any time during treatment. There was also a severe rash and a rash, requiring the withdrawal of Sourriad® therapy. Most often a rash of mild or moderate degree was noted. Patients with mild to moderate children should be under the supervision of a physician for possible progression of the rash, including the development of mucosal lesions (eg, mucosal lesions, conjunctivitis) or systemic manifestations.If the rash changes to severe form, therapy with Sovrirad® should be canceled. Patients should be carefully monitored until the appearance of the rash disappears.

Impaired liver function

The concentration of simsprevir in blood plasma is significantly increased in patients with severe liver failure (class C according to Child-Pyo). The safety and efficacy of simeprevir has not been studied in patients with hepatitis C with impaired liver function of moderate and severe degree (classes C and B on the Child-Pugh scale), as well as in patients with decompensation. Care should be taken when prescribing Sovrirad® to such patients.

The use of simeprevir the patients with chronic hepatitis C genotype 1a The parameters of a stable virologic response (SVR) of therapy with Sovriad in combination with peginterferon alfa and rpbavirin were reduced in patients with hepatitis C of genotype 1a with polymorphism NS3 Q80K compared with patients without polymorphism Q80K. If appropriate tests are available, consideration should be given to the possibility of defining the polymorphism Q80K in patients with hepatitis C of genotype 1a.In the case of such a determination, the results of testing should be taken into account when deciding whether to prescribe medication with Sovrirad ® in combination with peginterferon alfa and rpbavirin. It is necessary to consider the possibility of using alternative therapy in case the patient has polymorphism Q80K, and also in case of impossibility of carrying out of corresponding testing.

Effect on the ability to drive transp. cf. and fur:

Impact on the ability to drive vehicles and mechanisms

Currently, there are no known effects of the drug Sorrow * on the ability to drive vehicles and mechanisms. Special studies to evaluate the effect of the drug Sovriad® on the ability to drive vehicles and mechanisms were not conducted.

Combination therapy with septrevir, pegpferferon alfa and ribavirin can affect a patient's ability to drive vehicles and mechanisms. Information on the potential effects of peginterferon alfa and ribavirin on the ability to drive vehicles and mechanismsUse appropriate instructions for use.

Form release / dosage:

Capsules, 150 mg; 7 capsules per blister of PVC / PE / PVDC / Al. For 1 or 4 blisters per pack of cardboard along with instructions for use.

Packaging:

Capsules, 150 mg; 7 capsules per blister of PVC / PE / PVDC / Al. For 1 or 4 blisters per pack of cardboard along with instructions for use.

Storage conditions:

Store at a temperature of no higher than 25 ° C in a dark place. Keep out of the reach of children.

Shelf life:

2 of the year

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002384

Date of registration:27.02.2014

The owner of the registration certificate:Janssen-Sylag International N.V.Janssen-Sylag International N.V. Belgium

Manufacturer: & nbsp

JANSSEN-CILAG, S.p.A. Italy

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp05.08.2015

Illustrated instructions

Instructions

Sovrirad® (Sovriad)