Insivo

General characteristics. Structure:

Active agent: телапревир, 375 mg.

Excipients:

Tablet kernel: acetate gipromelloza succinate of 375,00 mg, sodium lauryl sulfate of 7,58 mg, calcium hydrophosphate of 75,76 mg, cellulose of microcrystallic 75,76 mg, silicon dioxide of colloid 7,58 mg, sodium of a kroskarmelloz of 30,30 mg, sodium of the stearylfumarating 29,29 mg.

Tablet cover: polyvinyl alcohol of 11,72 mg, macrogoal of 5,92 mg, talc of 4,33 mg, titanium dioxide (E171) of 7,00 mg, ferrous oxide yellow (E172) of 0,32 mg.

Pharmacological properties:

Pharmacodynamics.

Action mechanism.

Telaprevir – inhibitor of serinovy NS3-4A of protease of a virus of hepatitis C which is necessary for replication of a virus.

Activity of a telaprevir concerning the hepatitis C virus (HCV) (research in vitro). When using a method of biological assessment of VGS replicon of a subtype 1B value of concentration of the semi-maximum inhibition (IC50) in relation to VGS of wild type made 0,354 microns that was comparable to IC50 value in relation to a subtype 1A virus which made 0,28 microns.

Resistance. VGS options associated with lack of the virologic response to therapy or with emergence of a recurrence were revealed by method of biological assessment of replicon – site-directed mutagenesis. V36A/M, T54A/S, R155K/T and A156S options provided in vitro smaller resistance to a telaprevir (3 – 25-fold increase in IC50 of a telaprevir), and A156V/T and V36M+R155K options were associated with higher level of resistance to a telaprevir (> 25-fold increase in IC50 of a telaprevir). The replicon options created with use of the sequences received from the patient's material showed similar results.

In vitro ability to replication of telaprevir-resistant options was smaller, than ability to replication of such options in the analysis of a virus of wild type.

Cross resistance (stability). Options, resistant to a telaprevir, were analyzed regarding cross resistance to representatives of a class of inhibitors of protease in system of VGS replicon. Replicons with single replacements in a position 155 or 156 and double options with replacements in the remains 36 and 155 showed cross resistance to all protease inhibitors used in an experiment with a broad range of sensitivity. Options, all studied resistant to a telaprevir, remained completely sensitive to interferon alpha, a ribavirin and nukleozidny and nenukleozidny inhibitors of a polymerase of VGS in system of replicon. There are no clinical data on repeated therapy of patients at which inefficiency of therapy on the basis of inhibitor of NS3-4A VGS protease, such as телапревир, and also at the moment there are no clinical data testimonial of expediency of repeated carrying out a course of therapy telapreviry was noted.

Pharmacokinetics.

The pharmacokinetics of a telaprevir was studied at healthy adult volunteers and patients with persistent infection a hepatitis virus S. Telaprevir was appointed inside in vremyaeda on 3 (three) tablets on 375 mg (1125 mg totally) 2 (two) times a day within 12 weeks, in a combination with peginterferon an alpha and ribaviriny. Concentration telaprevi-ра in blood were higher at a concomitant use with peginterferon an alpha and ribaviriny, than at reception only than a telaprevir. Concentration of a telaprevir were identical as at a concomitant use with peginter-loretin alpha 2а and a ribaviriny, and concomitant use with peginterferon alpha 2b and ribaviriny.

Absorption. At intake телапревир, most likely, it is soaked up in a small intestine. Data on absorption in a large intestine are absent. The maximum concentration telaprevi-ра in plasma (Cmax) is reached in 4 – 5 hours. The researches in vitro on cells of the person of Caco-2 showed what телапревир is P-glycoprotein substrate.

The area under a curve "concentration time" of a telaprevir in an equilibrium state in in-to a tervala of 0 - 24 h (AUC24h, ss) whether was identical not is dependent on that the dose of 2250 mg in three (on 750 mg each 8 hours) or two (on 1250 mg 2 times a day) priye-ма was accepted sutoch-Nye.

Concentration of a telaprevir increased by 20% at a concomitant use with vysokoka-loriyny food with the high content of fats (56 g of fats, 928 kcal) in comparison with odes - novremenny meal of standard caloric content (21 g of fats, 561 kcal). Insivo's drug should be accepted during food since at reception of a telaprevir on an empty stomach the area under a curve "concentration time" (AUC) decreased by 73%, for 26% at one - temporary administration of drug with low-calorie food with the high content of protein (9 g of fats, 260 kcal) and for 39% at a concomitant use with low-calorie food with the low content of fats (3,6 g of fats, 249 kcal) in comparison with a concomitant use pi-Russian cabbage soup of normal caloric content.

Distribution. Telaprevir for 59%–76% contacts proteins of plasma, generally with alfa-1 an acid glycoprotein and albumine. After intake the seeming volume of distribution makes 252 l with individual variability of 72,2%.

Metabolism. Telaprevir is exposed to intensive metabolism in a liver by hydrolysis, oxide - a niya and recovery. Its numerous metabolites were found in Calais, a blood plasma and urine. At repeated intake R-diastereomer of a telaprevir which by 30 times is less active in comparison with a body - previry, pirazinovy acid and the inactive metabolite of a telaprevir recovered on α-ketoamide communication are considered as the main metabolites of a telaprevir.

The researches in vitro with use of isoforms recombinant human cyto - P450 (CYP) chrome showed that the isoenzyme of CYP3A4 is the main CYP isoform responsible for the CYP mediated metabolism of a telaprevir. The researches in vitro with use of recombinant aldoketoreductases showed that these and, perhaps, Wad Dra - gy reductases are also responsible for metabolism of a telaprevir. Other proteolytic enzymes also participate in hydrolysis of a telaprevir. Researches with use re-the kombinantny human isofermental CYP systems showed what телапревир yavlya-etsyatsya by CYP3A4 isoenzyme inhibitor. There are no certificates of inhibition telapreviry of - CYP1A2, CYP2C9, CYP2C19 enzymes, and CYP2D6 in vitro. In vitro is not revealed in-duktion telapreviry isoenzymes of CYP1A2, CYP2B6, CYP2C, and CYP3A. Nevertheless, based on results of clinical trials of medicinal interactions, induction of metabolic enzymes telapreviry cannot be excluded.

The researches in vitro showed what телапревир is not UGT1A9 or UGT2B7 inhibitor. The researches in vitro of recombinant UGT1A3 showed what телапревир mo-zht to inhibit this enzyme. Clinical value of this phenomenon is not clear as odes - novremenny reception of a telaprevir with one dose of buprenorphine, partial UGT1A3 substrate, healthy adult volunteers did not lead to increase in system influence of buprenorphine. In vitro is not revealed inhibition telapreviry alko-goldegidrogenaza.

Transport proteins. According to data of the researches in vitro телапревир is inhibitor of polypeptide carriers of organic anions - OATP1B1 and OATP2B1. In vitro was not observed inhibition telapreviry carriers organic katio-is new (OCT) OCT2, or carriers of organic anions (OAT) OAT1.

Removal. After intake of a single dose of 750 mg of a 14C-mechenny telaprevir at healthy volunteers of 90% of the general radioactivity it was revealed in Calais, urine and in expired air within 96 hours. Average values of the entered radioactive dose, it is found - ache in Calais, make 82%, in expired air – 9% and in urine – 1%. The ratio not - the changed 14C-mechenny telaprevir and VRT-127394 in radioactivity, обнаруженнойв Calais, makes 31,8% and 18,7%, respectively. After intake the seeming general clearance makes 32,4 l from an individual va-a riabelnost of 27,2%. The average elimination half-life after intake of a single dose of 750 mg of a telaprevir makes 4 – 4,7 h.

Linearity. Concentration of a telaprevir increases more than in proportion to a dose after one - multiple intake of doses in the range from 375 to 1875 mg during food, it is possible because of saturation of metabolic ways or an exit of transport proteins.

Special groups of patients.

Children. At the moment there are no data on use of drug of Insivo for children and teenagers up to 18 years.

Patients with a renal failure. Pharmacokinetics of a telaprevir studied at VGS-negativnykh volunteers with a heavy naru-a sheniye of function of kidneys (clearance of creatinine less than 30 ml/min.) after reception of a single dose of 750 mg. Average values of the maximum concentration (Cmax) and the area under a curve "a game - centration time" were 10% higher (AUC) of a telaprevir and 21% respectively, on srav-to a neniye with the same indicators at healthy volunteers.

Patients with an abnormal liver function. Telaprevir is generally metabolized in a liver. Equilibrium concentration telaprevi-ра decreases by 15% at patients with an easy abnormal liver function (a class A, 5 – 6 points on a scale of Chayld-Pyyu) in comparison with healthy volunteers. Equilibrium concentration of a telaprevir decreases by 46% at patients with an abnormal liver function of moderate severity (a class B, 7 – 9 points on a scale of Chayld-Pyyu) in comparison with healthy volunteers.

Influence of a floor. Dose adjustment depending on a sex of the patient is not required.

Race. Data of the pharmacokinetic analysis showed that race does not influence concentration those are a laprevira in blood.

Elderly patients. Now there are not enough data on efficiency and safety of use of a telaprevir for patients 65 years are more senior.

Indications to use:

Treatment of chronic hepatitis From a genotype 1 at adult patients with the compensated liver disease (including cirrhosis) in a combination with peginterferon an alpha and ribaviriny:

1. Earlier not receiving antiviral therapy against a hepatitis C virus;

2. Earlier receiving interferon an alpha (usual or peginterferon) separately or in a combination with ribaviriny, including having the previous recurrence or the partial response to therapy or not having the response to therapy.

Insivo's drug cannot be used as monotherapy or only with peginterferon an alpha or only with ribaviriny.

Route of administration and doses:

Treatment by drug.

The doctor having sufficient experience of therapy of chronic hepatitis C has to see off Insivo.

Dosing mode.

Inside on 2 (two) tablets of 375 mg (750 mg totally) 3 (three) times a day (each 8 hours) or on 3 (three) tablets of 375 mg (1125 mg totally) 2 (two) times a day during food. The general daily dose makes 6 tablets (2250 mg). Tablets should be swallowed entirely, without chewing, it is impossible to crumble or dissolve. Administration of drug of Insivo on an empty stomach, and also can lead non-compliance with the mode of dosing to decrease in concentration of a telaprevir in a blood plasma that, as a result, can reduce therapeutic effect of drug.

In case of the admission of reception of the next dose of drug of Insivo if from the planned time of reception there passed less than 6 hours, the passed dose should be accepted with food as soon as possible. If from the planned time of reception there passed more than 6 hours, then the passed dose should not be accepted, and it is necessary to accept the following next dose to the poobychny schedule. This recommendation is based that the elimination half-life of a telaprevir makes about 4 hours, and the recommended interdose interval - 12 hours.

Treatment duration at the adult patients who were earlier not receiving antiviral therapy of hepatitis C or having the previous recurrence. It is necessary to appoint Insivo's drug in a combination with peginterferon an alpha and ribaviriny. This combination of drugs has to be applied within the first 12 weeks of therapy.

Patients at whom in blood availability of RNA of a virus of hepatitis C (VGS RNA) on the 4th and 12th weeks of treatment is not revealed have to continue therapy only by peginterferon an alpha and ribaviriny within 12 weeks. The general duration of treatment at the same time makes 24 weeks.

Patients in whom in blood VGS RNA on the 4th or 12th weeks of treatment is found have to continue therapy only by peginterferon an alpha and ribaviriny within 36 weeks. The general duration of treatment at the same time will make 48 weeks. All patients with cirrhosis irrespective of whether VGS RNA on the 4th or 12th weeks of treatment was revealed, require therapy continuation only by peginterferon an alpha and ribaviriny within additional 36 weeks. The general duration of treatment at the same time will make 48 weeks.

During treatment it is necessary to define availability of VGS RNA at patients on the 4th and 12th weeks. It is necessary to take into account that absence in blood test of VGS RNA can be connected with the fact that the content of VGS RNA is below predelakolichestvenny definition in this research. It can lead to unreasonable reduction of therapy and, as a result, to increase in percent of a recurrence.  Cases at which treatment by a combination of drugs of Insivo, peginterferon an alpha and ribaviriny it is necessary to stop are listed in Table 1.

Duration of treatment of the adult patients who were earlier receiving antiviral therapy of hepatitis C, having the partial response to therapy or not having the response to therapy.

It is necessary to appoint Insivo's drug in a combination with peginterferon an alpha and ribaviriny. This combination has to be applied within the first 12 weeks of therapy then it is necessary to continue therapy only by peginterferon an alpha and ribaviriny within 36 weeks. The general duration of treatment at the same time will make 48 weeks.

During treatment an alpha and a ribavirina it is necessary to determine by a combination of drug of Insivo, peginterferon availability of VGS RNA at patients on the 4th and 12th weeks of treatment. Cases at which treatment by a combination of drug of Insivo, peginterferon an alpha and a ribavirina it is necessary to stop are listed in Table 1.

All patients. 

At patients with VGS RNA> 1000 ME/ml on the 4th or 12th weeks of treatment the alpha and ribaviriny is recommended to cancel therapy telapreviry, peginterferon (see tab. 1).

Table 1. Guide to the treatment termination of a combination of drugs of Insivo, peginterferon alpha and ribavirina (1).

VGS drug / RNA> 1000 ME/ml on the 4th week lecheniya2 / VGS RNA> 1000 ME/ml on the 12th week of treatment (2).

Insivo / Insivo's Treatment is stopped Completing reception finally/.

Peginterferon an alpha and рибавирин / to Complete reception finally.

(1) This management is not applicable if before an initiation of treatment the preliminary phase of treatment using peginterferon an alpha and a ribavirina was carried out to reveal patients with lack of the virologic answer.

(2) Treatment by a combination of drugs of Insivo, peginterferon alpha and ribavirina.

At patients with lack of the virologic answer in the anamnesis it is necessary to consider need of carrying out additional tests for definition of VGS RNA between the 4th and 12th weeks of treatment. If concentration of VGS RNA exceeds 1000 ME/ml, treatment by a combination of drugs of Insivo, peginterferon an alpha and a ribavirina should be stopped.

Patients to whom the 48 weeks course of treatment is appointed should stop therapy by peginterferon an alpha and ribaviriny if on the 24th or 36th weeks of treatment VGS RNA was found in them.

Criteria of dose adjustment, interruption, cancellation and resuming of reception of peginterferon an alpha and a ribavirina are specified in application instructions of the corresponding drugs.

Special categories of patients.

Renal failure. Now there are no data on use of a telaprevir for patients with VGS with a renal failure of average or heavy degree (clearance of creatinine ≤ 50 ml/min.). At VGS-negativnykh RNA of volunteers with a renal failure of heavy degree clinically significant change of concentration of a telaprevir in blood was not noted. Therefore patients have no need for dose adjustment of a telaprevir with a renal failure.

Clinical data on use of drug of Insivo for the patients who are on a hemodialysis no. 

Use of a ribavirin is contraindicated at patients with clearance of creatinine less than 50 ml/min. (see the application instruction of a ribavirin).

Abnormal liver function. Insivo's drug is not recommended to be used to patients with an abnormal liver function of average or heavy degree (the classes B or C, ≥ 7 points on a scale of Chayld-Pyyu) or with dekompensirovanny cirrhosis (ascites, bleeding owing to portal hypertensia, the encephalopathy or jaundice which is not caused by Gilbert's syndrome). Dose adjustment of drug of Insivo is not required to patients with an easy abnormal liver function (a class A, 5-6 points on a scale of Chayld-Pyyu). See also application instruction of a ribavirin and peginterferon an alpha. Both drugs are contraindicated to patients with an abnormal liver function of average and heavy degree (≥ 6 points on a scale of Chayld-Pyyu).

Elderly patients.

Now there are not enough data on efficiency and safety of use of a telaprevir for patients 65 years are more senior.

Children.

Data on efficiency and safety of use of drug of Insivo for children is younger than 18 years are absent.

Features of use:

Insivo's drug should be used only in a combination with peginterferon an alpha and ribaviriny, otherwise treatment will be inefficient. The dose of drug of Insivo cannot be reduced as it can result in inefficiency of therapy.

Insivo's drug cannot be used as monotherapy or only with peginterferon an alpha or only with ribaviriny.

Before use of drug of Insivo it is necessary to study application instructions of peginterferon an alpha and a ribavirina.

Insivo is absent clinical data on use of drug of Insivo for the patients who did not have effect of the therapy including inhibitor of NS3-4A VGS protease or on repeated use of drug.

If it is required to stop use of drug of Insivo because of emergence of serious undesirable side reactions on drug or the insufficient virologic answer, then afterwards it is impossible to resume treatment by Insivo's drug.

Rash.

Against the background of treatment the combination of drugs of Insivo, peginterferon an alpha and рибавирин recorded severe forms of skin reactions (including a toxic epidermal necrolysis), potentially capable to create threat of life of the patient or to lead to a lethal outcome. Lethal outcomes were observed at the patients with the progressing rash which is followed by system manifestations continuing to receive телапревир as a part of a combination therapy after detection of rash of heavy degree.

Cases of emergence of a syndrome of Stephens-Johnson were noted less than at 0,1% of patients. In all cases rash was resolved after the therapy termination. The patient has to be informed on probability of development of heavy rash and need of consultation with the attending physician at emergence of new rashes or strengthenings of severity of already available rash.

Recommendations about assessment of severity and correction are provided in table 4

Table 4. Recommendations about assessment of severity and correction of rash.

Severity / Recommendation.

Rash of easy degree: the localized rash and/or the localized rash with defeat of a limited part of a body surface (can appear on several isolated body parts) / It is necessary to control a rash progression up to the full permission simp-volumes.

Rash of moderate severity: the diffusion rash covering ≤ 50% of a body surface / It is necessary to control a progression of rash or system symptoms until rash does not disappear. Races - to watch a possibility of receiving consultation of the dermatologist. In case of progressing of rash it is necessary to consider the possibility of phase-out of drug of Insivo. If rash of moderate severity continues to develop and improvement does not occur within 7 days after drug withdrawal of Insivo, it is necessary to stop use of a ribavirin. Earlier termination of reception of a ribavirin in case of considerable progressing of rash after cancellation of a telaprevir can be required. It is possible to continue peginterferon use an alpha, except for cases when on medical indications peginterferon phase-out an alpha is required. In case of progressing of rash of moderate severity to heavy degree (at defeat more than 50% of the area of a body) it is necessary to cancel administration of drug of Insivo finally.

Rash of heavy degree: rash zakhva-tyvat more than 50% of a body surface or is connected with considerable system symptoms, vozniknove-niy bubbles, blisters, mucous membrane ulcers, damage of target organs, peeling of epidermis / It is necessary to stop immediately administration of drug of Insivo, to consult with the dermatologist, to control a condition of the patient to deflorescence. Therapy ribaviriny and peginterferon an alpha can be continued. If improvement of a condition of the patient within 7 days after drug withdrawal of Insivo is not observed, the simultaneous or consecutive temporary or constant termination of reception of a ribavirin and/or peginterferon an alpha is recommended. On medical indications earlier termination of reception or cancellation of a ribavirin and/or peginterferon an alpha can be required.

Diagnosing or suspicion of generalized violent rash, DRESS syndrome, Stephens-Johnson's syndrome / toxic epidermal necrolysis, acute generalized ekzentematozny пустулез, poliformny exudative erythema. Symptoms of a syndrome of Stephens-Johnson: widespread rash of heavy degree with a peeling of skin which can be followed by fever, grippopodobny symptoms, blisters in an oral cavity in eyes and/or on genitalias / It is necessary to stop immediately completely use of drug of Insivo, peginterferon an alpha and a ribavirina, to address for consultation the dermatologist. It is also necessary to consider the possibility of cancellation of other accepted drugs possessing side effect in the form of skin rash of heavy degree.

It is impossible to resume treatment by Insivo's drug again after his cancellation. See also information on development of skin reactions in application instructions of a ribavirin and peginterferon an alpha.

Anemia.

At use of drug of Insivo in a combination with peginterferon the alpha and ribaviriny raises the frequency of developing of anemia, including heavy degree. It is recommended to control concentration of hemoglobin before the beginning and during therapy.

See recommendations about change of dosing of a ribavirin for patients with anemia in the application instruction of a ribavirin. In case of cancellation of a ribavirin in connection with development of anemia it is also necessary to cancel therapy telapreviry. At cancellation of a telaprevir in connection with development of anemia patients can continue treatment ribaviriny and peginterferon an alpha during the appointed term. Treatment ribaviriny can be resumed according to the recommendation of the application instruction of a ribavirin. It is impossible to reduce a dose of a telaprevir and to resume treatment telapreviry in case of its cancellation.

Pregnancy and requirements to contraception.

As Insivo's drug is accepted together with peginterferon an alpha and ribaviriny, the contraindications and precautionary measures relating to these drugs belong also to a combination therapy.

Ribavirin has the expressed teratogenic and/or embriotoksichesky effect at all studied animal species (see the application instruction of a ribavirin). Therefore it is necessary to show exclusive care for contraception at female patients and at partners of male patients. It is necessary to use at least two effective methods of contraception during treatment by a combination of drugs of Insivo, peginterferon an alpha and рибавирин and within 6 months after its end.

Treatment can be begun only after receiving a negative take of the test for pregnancy which is carried out just before an initiation of treatment. The test for lack of pregnancy should be carried out monthly to the period of a combination therapy and within 6 months after completion of treatment.

Use of drug of Insivo along with the hormonal contraceptives containing estrogen reduces system influence of ethinylestradiol. As hormonal contraceptives during treatment by Insivo's drug can be unreliable, the female patients capable to a child-bearing, have to use two other effective non-hormonal methods of contraception during the combination therapy including Insivo's drug and within 2 months after the last reception of Insivo. For example, it is possible to use a male condom with the OR spermicidal gel a female condom with spermicidal gel (not both at the same time), a diaphragm with spermicidal gel, a cap on a neck of uterus with spermicidal gel. In 2 months after completion of treatment by Insivo's drug it is possible to resume reception of the hormonal contraceptives containing estrogen as one of two necessary effective methods of contraception however it is necessary to consider the recommendations provided in application instructions of the corresponding drugs. Male patients, whose partners are pregnant, have to use condom for minimization of impact of a ribavirin on the partner.

Medicinal interactions.

The list of drugs which cannot be accepted along with Insivo's drug because of the possible life-threatening adverse phenomena, considerable medicinal interactions or loss of therapeutic effect of drug of Insivo is provided in the section "Contraindications". Other known and potentially significant lekarstvennyevzaimodeystviye are described in the section "Interaction with Other Medicines".

According to data of the researches in vitro телапревир is not substrate of polypeptide carriers of organic anions - OATP1B1 and OATP2B1, but is their inhibitor. Thus, it is necessary to apply with care телапревир along with substrates of polypeptide carriers of organic anions (for example, fluvastatiny, pravastatiny, rozuvastatiny and repaglinidy).

Lengthening of an interval of QT.

It is necessary to be careful at co-administration of drug of Insivo with the medicines which are substrates of an isoenzyme CYP3A and increasing QT interval such as erythromycin, кларитромицин, телитромицин, позаконазол, вориконазол, кетоконазол, такролимус, салметерол. It is necessary to avoid co-administration of a domperidon and a telaprevir. As телапревир is also CYP3A isoenzyme substrate, it can inhibit metabolism of these drugs. Strengthening or prolongation of their action including side effects from cardiovascular system can be result of it. If co-administration of a telaprevir and such drugs is necessary, it is necessary to carry out careful control of a clinical condition of the patient, including control of an ECG.

It is undesirable to appoint Insivo's drug to the patients having inborn lengthening of an interval of QT or inborn lengthening of an interval of QT in the family anamnesis. If purpose of a telaprevir to such patients is necessary, it is necessary to carry out careful control of a clinical condition of the patient, including control of an ECG.

The following groups of patients should appoint Insivo's drug with care:

- with the acquired lengthening of an interval of QT in the anamnesis;

- with clinically significant bradycardia (resistant heart rate less than 50 уд. / mines)

- with heart failure with decrease in fraction of emission of a left ventricle in the anamnesis;

- the medicines needing use which are capable to extend QT interval, but metabolism of which not strongly depends on CYP3A4 isoenzyme (for example, methadone).

Electrolytic disturbances (such as hypopotassemia, a hypomagnesiemia and a hypocalcemia) are subject to control and if necessary - corrections prior to the beginning of and throughout therapy by Insivo's drug.

Laboratory indicators.

Availability of VGS RNA should be controlled on the 4th and 12th weeks, and also according to clinical indications.

At all patients prior to the combined treatment using Insivo's drug it is necessary to carry out the following laboratory estimates: an integrated analysis of blood with a leukocytic formula, concentration of electrolytes, serumal creatinine, TTG (thyritropic hormone), uric acid.

The recommended reference values of laboratory indicators at which it is possible to begin the combined treatment using Insivo's drug are included below:

- hemoglobin ≥ 12 g/dl (woman); ≥ 13 g/dl (man);

- thrombocytes ≥ 90 000/mm3;

- absolute number of neutrophils> 1500/mm3;

- adequately controlled function of a thyroid gland (TTG);

- settlement clearance of creatinine ≥ 50 ml/min.;

- potassium concentration ≥ 3,5 mmol/l; - albumine> 3,3 g/dl.

Performing the general blood tests (including with the analysis of a leukocytic formula) is recommended on the 2nd, 4th, 8th and 12th weeks, and further according to clinical indications. Biochemical analysis of blood (concentration of electrolytes, serumal creatinine, uric acid, liver enzymes, bilirubin, TTG) is recommended to be carried out with the same frequency, as the general blood tests, or according to clinical indications.

See the application instruction of drugs peginterferon an alpha and рибавирин, including requirements to testing for pregnancy.

Insufficient response to treatment.

At patients with the unsatisfactory response to antiviral therapy it is necessary to stop treatment.

Use of drug of Insivo in a combination with peginterferon alpha 2b. All clinical trials 3 phases were conducted with use of peginterferon alpha 2а in a combination with Insivo's drug and ribaviriny. Data on Insivo's use in a combination with peginterferon alpha 2b at the patients who were earlier receiving treatment, no, and data on use for the patients who were earlier not receiving treatment are limited. At the patients who were earlier not receiving treatment when performing therapy peginterferon alpha 2а/рибавирином (n = 80) or peginterferon alpha 2b/ribavirinom (n = 81) in a combination with Insivo in an open research, noted the comparable frequency of the resistant virologic answer. However at the patients receiving therapy by peginterferon alpha 2b increase in virus loading was more often observed, and they corresponded to criteria of reduction of the general duration of therapy less often.

Use of drug of Insivo at treatment of other genotypes of VGS.

There are no sufficient clinical data about treatment of patients with other genotypes of VGS, in addition to the 1st genotype. In this regard use of drug of Insivo for patients with other genotypes of VGS, in addition to the 1st, is not recommended.

Renal failure.

Safety and efficiency was not established concerning patients with a renal failure of average or heavy degree (clearance of creatinine <50 ml/min.) or the patients who are on a hemodialysis. See also application instruction of a ribavirin for patients with clearance of creatinine <50 ml/min.

Abnormal liver function.

Use of drug of Insivo for patients with a heavy abnormal liver function (a class C,> 10 points on a scale of Chayld-Pyyu) or dekompensirovanny cirrhosis of function of a liver (ascites, bleeding owing to portal hypertensia, the encephalopathy or jaundice which is not caused by Gilbert's syndrome) was not studied. Therefore use of a telaprevir for such patients is not recommended.

Use of a telaprevir is also not studied at patients with an abnormal liver function of moderate severity (a class B, 7-9 points on a scale of Chayld-Pyyu). The recommended doses of drug of Insivo for this category of patients are not established. Therefore purpose of drug of Insivo of this category of patients it is not recommended. See the application instruction of drugs peginterferon an alpha and рибавирин which have to be appointed along with Insivo's drug.

Transplantation.

There are no clinical data on treatment by Insivo's drug in a combination with peginterferon an alpha and ribaviriny patients before transplantation, in the blizhayshemperitransplantatsionny period or transferred transplantation earlier. In this regard use of drug of Insivo for the patients who are candidates for transplantation or transferred transplantation is not recommended (see also section "Interaction with Other Medicines", the item of Immunodepressanta).

To - an infection of VGS/VICh (human immunodeficiency virus).

Use of a telaprevir with peginterferon an alpha and ribaviriny at patients with coinfection of VGS/VICh was estimated at combinations in a research with participation of 60 HIV - the infected patients, at the same time one group of patients did not receive anti-retrovirus treatment earlier, other group received anti-retrovirus therapy with inclusion of an efavirenz or combination of an atazanavira/ritonavir in combination with tenofoviry dizoproksily fumaraty and emtritsitabiny or lamivudiny.

The profile of safety of a telaprevir at treatment of patients with coinfection who or did not receive earlier anti-retrovirus therapy, or received anti-retrovirus therapy efavirenzy in a combination with tenofoviry earlier dizoproksit fumaraty and emtritsitabiny, was similar to a profile of safety of a telaprevir at treatment mono - the infected patients (only VGS). At the patients receiving at the same time anti-retrovirus therapy atazanavirom/ritonaviry and therapy against a hepatitis virus With a combination of drugs telaprevir/ribavirin/peginterferon short-term increase in concentration of bilirubin on the 2nd week of treatment was observed. Concentration of bilirubin was returned to norm by 12th week of treatment. In 12 weeks after the end of a research higher performance of the triple scheme of therapy with Insivo's inclusion exceeding efficiency of double therapy (PEG-IFN+RBV) was shown.

The accompanying VGS/VGV infection (hepatitis B virus).

There are no data on use of drug of Insivo for patients with accompanying VGS/VGV infection.

Use for children.

Insivo's drug is not recommended to be used at children and teenagers 18 years as its safety and efficiency in this population are not established are younger.

Diseases of a thyroid gland.

During the combined treatment including Insivo's drug increase in blood of concentration of thyritropic hormone (TTG) which can demonstrate aggravation or a recurrence of the hypothyroidism which was earlier available or postponed vproshly or emergence of a hypothyroidism of de novo is possible. Concentration of TTG in blood should be controlled to and during treatment by the combination including Insivo. Treatment is carried out according to clinical expediency, including dose adjustment of replacement therapy by thyroid hormones at patients with already existing hypothyroidism can be required.

Important information on some excipients which are a part of drug of Insivo.

This medicine contains 2,3 mg of sodium in one tablet that it is necessary to take into account at treatment of the patients receiving a diet with the controlled content of sodium.

Influence on ability to manage vehicles, mechanisms.

Insivo's drug does not exert or exerts insignificant impact on ability to manage vehicles and to work with mechanisms. The corresponding researches were not conducted. The faint and a retinopathy were registered at some patients accepting Insivo's drug that needs to be considered at assessment of ability of the patient to manage vehicles or to work with mechanisms. See also application instructions of peginterferon an alpha and a ribavirina for more information.

Side effects:

At administration of drug of Insivo the following undesirable reactions arose with a frequency ≥ 1%: anemia (frequency ≥ 5%), rash (≥ 5%), thrombocytopenia, lymphopenia, itch (≥ 5%), tosh-note (≥ 5%), diarrhea (≥ 5%). It is important to note that because of need of administration of drug of Insivo for a combination with peginterferon an alpha and ribaviriny, the undesirable reactions caused by these pre-parata can also take place (see instructions on primene-a peginterferon niya an alpha and a ribavirina).

The uses of drug of Insivo given about safety received from clinical issle-of a giving are systematized concerning each of systems of bodies depending on cha-occurrence stota with use of the following classification: very frequent (≥1/10), frequent (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very much red-Kia (less than 1/10000).

Infections and parasitic diseases:

Frequent: candidiasis of an oral cavity.

Disturbances from blood and lymphatic system: 

Very frequent: anemia.

Disturbances from immune system:

Infrequent: small tortoiseshell;

Rare: Stephens-Johnson's syndrome.

Disturbances from endocrine system:

Frequent: hypothyroidism.

Disturbances from a metabolism and food:

Infrequent: gout.

Disturbances from a nervous system:

Frequent: syncope.

Disturbance from organs of sight:

Infrequent: retinopathy.

Disturbances from digestive tract:

Very frequent: nausea, diarrhea, vomiting, hemorrhoids, proctalgia;

Frequent: food faddism, rectal bleeding, proctal crack, anorectal itch;

Infrequent: proctitis.

Disturbances from skin and hypodermic fabrics:

Very frequent: itch, rash;

Frequent: eczema, face edema, exfoliative rash;

Infrequent: medicinal rash with an eosinophilia and system (DRESS-) symptoms.

General frustration:

Infrequent: peripheral hypostasis.

Disturbances from laboratory indicators:

Frequent: a hyperbilirubinemia, thrombocytopenia, a lymphopenia, a hyperuricemia, giperkali-an emiya, decrease in concentration of hemoglobin in blood, decrease in quantity of leukocytes in blood, increase in concentration of lipoproteins of low density, increase kontsen-tration of the general cholesterol;

Infrequent: increase in concentration of creatinine in blood.

It should be noted that by 24th week of treatment the majority of laboratory indicators were returned to the values comparable to those at therapy only peginterfero-number an alpha and ribaviriny. The exception was made by an indicator of number of thrombocytes which remained below the value observed at therapy only by peginterferon an alpha and ri-baviriny up to the 48th week of a combination therapy.

Increase in concentration of uric acid in a blood plasma was very often noted during therapy by a combination of drugs of Insivo, peginterferon an alpha and a ribavirina. Concentration of uric acid usually decreased within the next 8 weeks, and was comparable to values which were observed at the patients receiving leche-ny only peginterferon an alpha and ribaviriny.

It was shown that the profile of safety of drug of Insivo is identical as at reception on 1125 mg (3 tablets on 375 mg) 2 times a day and at reception on 750 mg (2 tablets on 375 mg) each 8 hours.

Rash.

Cases of developing of rash were more often observed at the patients accepting телапревир with peginterferon an alpha and ribaviriny than at the patients accepting only pegin-терферон an alpha and рибавирин. In 90% of cases rash easy or average a step - weights at which drug withdrawal of Insivo was not required was observed. Usually against the background of priye-ма a telaprevira the eczematic rash with an itch taking less than 30% on - body verkhnost took place. Some cases of rash were described as makulopapulezny or erite-matozny. More than a half of cases of undesirable skin reactions were found in those - a cheniye of the first 4 weeks of therapy, however rash could develop during any period of reception of a combination therapy.

See the section "Special Instructions" on monitoring of rash and rules of cancellation of Insivo, ribavi-Rihn and peginterferon an alpha. Patients with rash easy and moderate severity dolzh-ны to be observed regarding progressing of expressiveness of skin symptoms; however, progressing is observed seldom (less than in 10% of cases). For correction nezhela-telny skin reactions purpose of antihistaminic drugs and places - ny glucocorticosteroids is recommended. Permission of rash was observed after the termination or from - exchanges of reception of Insivo. However in certain cases for this purpose could be required not - how many weeks.

Anemia.

Decrease in concentration of hemoglobin was stronger and more often was observed at the patients accepting телапревир in a combination with peginterferon an alpha and ribaviriny than at the patients accepting only peginterferon an alpha and рибавирин. Anemia heavy ste-a penalty fee was noted at 2 – 3% of the patients receiving телапревир.

Anorectal syndrome.

The majority of the described cases of emergence of an anorectal syndrome (hemorrhoids, anorectal discomfort, an anorectal itch and anorectal burning) were easy or moderate severity, very seldom led to drug withdrawal and, as a rule, about - went after end of a combination therapy.

The undesirable side reactions revealed during post-registration use of a combination of drugs of Insivo, peginterferon an alpha and рибавирин.

Following undesirable side reactions were revealed in the course postregi-stratsionny use of a combination of drugs of Insivo, peginterferon an alpha and riba-a virina.

Frequency of occurrence of these undesirable reactions and their connection with administration of drug is not established as information these undesirable side reactions is obtained from spontaneous messages.

Disturbances from skin and hypodermic fabrics:

Frequency is not established: polymorphic exudative erythema, toxic epidermal-ny necrolysis.

Disturbances from secretory system:

Frequency is not established: a prerenalny azotemia with an acute renal failure or without it, an urate nephropathy.

Interaction with other medicines:

Telaprevir is generally metabolized in a liver by CYP3A isoenzyme, and also is R-glycoprotein substrate. All medicines, metaboliziruyemy it from - enzyme and/or the R-glycoprotein or influencing its activity, can change pharmacokinetics of a telaprevir. 

The concomitant use of a telaprevir and the drugs which are inhibitors izofermen-that CYP3A and/or the R-glycoprotein can lead to increase in concentration telapre-a vir in a blood plasma. Reception of a telaprevir can increase system influence prepara-t, metaboliziruyemy an isoenzyme of CYP3A and/or the R-glycoprotein that can usili-vat or extend their therapeutic effect and undesirable medicinal reactions. According to data of the researches in vitro телапревир polypeptide - ny carriers of organic anions - OATP1B1 and OATP2B1 is not substrate, but is their inhibitor. Thus, it is necessary to appoint with care a concomitant use of a body - a previr and substrates of polypeptide carriers of organic anions (for example, флувастатин, правастатин, розувастатин, and репаглинид).

The researches in vitro of assessment in situ-induction showed what телапревир is not the inductor of isoenzymes CYP1A2, CYP2B6, CYP2C, and CYP3A. However, based on results of clinical trials of medicinal interactions, induction metabo-lichesky enzymes telapreviry cannot be excluded.

Drugs which reception is contraindicated along with reception of a telaprevir.

CYP3A isoenzyme substrates with a narrow therapeutic range.

Insivo's drug cannot be used along with the drugs which are substra-weary an isoenzyme of CYP3A and having narrow therapeutic range. It can do at - to drive to increase in concentration of these drugs in a blood plasma and to emergence of serious and/or life-threatening undesirable reactions, including to disturbance of a heart rhythm (Amiodaronum, астемизол, bepridit, цизаприд, Pimozidum, quinidine, терфенадин), to a spasm of peripheral vessels or ischemia (ergotamine, dihydroergotamine, эргоновин, метилэргоновин), myopathies, including рабдомиолиз (ловастатин, симвастатин, atorvasta-oozes), to the long or strengthened sedative action or respiratory depression (a feather - rolled midazolam, to triazoles), to falling of arterial pressure and disturbance of a heart rhythm (алфузозин and sildenafit, applied to treatment of pulmonary hypertensia). Insivo's drug cannot be used at the same time with one drug from a class of IA, IC or a class III of antiarrhytmic drugs, except for lidocaine for intravenous administration.

Rifampicin.

Rifampicin reduces the area under a curve "concentration time" (AUC) of a telaprevir in a blood plasma approximately by 92%. Therefore Insivo's drug cannot be used odnovremen-but with rifampicin.

Drugs on the basis of the St. John's Wort of made a hole (Hypericum perforatum).

Reception of vegetable drugs on the basis of the St. John's Wort of made a hole (Hypericum perforatum) along with Insivo's drug can reduce concentration of a telaprevir in a blood plasma. Therefore vegetable drugs on the basis of the St. John's Wort which is made a hole cannot be used along with Insivo's drug.

Carbamazepine, Phenytoinum and phenobarbital.

Simultaneous use of a telaprevir and inductors of liver enzymes can lead to reduction of exposure of a telaprevir and probable decrease in an effective sta. Potential inductors of an isoenzyme CYP3A, such as carbamazepine, Phenytoinum and phenobarbital are contraindicated.

Inductors of an isoenzyme CYP3A of weak and average action.

It is necessary to avoid simultaneous use of triple therapy and inductors izofermen-that CYP3A of weak and average action, in particular, at patients at whom the response to therapy was not observed earlier (partial or total absence of the response to therapy by peginterferon an alpha and ribaviriny) unless are given a game - kretny recommendations about a dosage.

Contraindications:

Hypersensitivity to a telaprevir or any excipient of drug. Safety and efficiency of a telaprevir at patients up to 18 years are also more senior 65 now is not established. Therefore телапревир it is not necessary to apply at these groups of patients, additional data will not be obtained yet.

Insivo's drug cannot be accepted along with drugs which clearance depends on activity of an isoenzyme of CYP3A and which increase in concentration in a blood plasma is followed by the serious and/or life-threatening phenomena (i.e. having a narrow therapeutic index).

Insivo's drug cannot be accepted along with the antiarrhytmic drugs Ia, Ic or III of a class, except for lidocaine for intravenous administration.

Insivo's drug cannot be accepted along with the drugs activating CYP3A isoenzyme as it can be followed by loss of effect of drug of Insivo.

Drugs which cannot be applied along with Insivo's drug are listed in Table 1. (see also section "Interaction with Other Medicines").

Table 1. Drugs which cannot be applied along with Insivo's drug.

Class                                                       drugs / Drug.

Blockers α1-адренорецепторов                               / Alfuzozin

Antiarrhytmic means of Ia, Ic and the III classes / Amiodaronum, bepridit, флекаинид, пропафенон, quinidine

                                       Antihistamines / Astemizol, терфенадин

            Anticonvulsants / Carbamazepine, phenobarbital, Phenytoinum

Antituberculous remedies                               / Rifampicin

Derivatives of alkaloids ergot / Digidroergotamin, эргоновин, ergotamine, метилэргоновин

The means influencing motility GIT                      / Tsizaprid

Vegetable  drugs / Drugs on the basis of the St. John's Wort of made a hole (Hypericum perforatum)

Inhibitors HMG-CoA reductase     / Lovastatin, симвастатин, аторвастатин

                                                           Neuroleptics / Pimozidum

Phosphodiesterase-5 inhibitors (FDE-5) / Sildenafil, tadalafit (only at use for treatment of pulmonary hypertensia)

Sedative / hypnagogues / Peroral midazolam, to triazoles

Contraindications to use of drugs рибавирин and peginterferon an alpha:

As Insivo's drug is used only in a combination with ribaviriny and peginterferon the alpha, the contraindications and precautionary measures relating to these drugs belong also to a combination therapy, including:

- the combination therapy should not be appointed during pregnancy and in the period of a lactation;

- the combination therapy should not be appointed to patients with a renal failure (clearance of creatinine ≤ 50);

- the combination therapy should not be appointed to patients with a heavy abnormal liver function (classes B and C on a scale of Chayld-Pyyu).

The complete list of drugs which it is impossible to appoint along with peginterferon an alpha and ribaviriny, see in application instructions of these drugs.

With care.

Insivo's drug has to be used with care:

1. When lengthening an interval of QT:

• with inborn lengthening of an interval of QT;

• with the acquired lengthening of an interval of QT in the anamnesis;

• with clinically significant bradycardia (resistant heart rate me-it 50 уд. / mines);

• with heart failure with decrease in fraction of emission of a left ventricle in the anamnesis;

• the medicines needing use which are capable udli-нять QT interval, but metabolism of which slightly depends on CYP3A4 isoenzyme (for example, methadone).

2. In the presence of electrolytic disturbances (a hypopotassemia, a hypomagnesiemia).

3. At a concomitant use with substrates of polypeptide carriers organiche-sky anions (for example, fluvastatiny, pravastatiny, rozuvastatiny, and repaglini-the house).

Overdose:

At administration of drug of Insivo in a dose of 1875 mg each 8 hours within 4 days were observed the following side reactions: nausea, headache, diarrhea, loss of appetite, food faddism and vomiting.

There is no specific antidote for a telaprevir. Treatment of overdose includes the general supporting measures, including control of indicators of vital signs and a clinical condition of the patient. If necessary, not soaked up active agent is deleted by stimulation of vomiting or a gastric lavage. Reception of absorbent carbon is also effective.

It is unknown whether is removed телапревир by peritoneal dialysis or a hemodialysis.

Storage conditions:

At a temperature not above 30 °C. To store drug in original packaging. To store a bottle well corked for protection against moisture. Not to throw out bags of a dehumidifier. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 375 mg On 42 tablets in a bottle from polyethylene of high density with the polypropylene screwing-up cover with control of the first opening protected from accidental opening by children. The bottle contains bags of a dehumidifier (silica gel). 1 or 4 bottles together with the application instruction place in a pack cardboard.