Sovriad

General characteristics. Structure:

Active agent – симепревир sodium of 154,40 mg (in terms of симепревир 150,00 mg).

Excipients: sodium lauryl sulfate of 1,25 mg, magnesium stearate of 2,50 mg, silicon dioxide of colloid 0,75 mg, croscarmellose sodium of 12,50 mg, lactoses monohydrate of 78,40 mg; cover: titanium dioxide, gelatin; the structure blackened: shellac, ferrous oxide black, propylene glycol.

Pharmacological properties:

Pharmacodynamics.

Action mechanism.

Simeprevir is inhibitor of the protease of a virus of the hepatitis C NS3/4A playing a key role in replication of a virus. By results of biochemical analysis of blood симепревир inhibited proteolytic activity of recombinant proteases of a virus of hepatitis C of genotypes 1a and 1b NS3/4A with a median of Ki 0,5 and 1,4 values nmol/l, respectively.

Pharmacokinetics.

Pharmacokinetic properties of a simeprevir were estimated at adult healthy volunteers and at the adult patients infected with a hepatitis C virus. Cmax values in plasma and the area under a curve "concentration time" (AUC) after multiple dose of drug in doses from 75 mg a day increased to 200 mg of 1 times with an advancing of direct proportionality to a dose; after multiple dose of drug its accumulation was observed. The equilibrium state was reached after 7 days of reception of 1 times a day. Level of a simeprevir in plasma (AUC) at the patients infected with a virus of hepatitis C by 2-3 times exceeded the corresponding values at healthy volunteers. Cmax and AUC values of a simeprevir in plasma at combined use an alpha and ribaviriny and at monotherapy simepreviry were similar to peginterferon.

Absorption.

Simeprevir has good bioavailability at intake. The maximum concentration in plasma (Cmax) are usually reached in 4-6 hours after administration of drug. Reception of a simeprevir during food at healthy volunteers increased relative bioavailability (AUC) for 61% and 69% after a high-calorific breakfast with the high content of fats (928 kcal) and after a breakfast with the normal caloric content (533 kcal) respectively, at the same time increase in time of absorption for 1 and 1,5 hours respectively was observed. By results of in vitro experiments with cells of Caco-2 of the person симепревир is P-glycoprotein substrate.

Distribution.

Simeprevir substantially contacts proteins of plasma (> 99,9%), is preferential with albumine and to a lesser extent with α1-кислым a glycoprotein. At patients with a renal failure or a liver of significant changes of linkng with proteins of plasma it is not registered. At animals симепревир substantially comes to tissues of intestines and liver (a ratio of content in a liver and blood at rats 29:1).

Metabolism.

Simeprevir is metabolized in a liver. By results of the researches in vitro on microsomes of a liver of the person симепревир preferential is exposed to oxidizing metabolism by means of a liver CYP3A isoenzyme. It is also impossible to exclude participation of isoenzymes of CYP2C8 and 2C19.

Information on effects of inhibitors or inductors of isoenzymes of CYP concerning pharmacokinetics of a simeprevir, and also information on the inhibiting potential of a simeprevir concerning CYP isoenzymes in the section "Interaction with Other Medicines".

After a single dose in a 14C-simeprevir in a dose of 200 mg at healthy volunteers the most part of radioactive material in plasma (to 98%) represented not changed drug, and only an insignificant part represented metabolites (any of which was not a significant metabolite). The metabolites identified in Calais were formed as a result of oxidation of macrocyclic or aromatic group or both groups, and also as a result of O-demethylation with the subsequent oxidation.

Removal.

Removal of a simeprevir happens to bile. Kidneys are of little importance in drug removal. After a single dose in 14C of a simeprevir in a dose of 200 mg of uzdorovy volunteers on average 91% of radioactive materials were allocated through intestines, <1% of the accepted dose was allocated with kidneys. Not changed симепревир in Calais averaged 31% of the accepted dose.

The elimination half-life of a simeprevir at reception in a dose of 200 mg at healthy volunteers made 10-13 h, and at the patients infected with a hepatitis C virus – 41 h.

Special groups of patients.

Children (18 years are younger).

Researches on studying of pharmacokinetics of a simeprevir at children were not conducted.

Elderly patients.

There is a limited volume of data on use of Sovriad® medicine for patients 65 years are more senior. On the basis of the population analysis of pharmacokinetics at the patients infected with a virus of hepatitis C receiving симепревир the age (18-73 years) did not render clinically significant effect on pharmacokinetics of a simeprevir. It is not required from elderly patients of dose adjustment.

Patients with renal failures.

Removal of a simeprevir kidneys slightly. In comparison with patients without chronic hepatitis C with the normal function of kidneys (classified with use of a formula of Modification of a diet at diseases of kidneys [MDRD] for calculation of a glomerular filtration rate; rated speed of glomerular filtering ≥ 80 ml/min.), average AUC values of a simeprevir in an equilibrium state at patients without chronic hepatitis C and with a renal failure of heavy degree (a glomerular filtration rate less than 30 ml/min.) were 62% higher. On the basis of the studied and expected changes of concentration of a simeprevir in a blood plasma, dose adjustment of the drug Sovriad® is not required from patients with a renal failure of easy, average and heavy degree. Efficiency and safety of the drug Sovriad® is not studied at patients with chronic hepatitis C with a renal failure of heavy degree or with an end-stage of a renal failure, including patients who need a hemodialysis. By results of the population analysis of pharmacokinetics at patients with a renal failure of easy or average degree, at therapy by Sovriad® medicine in a dose of 150 mg of 1 times a day, the clearance of creatinine did not influence parameters of pharmacokinetics of a simeprevir. Thus, clinically significant influence of a renal failure of easy or average degree on the level of a simeprevir is not expected. As симепревир substantially contacts proteins of plasma, removal of significant amount of this drug by means of a hemodialysis is improbable.

Information on therapy an alpha and ribaviriny at patients with a renal failure is provided by peginterferon in the corresponding application instructions.

Patients with abnormal liver functions.

Simeprevir is metabolized preferential in a liver. In comparison with healthy volunteers with normal function of a liver at patients with an abnormal liver function of average degree (a class B on a scale of Chayld-Pyyu) the average znacheniyeauc a simeprevir in equilibrium was 2,4 times higher than a state while at patients with an abnormal liver function of heavy degree (a class C on a scale of Chayld-Pyyu) it was 5,2 times higher. Dose adjustment of the drug Sovriad® is not required from patients with an abnormal liver function of easy degree (a class A on Chayld-Pyyu). At patients with hepatitis C with an abnormal liver function of average or heavy degree (the classes C and B on a scale of Chayld-Pyyu) safety and efficiency of a simeprevir were not studied. During clinical trials increase in concentration of a simeprevir in blood caused increase in frequency of emergence of side effects, including rash and photosensitivity. For patients with an abnormal liver function of average or heavy degree there are no recommendations about dose adjustment of a simeprevir. The potential advantage and risk of use of the drug Sovriad® have to be estimated carefully before use for patients with an abnormal liver function of average or heavy degree.

On the basis of the population analysis of pharmacokinetics at the patients with hepatitis C receiving Sovriad® medicine, the stage of fibrosis of a liver did not render clinically significant effect on pharmacokinetics of a simeprevir. Information on therapy an alpha and ribaviriny is provided by peginterferon in the corresponding application instructions.

Other groups of patients.

Dose adjustment depending on a floor, the body weight or an index of body weight is not required. On the basis of the population analysis of pharmacokinetics at the patients infected with a virus of hepatitis C receiving Sovriad® medicine, these characteristics do not render clinically significant effect on pharmacokinetics of a simeprevir.

Patients with VICh-1 koinfitsirovaniye.

Parameters of pharmacokinetics of a simeprevir at patients 1 to a koinfitsirovaniye of VICh-1 or without it were comparable to hepatitis C of a genotype.

Race.

By results of researches at patients without hepatitis C and at patients with hepatitis C, concentration of a simeprevir in a blood plasma at patients of Mongoloid race were higher in comparison with those at patients of Caucasian race. In researches 3 phases average concentration of a simeprevir at patients of Mongoloid race was 3,4 times higher in comparison with all other patients. During clinical trials higher concentration of a simeprevir in blood caused increase in frequency of emergence of side effects, including rash and photosensitivity. The available data on safety are insufficient for providing any recommendations for patients of an East Asian origin.

The potential advantage and risk of use of the drug Sovriad® have to be estimated carefully before use for patients of an East Asian origin. The population pharmacokinetic analysis showed that concentration of a simeprevir in a blood plasma were comparable at patients of Caucasian race to hepatitis C and patients of negroid race to hepatitis C.

Indications to use:

Treatment of chronic hepatitis C of a genotype 1 in a combination with peginterferon an alpha and ribaviriny at the adult patients with the compensated liver disease (including cirrhosis) who were earlier not receiving treatment or which have a previous treatment (on the basis of interferon (pegylated or not pegylated) with ribaviriny or without it) was inefficient.

The drug Sovriad® cannot be used as monotherapy.

Route of administration and doses:

The recommended drug Sovriad® dose – one capsule (150 mg) inside once a day during food. The type of food does not influence pharmacokinetic parameters of a simeprevir. It is necessary to swallow of capsules entirely.

Совриад® it is necessary to apply in a combination with peginterferon an alpha and ribaviriny. Information on a route of administration and doses of peginterferon the alpha and a ribavirina are given in the corresponding application instructions.

Treatment duration the Recommended treatment duration the drug Sovriad® in a combination with peginterferon the alpha and ribaviriny makes 12 weeks.

At all patients therapy by Sovriad® medicine needs to be begun in combination with peginterferon an alpha and ribaviriny; treatment continues within 12 weeks. At the patients and patients who were earlier not receiving therapy with a recurrence in the anamnesis, including patients with cirrhosis, after completion of 12 weeks treatment by Sovriad® medicine in a combination with peginterferon an alpha and ribaviriny, therapy by peginterferon the alpha and ribaviriny has to be continued within 12 weeks (the general duration of therapy – 24 weeks).

At patients with inefficiency of the previous therapy (including lack of the answer or the partial answer), including patients with cirrhosis, after completion of 12 weeks therapy by Sovriad® medicine in a combination with peginterferon an alpha and ribaviriny, therapy by peginterferon the alpha and ribaviriny has to be continued within 36 weeks (the general duration of therapy – 48 weeks).

Table 1. The recommended treatment duration the drug Sovriad® in a combination with peginterferon an alpha and ribaviriny.

Treatment by the drug Sovriad® in a combination with peginterferon an alpha and ribaviriny (1):

- The patients and patients who were earlier not receiving therapy with a recurrence in anamneze2, including patients with cirrhosis - the first 12 weeks;

- Patients with the inefficiency previous terapii3 (including lack of the answer or the partial answer), including patients with cirrhosis - the first 12 weeks.

Treatment by peginterferon alpha and ribaviriny (1):

- The patients and patients who were earlier not receiving therapy with a recurrence in the anamnesis (2), including patients with cirrhosis - additional 12 weeks;

- Patients with inefficiency of the previous therapy (3) (including lack of the answer or the partial answer), including patients with cirrhosis - additional 36 weeks.

General duration of treatment (1):

- The patients and patients who were earlier not receiving therapy with a recurrence in anamneze2, including patients with cirrhosis - 24 weeks;

- Patients with the inefficiency previous terapii3 (including lack of the answer or the partial answer), including patients with cirrhosis - 48 weeks.

(1) – the recommended treatment duration if therapy cancellation is not required (see table 2).

(2) – patients with a recurrence in the anamnesis are patients in whom RNA of a virus of hepatitis C was not found after completion of the previous therapy on the basis of interferon, but it was found in the course of the subsequent observation.

(3) – patients with the partial answer are patients at whom the RNA level of a virus of hepatitis C decreased not less than on 2 log10 ME/ml in 12 weeks, and also it was found after completion of the previous therapy on the basis of interferon; patients with the zero answer are patients at whom the RNA level of a virus of hepatitis C decreased less than on 2 log10 ME/ml in 12 weeks of the previous therapy on the basis of interferon.

During performing treatment at patients it is necessary to control the hepatitis C virus RNA level. At the same time it is recommended to use a sensitive method with the lower bound of definition of 25 ME/ml. Information on necessary laboratory tests during therapy an alpha and ribaviriny are provided by peginterferon in the corresponding application instructions.

Therapy cancellation.

Achievement of the steady virologic answer (SVA) at patients with the inadequate virologic answer during treatment is improbable. Therefore at such patients it is recommended to cancel treatment. The threshold values of the RNA levels of a virus of hepatitis C which are the basis for therapy cancellation are presented in table 2.

Table 2. Rules of the termination of therapy at patients with the inadequate virologic response to treatment:

Hepatitis virus RNA level C / Necessary action.

4 week of therapy: not less than 25 ME/ml / to Cancel Sovriad®, peginterferon an alpha and рибавирин

12 week of therapy: not less than 25 ME/ml / to Cancel peginterferon an alpha and рибавирин

24 week of therapy: not less than 25 ME/ml / to Cancel peginterferon an alpha and рибавирин

In case of peginterferon cancellation an alpha or a ribavirina for any reason, therapy by Sovriad® medicine needs also to be cancelled.

Dose adjustment or suspension of therapy.

For the purpose of prevention of inefficiency of therapy it is not allowed to reduce a dose or to stop therapy by Sovriad® medicine.

In case of therapy cancellation by Sovriad® medicine on an origin of undesirable reactions or the inadequate virologic answer therapy resuming by this drug is not allowed. In case of development of the undesirable reactions which are potentially connected with peginterferon an alpha or ribaviriny, and demanding dose adjustment or suspension of therapy by any of these medicines it is necessary to be guided by the instructions stated in application instructions of the corresponding medicine.

Admission of a dose.

If delay in reception of Sovriad® medicine made less than 12 hours, then the passed dose should be accepted as soon as possible together with food and to renew the usual mode of dosing. If delay in reception of Sovriad® medicine made more than 12 hours, then the passed dose should not be accepted; the following dose is accepted in usual time.

Special groups of patients.

Children and teenagers (18 years are younger).

Safety and efficiency of Sovriad® medicine at children and teenagers is not studied.

Elderly patients (65 years are more senior).

Data on safety and efficiency of Sovriad® medicine at patients are more senior than 65 years are limited. Dose adjustment is not required from elderly patients.

Renal failure.

Dose adjustment of Sovriad® medicine with a renal failure of easy and average degree is not required from patients. Safety and efficiency of Sovriad® medicine at patients with a renal failure of heavy degree (clearance of creatinine less than 30 ml/min.) or an end-stage of a renal failure, including the patients who are on a hemodialysis was not studied. Simeprevir is characterized by high extent of linkng with proteins of a blood plasma. Thus, the hemodialysis with high degree of probability will not lead to considerable removal of a simeprevir. Information on peginterferon use an alpha and a ribavirina at patients with a renal failure is provided in application instructions of the corresponding medicines.

Abnormal liver function.

It is not possible to provide any recommendations about dose adjustment at patients with an abnormal liver function of average and heavy degree (the class B or C across Chayld-I Drink) because of higher concentration of a simeprevir in blood. During clinical trials increase in concentration of a simeprevir in blood caused increase in frequency of emergence of side effects in such patients, including rash and photosensitivity. Efficiency and safety of the drug Sovriad® was not studied at patients with hepatitis C and an abnormal liver function of average and heavy degree (the class B or C on Chayld-Pyyu). Use of a combination of peginterferon an alpha and a ribavirina contraindicated at patients sdekompensirovanny cirrhosis (dysfunction baking of average and heavy degree). The potential advantage and risk of use of the drug Sovriad® have to be estimated carefully before use for patients with an abnormal liver function of average and heavy degree.

Koinfitsirovaniye 1 (VICh-1) human immunodeficiency virus.

With hepatitis C of a genotype 1 or 4 and koinfitsirovaniy VICh-1 of dose adjustment of Sovriad® medicine it is not required from patients.

Race.

Higher concentration of a simeprevir in a blood plasma are found in patients of an East Asian origin. During clinical trials higher concentration of a simeprevir in blood caused increase in frequency of emergence of side effects, including rash and photosensitivity. The available data on safety are insufficient for providing any recommendations for patients of an East Asian origin. The potential advantage and risk of use of the drug Sovriad® have to be estimated carefully before use for patients of an East Asian origin.

Features of use:

Use of Sovriad® medicine as means of monotherapy is not allowed. Simeprevir it is necessary to appoint in combination with peginterferon an alpha and ribaviriny. Thus, prior to therapy it is necessary to study application instructions of peginterferon an alpha and a ribavirina.

Safety and efficiency of a simeprevir in combination with medicines for treatment of hepatitis C, except peginterferon an alpha and a ribavirina, is not studied. The special instructions described for peginterferon an alpha and a ribavirina will also be applied to a combination therapy with simepreviry.

Pregnancy and requirements to contraception.

As Sovriad® medicine is intended for use in combination with peginterferon an alpha and ribaviriny, the instructions concerning pregnancy and requirements to contraception for all drugs which are a part of this combination are applied to a combination therapy.

Ribavirin is capable to cause malformations and/or death of a fruit during pre-natal development. Thus, it is necessary to observe extreme care to avoid pregnancy at the women receiving treatment and at partners of the men undergoing treatment. See also application instruction of a ribavirin.

Women, capable to child-bearing, and their partners and also undergoing treatment of the man with their partners during therapy and throughout the period specified in the application instruction of a ribavirin after its termination have to use a combination of 2 effective methods of contraception.

Laboratory indicators.

The RNA levels of a virus of hepatitis C need to be estimated on 4 and 12 weeks according to clinical indications. For monitoring of the RNA level of a virus of hepatitis C during therapy it is recommended to use sensitive quantification of RNA of a virus of hepatitis C.

Requirements to the initial, and also received during treatment and after it results of the general clinical blood test, biochemical analysis of blood (including analyses of enzymes of a liver and bilirubin) and to tests for pregnancy are provided in application instructions of peginterferon an alpha and a ribavirina.

Use for patients after inefficiency of the previous therapy by antiviral drugs of direct action against a viral hepatitis of C.

Safety and efficiency of a simeprevir at patients after inefficiency of the previous therapy simepreviry or other antiviral drugs of direct action for treatment of hepatitis C was not studied.

Use for patients with other genotypes of a virus of hepatitis C.

Now there are not enough clinical data in support of use of Sovriad® medicine for patients with hepatitis C of genotypes 2, 3, 5 or 6.

Interactions with medicines.

Combined use of Sovriad® medicine with the drugs having the strong inducing or inhibiting effect concerning CYP3A isoenzyme is not recommended as it can lead to considerable decrease or increase in concentration of a simeprevir.

Koinfitsirovaniye hepatitis B virus.

Safety and efficiency of a simeprevir as means of monotherapy or in combination with peginterferon an alpha and ribaviriny at therapy of hepatitis C at patients, koinfitsirovanny a hepatitis B virus, was not studied.

Organ transplantation.

Safety and efficiency of a simeprevir as means of monotherapy or in combination with peginterferon an alpha and ribaviriny at patients after organ transplantation was not studied.

Photosensitivity.

Photosensitivity reactions (which were preferential easy or average degree) were observed at the patients accepting treatment by the drug Sovriad® in a combination with peginterferon an alpha and ribaviriny. It is necessary to use appropriate means of protection against the sun during therapy by the drug Sovriad® in a combination with peginterferon an alpha and ribaviriny. Use of means for suntan strengthening, and also long stay under direct sunshine is contraindicated during therapy by the drug Sovriad® in a combination with peginterferon an alpha and ribaviriny.

Rash.

Rash was observed at the patients undergoing therapy by the drug Sovriad® in a combination with peginterferon an alpha and ribaviriny. Rash most often developed in the first 4 weeks of therapy, but its emergence is possible at any time during treatment. Also the rash of heavy degree and rash demanding therapy cancellation by the drug Sovriad® was observed. Rash of easy or average degree was most often noted. Patients with rash of easy and average degree have to be under observation of the doctor regarding possible progressing of rash, including development of damages of mucous membranes (for example, damages of a mucous membrane of an oral cavity, conjunctivitis) or system manifestations. If rash passes into a severe form, therapy by the drug Sovriad® has to be cancelled. Patients have to be under careful observation until displays of rash do not disappear.

Polymorphism of NS3 Q80K.

Indicators of the steady virologic answer (SVA) of therapy an alpha and ribaviriny were lowered by the drug Sovriad® in a combination with peginterferon at patients with hepatitis From a genotype 1a with polymorphism of NS3 Q80K in comparison with patients without polymorphism of NS3 Q80K. In case of availability of the corresponding tests it is necessary to consider the possibility of carrying out определениея polymorphism of Q80K at patients with hepatitis From a genotype 1a. In case of carrying out such definition, results of testing have to be considered during making decision on purpose of therapy by the drug Sovriad® in a combination with peginterferon an alpha and ribaviriny. Besides, for control of the response to treatment it is possible to use results of determination of the RNA level of a virus of hepatitis C.

Influence on ability to manage vehicles and mechanisms.

Now any effects of Sovriad® medicine on ability to control of vehicles and mechanisms are unknown. Special researches on impact assessment of Sovriad® medicine on ability to control of vehicles and mechanisms were not conducted. The combination therapy simepreviry, peginterferon an alpha and ribaviriny can affect abilities of the patient to control of vehicles and mechanisms. Information on potential effects of peginterferon an alpha and a ribavirina concerning abilities to control of vehicles and mechanisms is provided in the corresponding application instructions.

Side effects:

Sovriad® medicine needs to be used in combination with peginterferon an alpha and ribaviriny. The undesirable reactions observed at therapy by peginterferon an alpha and ribaviriny are described in the corresponding application instructions.

The general profile of safety for a combination of Sovriad® medicine at use in a combination with peginterferon an alpha and ribaviriny at the patients with hepatitis C of a genotype 1 who were earlier not receiving therapies or with inefficiency of the previous treatment on the basis of interferon with ribaviriny or without it, is based on aggregated data from two clinical trials of IIb of a phase (research C205 and C206) and 3 clinical trials of the III phase (research C208, C216 and HPC3007). Aggregated data from the researches IIb and III of a phase included information on 1486 patients accepting симепревир in combination with peginterferon an alpha and ribaviriny (from them 924 patients accepted симепревир in a dose 150 mg of 1 times a day within 12 weeks), and to 540 patients receiving placebo with peginterferon an alpha and ribaviriny.

In the table at least moderately severe undesirable reactions (i.e., degrees ≥ 2) registered at patients during 12 weeks therapy by Sovriad® medicine in a dose of 150 mg of 1 times a day or placebo in combination with peginterferon an alpha and ribaviriny according to aggregated data from researches III of a phase (research C208, C216 and HPC3007) are listed below. These side effects are listed according to system and organ classes and frequency. No other side effects in other clinical trials are registered.

In aggregated data on safety from phase researches III the majority of the registered undesirable reactions during 12 weeks therapy by Sovriad® medicine on the weight belonged to degree 1 or 2. Side effects of degree 3 or 4 were registered at 2,8% of the patients receiving Sovriad® medicine in combination with peginterferon an alpha and ribaviriny and at 0,5% of patients from groups of placebo with peginterferon an alpha and ribaviriny. Serious side effects were registered at 0,3% of the patients receiving симепревир while in groups of placebo with peginterferon an alpha and ribaviriny such reactions are noted. Cancellation of Sovriad® medicine or placebo owing to undesirable reactions was required from 0,9% and 0,3% of the patients receiving симепревир with peginterferon an alpha and ribaviriny or placebo with peginterferon an alpha and ribaviriny, respectively.

Table: The side effects, at least, moderate severity (i.e., degrees 2-41) registered at adult patients with hepatitis C of a genotype 1 (by results of researches III of the phase C208, C216 and HPC3007; first 12 weeks of therapy; the analysis according to the appointed treatment).

Disturbances from a gastro intestinal path:

- lock (2):  

- 2 (0,3%) - Sovriad® + peginterferon an alpha + рибавирин N=781; n (%);

- 2 (0,5%) - Placebo + peginterferon an alpha + рибавирин N=397; n (%);

Disturbances from a liver and biliary tract:

- increase in level of bilirubin in blood (3):

- 42 (5,4%) - Sovriad® + peginterferon an alpha + рибавирин N=781; n (%);

- 9 (2,3%) - Placebo + peginterferon an alpha + рибавирин N=397; n (%);

Disturbances from skin and hypodermic cellulose:

- rash (4):

- 59 (7,6%) - Sovriad® + peginterferon an alpha + рибавирин N=781; n (%);

- 15 (3,8%) - Placebo + peginterferon an alpha + рибавирин N=397; n (%);

- itch (5):

- 24 (3,1%) - Sovriad® + peginterferon an alpha + рибавирин N=781; n (%);

- 3 (0,8%) - Placebo + peginterferon an alpha + рибавирин N=397; n (%);

- reaction of photosensitivity (6):

- 6 (0,8%) - Sovriad® + peginterferon an alpha + рибавирин N=781; n (%);

- 0 (0,0%) - Placebo + peginterferon an alpha + рибавирин N=397; n (%);

Disturbances from respiratory system, bodies of a thorax and a mediastinum:

- asthma (7):

- 92 (12%) - Sovriad® + peginterferon an alpha + рибавирин N=781; n (%);

- 30 (8%) - Placebo + peginterferon an alpha + рибавирин N=397; n (%);

(1). In compliance with a scale of assessment of degree of toxicity of WHO.

(2). The group term "lock" includes the preferable term a lock.

(3). The group term "increase in level of bilirubin in blood" includes the following preferable terms: increases in level of the conjugated bilirubin, increase in level of bilirubin in blood, increase in level of not conjugated bilirubin and a hyperbilirubinemia.

(4). The group term "rash" includes the following preferable terms: a blister, medicinal dermatitis, an erythema, an erythema a century, exfoliative rash, generalized hypostases, a spot, a palmar erythema, a papule, pink deprive, slight polymorphic rashes, rash, erythematic rash, follicular rash, generalized rash, makulezny rash, makulopapulezny rash, korepodobny rash, the papular rash which is followed by an itch rash, pustular rash, a scrotum erythema, a skin peeling, irritation of skin, skin reaction, toxic skin rashes, an umbilical erythema and vaskulitny rash.

(5). The group term "itch" includes the following preferable terms: itch century, пруриго, itch and generalized itch.

(6). The group term "photosensitivity reaction" includes the following preferable terms: photodermatosis, photosensitivity reaction, solar dermatitis and sunblisters.

(7). The group term "asthma" includes the preferable term an asthma and an asthma at an exercise stress.

Rash and itch.

For 12 weeks of therapy rash and an itch were registered by Sovriad® medicine at 21,8% and 21,9% of the patients accepting симепревир in comparison with 16,6% and 14,6% of patients from group of placebo with peginterferon an alpha and ribaviriny, respectively. The patients accepting Sovriad® medicine had easy majority of displays of rash and itch or moderately severe (degrees 1 or 2). Rash or an itch of degree 3 were registered at 0,5% and 0,1% of the patients receiving симепревир, respectively. Messages on rash or an itch of degree 4 are not registered. The termination by the terapiilekarstvenny drug Sovriad® owing to rash or an itch was required from 0,8% and 0,1% of the patients applying симервеир in comparison with 0,3% and 0% of patients from group of placebo with peginterferon an alpha and ribaviriny, respectively.

Asthma.

Within 12 weeks of therapy an asthma was noted at 12% of patients from the group receiving the drug Sovriad® in comparison with 8% of patsent from group of placebo. The patients receiving the drug Sovriad® had easy all cases of an asthma or moderately severe (the 1st and 2nd degree). An asthma 3 or 4 degrees did not arise. Besides any patient did not stop treatment because of an asthma. 61% of all cases of an asthma were noted within the first 4 weeks of therapy by the drug Sovriad®.

Increase in level of bilirubin.

For 12 weeks of therapy increase in level of bilirubin in blood was registered by Sovriad® medicine at 7,4% of the patients receiving симепревир in comparison with 2,8% of the patients receiving placebo with peginterferon an alpha and ribaviriny. Increase in level of bilirubin in blood of degree 3 or 4 was registered at 2% and 0,3% of the patients accepting Sovriad® medicine, respectively (by results of phase researches II). The therapy termination simepreviry owing to increase in level of bilirubin in blood was required seldom (0,1%; n=1).

Increase in a direct and indirect bilirubin was preferential easy or moderately severe and had reversible character. Increases in level of bilirubin usually were not followed by increase in level of transaminases of a liver and were caused by decrease in elimination of bilirubin owing to inhibition of transport proteins of hepatocytes of OATP1B1 and MRP2 under the influence of a simeprevir. These changes are not regarded as clinically significant.

Photosensitivity reactions.

Throughout 12 weeks therapy were registered by Sovriad® medicine of reaction of photosensitivity at 4,7% of patients from group of a simeprevir in comparison with 0,8% of patients from group of placebo with peginterferon an alpha and ribaviriny. The patients accepting Sovriad® medicine had easy majority of reactions of photosensitivity or moderately severe (degrees 1 or 2); at 0,1% of the patients accepting симепревир these reactions of degree 3 were registered. Reaction of photosensitivity of degree 4 is noted. Any of patients did not stop therapy owing to emergence of reactions of photosensitivity.

Deviations from laboratory indicators.

Distinctions in the level of hemoglobin or quantity of neutrophils and thrombocytes between groups are not registered. The deviations which arose during therapy from laboratory indicators which were registered with a bigger frequency at therapy by Sovriad® medicine in comparison with a placebo combination with peginterferon an alpha and ribaviriny are given in the table below.

Table: The deviations which arose during treatment from laboratory indicators (with the greatest degree of toxicity on a scale of WHO from 1 to 4) being registered with higher frequency at therapy by Sovriad® medicine (by results of researches III of the phase C208, C216 and HPC3007; first 12 weeks of therapy; the analysis according to the appointed treatment).

Biochemical analysis of blood:

Range for the corresponding degree of toxicity on WHO:

Alkaline phosphatase:

- Degree 1: from ≥ 1,25 to ≤ 2,50 VGN;

- Degree 2: from> 2,50 to ≤ 5,00 VGN.

Hyperbilirubinemia:

- Degree 1: from ≥ 1,1 to ≤ 1,5 VGN;

- Degree 2: from> 1,5 to ≤ 2,5 VGN;

- Degree 3: from> 2,5 to ≤ 5,0 VGN;

- Degree 4: from> 5,0 VGN.

Совриад® + peginterferon alpha + рибавирин N=781 n (%):

Alkaline phosphatase:

- Degree 1: 26 (3,3%);

- Degree 2: 1 (0,1%).

Hyperbilirubinemia:

- Degree 1: 208 (26,7%);

- Degree 2: 143 (18,3%);

- Degree 3: 32 (4,1%);

- Degree 4: 3 (0,4%).

Placebo + peginterferon of alphas + рибавирин N=397 n (%):

Alkaline phosphatase:

- Degree 1: 5 (1,3%);

- Degree 2: 0 (0%).

Hyperbilirubinemia:

- Degree 1: 61 (15,4%);

- Degree 2: 36 (9,1%);

- Degree 3: 6 (1,5%);

- Degree 4: 0 (0%).

VGN = the upper bound of norm of Deviations from the level of an alkaline phosphatase of degree 3 or 4 is not registered.

Additional information on special groups of patients.

Patients with VICh-1 koinfitsirovaniye.

The profile of safety of Sovriad® medicine at patients 1 to a koinfitsirovaniye of VICh-1 (N=106) and without it is comparable to hepatitis C of a genotype.

Safety at adult patients with hepatitis C of a genotype 4.

The profile of safety of Sovriad® medicine at patients 4 (N=107) and a genotype 1 is comparable to hepatitis C of a genotype.

Interaction with other medicines:

The main isoenzyme participating in metabolism of a simeprevir is CYP3A. Thus, development of CYP3A of clinically significant effects of other medicines mediated by an isoenzyme on pharmacokinetics of a simeprevir is possible. Simeprevir has no the inducing effect on isoenzymes of CYP1A2 or 3A4 in hepatocytes of the person. By results of the researches in vitro симепревир is moderate inhibitor of activity of isoenzymes CYP2A6, 2C8 and 2D6 (IC50 values> of 32 mkg/ml) and weak inhibitor of isoenzymes of CYP2C19 and 3A (IC50 values> of 64 mkg/ml).

Simeprevir is not clinically significant inhibitor of enzymatic activity of cathepsine A (IC50> of 37 mkg/ml).

According to the researches in vitro симепревир is substrate of transport proteins of medicines, including a P-glycoprotein, MRP2, BCRP, OATP1B1, OATP2B1 and OATP1B3. Simeprevir inhibits transport proteins of capture of OATP1B1 and NTCP, and also transport proteins of active removal from a cell a P-glycoprotein/MDR1, MRP2 and BSEP. Squirrels of OATP1B1 and MRP2 participate in bilirubin transport in hepatocytes and back.

Combined use of a simeprevir with powerful inhibitors of an isoenzyme CYP3A can lead to substantial increase of level of a simeprevir in plasma while combined use with powerful inductors of an isoenzyme CYP3A can reduce considerably the level of a simeprevir in plasma and lead to loss of its efficiency. Thus, combined use of Sovriad® medicine with the substances which are powerful inhibitors or inductors of activity of an isoenzyme CYP3A is not recommended.

Simeprevir is weak inhibitor of activity of isoenzymes of CYP1A2 and 3A4 in intestines while influence on activity of an isoenzyme of CYP3A4 in a liver is absent. Combined use of Sovriad® medicine with drugs, metaboliziruyemy preferential CYP3A4 isoenzyme, can lead to increase in concentration of these drugs in plasma. Combined use of Sovriad® medicine with the drugs which are substrates of transport proteins OATP1B1 and a P-glycoprotein can lead to increase in concentration of such drugs in plasma.

Contraindications:

- hypersensitivity to a simeprevir or any auxiliary component of drug;

- children's age up to 18 years;

- pregnancy, including pregnancy of the female partner of the man undergoing treatment by the drug Sovriad® in a combination with peginterferon an alpha and ribaviriny;

- lactation period;

- deficit of lactase;

- lactose intolerance;

- glyukozo-galaktozny malabsorption;

- a concomitant use with the drugs which are moderate or powerful inductors or inhibitors of an isoenzyme CYP3A: anticonvulsant drugs (carbamazepine, окскарбазепин, phenobarbital, Phenytoinum), H1 blockers - histamine receptors (астемизол, терфенадин), antibiotics (erythromycin, кларитромицин, телитромицин), antifungal drugs for intake (итраконазол, кетоконазол, позаконазол, флуконазол, вориконазол), antitubercular drugs (rifampicin/Rifampinum, рифабутин, rifapentine), glucocorticosteroid drugs (dexamethasone at system use), prokinetics (цизаприд), vegetable drugs (a thistle spotty (Silybum marianum), a St. John's Wort (Hypericum perforatum), drugs for treatment of HIV infection (the drugs containing кобицистат; nenukleozidny inhibitors of the return transcriptase: эфавиренз, делавирдин, этравирин, not Virapinum; protease inhibitors: combination darunavir/ritonavir, ритонавир, атазанавир, фосампренавир, ампренавир, лопинавир, индинавир, нелфинавир, саквинавир, типранавир);

- contraindications to therapy by peginterferon an alpha and ribaviriny are also applicable also to a combination therapy with Sovriad® medicine: a renal failure (clearance of creatinine less than 50 ml/min.), dekompensirovanny cirrhosis, an abnormal liver function of average and heavy degree (classes B and C on Chayld-Pyyu). The full list of contraindications to therapy by peginterferon an alpha and ribaviriny is provided in the corresponding application instructions.

With care:

The drug Sovriad® has to be used with care:

- at patients with a renal failure of heavy degree (clearance of creatinine less than 30 ml/min.);

- at elderly patients (the age is more senior than 65 years);

- at a concomitant use with drugs, metaboliziruyemy preferential CYP3A4 isoenzyme, and also with the drugs which are P-glycoprotein substrates: antiarrhytmic medicines (Amiodaronum, Disopyramidum, флекаинид, lidocaine (systemically), мексилетин, пропафенон, quinidine), blockers of "slow" calcium channels (амлодипин, bepridit, diltiazem, фелодипин, никардипин, nifedipine, нисолдипин, verapamil), sedative drugs / anxiolytics (midazolam, to triazoles).

Overdose:

Symptoms.

Information on overdose simepreviry at the person is limited. At a single dose of a simeprevir in doses to 600 mg or at multiple dose in doses to 400 mg of 1 times a day within 5 days at healthy adult volunteers, and also in a dose of 200 mg of 1 times within 4 weeks at adult patients with hepatitis C this drug was, as a rule, transferred to days well.

Treatment.

The specific antidote is unknown. In case of overdose carrying out a maintenance therapy (for example, washing of digestive tract) and observation of a condition of the patient is recommended. Simeprevir is characterized by high extent of linkng with proteins of a blood plasma therefore the hemodialysis with high degree of probability will not lead to considerable removal of a simeprevir.

Storage conditions:

To store at a temperature not above 25 °C  in the place protected from light. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules, 150 mg; on 7 capsules in the blister from the PVC/PE/PVDH/ave. On 1 or 4 blisters in a pack cardboard together with the application instruction.