Insivo (Insivo)

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  • Insivo
    pills inwards 
    Johnson & Johnson, LLC     Russia
    • Dosage form: & nbspfilm coated tablets
    Composition:

    Each tablet contains:

    Active substance: telaprevir, 375 mg.

    Excipients:

    Core pills: hypromellose acetate succinate 375.00 mg, sodium lauryl sulfate 7.58 mg, calcium hydrophosphate 75.76 mg, cellulose microcrystalline 75.76 mg, silicon dioxide colloid 7.58 mg, sodium croscarmellose 30.30 mg, sodium stearyl fumarate 29.29 mg .

    Casing of the tablet: polyvinyl alcohol 11.72 mg, macrogol 5.92 mg, talc 4.33 mg, titanium dioxide (E171) 7.00 mg, iron oxide yellow (E172) 0.32 mg.

    Description:

    Capsule-shaped tablets covered with a film coating of a yellowish-brown color with engraving "T375" on one side.

    On the break the tablets are white or almost white in color.

    Pharmacotherapeutic group:Antiviral agent
    ATX: & nbsp

    J.05.A.E.11   Telaprevir

    Pharmacodynamics:

    Mechanism of action

    Telaprevir is a serine inhibitor NS3-4A protease of hepatitis C virus, which is necessary for replication of the virus.

    Activity of telaprevir against hepatitis C virus (HCV) (studies in vitro)

    When using the method of biological evaluation of the replicon of HCV subtype lb value of half-maximal inhibition concentration (IC50) with respect to wild type HCV was 0.354 μM, which was comparable to IC50 with respect to the virus of subtype 1a, which was 0.28 μM.

    Resistance

    HCV variants associated with the absence of a virologic response to therapy or the occurrence of a relapse were identified by the biological replicon-site-directed mutagenesis method. Options V36A / M, T54A / S, R155K / T and A156S provided in vitro less resistance to telaprevir (3 - 25-fold increase in IC50 telaprevir), and options A156V / T and V36M + R155K were associated with a higher level of resistance to telaprevir (> 25-fold increase in IC50 telaprevir). Replicon variants created using sequences derived from patient material showed similar results.

    In vitro the ability to replicate telaprevir-resistant variants was less than the ability to replicate such variants in the analysis of wild-type virus.

    Cross-resistance (resistance)

    Resistant to telaprevir variants were analyzed for cross-resistance to representatives of the class of protease inhibitors in the HCV replicon system.Replicons with single replacements at position 155 or 156 and double variants with substitutions at residues 36 and 155 demonstrated cross-resistance to all protease inhibitors used in the experiment with a wide range of sensitivity. All the studied telapresvir resistant variants remained completely sensitive to interferon-alpha, ribavirin and nucleoside and non-nucleoside inhibitors of HCV polymerase in the replicon system. There are no clinical data on the re-therapy of patients who have experienced ineffective therapy based on a protease inhibitor NS3-4A HCV, such as telaprevir, and also at the moment there are no clinical data suggesting the advisability of a second course of therapy with telaprevir.
    Pharmacokinetics:

    The pharmacokinetics of telalrevir has been studied in healthy adult volunteers and patients with chronic hepatitis C virus infection. Telaprevir was administered orally with two 375 mg tablets (750 mg total) every 8 hours for 12 weeks, in combination with peginterferon alfa and ribavirin. Concentrations of telaprevir in the blood were higher with simultaneous admission with peginterferon alfa and ribavirin than with only telaprevir.The concentrations of telaprevir were the same as in the simultaneous administration with peginterferon alfa-2a and ribavirin, and simultaneous admission with peginterferon alfa-2b and ribavirin.

    Suction

    Ingestion telaprevir, most likely, absorbed in the small intestine. There is no data on absorption in the large intestine. The maximum concentration of telaprevir in plasma (Cmax) is achieved in 4-5 hours. Research in vitro on human cells Saso-2 showed that telaprevir is a substrate of P-glycoprotein.

    The area under the concentration-time curve of telaprevir in the equilibrium state in the range of 0-24 hours (AUC24h, ss) was the same regardless of whether a daily dose of 2250 mg was taken in three (750 mg every 8 hours) or two (1250 mg twice daily).

    The concentration of telprevir increased by 20% with simultaneous intake with a high-calorie diet high in fat (56 g fat, 928 kcal) compared with the simultaneous intake of standard caloric intake (21 g fats, 561 kcal).

    The preparation of Insivo should be taken with food, because when taking teloprevir on an empty stomach the area under the curve "concentration-time" (AUC) decreased by 73%, by 26% while taking the drug with a low-calorie food with a high protein content (9 g fats, 260 kcal), and 39% while taking low-calorie food with a low fat content (3.6 g fat, 249 g kcal) compared with the simultaneous intake of normal caloric intake.

    Distribution

    Telaprevir is associated with plasma proteins, 59% -76%, mainly with alpha-1 acid glycoprotein and albumin. After ingestion, the apparent volume of distribution is 252 liters with an individual variability of 72.2%.

    Metabolism

    Telaprevir undergoes intensive metabolism in the liver by hydrolysis, oxidation and reduction. Its numerous metabolites were found in feces, blood plasma and urine. When re-ingesting the main metabolites of telprevir, the R-diastereomer of telaprevir is considered, which is 30 times less active than telaprevir, pyrazinic acid and the inactive metabolite of telaprevir reduced on a-ketoamide linkage.

    Research in vitro using recombinant human cytochrome P450 isoforms (CYP) showed that isoenzyme CYP3A4 is the main isoform CYP, responsible for the metabolism of telaprevir. Other proteins can also be involved in the metabolism of telaprevir.Studies using recombinant human isoenzyme systems CYP showed that telaprevir is an inhibitor of the isoenzyme CYP3A4. Evidence of inhibition by telaprevir of isoenzymes CYP1A2, CYP2C9, CYP2C19, and CYP2D6 in vitro no. Also research in vitro showed that telaprevir Has a weak inducing activity against isoenzyme CYP2C, CYP3A and CYP1And therefore it is unlikely that telaprevir shows the properties of the inductor when combined with the substrates of the corresponding enzymes.

    Transport proteins

    According to the research, in vitro telposprir is an inhibitor of polypeptide carriers of organic anions - OATP1B1 and OATP2B1.

    In vitro, there was no inhibition by telaprevir of organic cation transferers (OCTs) of OCI, or carriers of organic anatoms (OAT) OAT1. Telaprevir is a weak in vitro inhibitor of the MATE I MATE2-K family of carriers (mullidrug and toxin extrusion), responsible for multiple drug resistance and toxin removal from the cell, with IC50 28.3 pM and 32.5 pM, respectively. The clinical significance of this effect is currently unknown.

    Excretion

    After ingestion of a single dose of 750 mg 14C-labeled telprevir in healthy volunteers 90% of the total radioactivity was detected in feces, urine and in exhaled air for 96 hours. The average values ​​of the introduced radioactive dose found in the stool are 82%, in the exhaled air - 9% and in urine - 1%. The ratio of unchanged 14C-labeled telaprevir and VRT-127394 in the radioactivity found in stool is 31.8% and 18.7%, respectively.

    After oral administration, the apparent overall clearance is 32.4 liters with an individual variability of 27.2%. The average half-life after oral administration of a single dose of 750 mg of telaprevir is 4 to 4.7 hours.

    Linearity

    The concentration of telaprevir increases more than in proportion to the dose after single ingestion of doses in the range of 375 to 1875 mg during meals, possibly because of the saturation of metabolic pathways or the release of transport proteins.

    Special patient groups

    Children

    At present, there are no data on the use of Insivo in children and adolescents under 18 years of age.

    Patients with impaired renal function

    The pharmacokinetics of telaprevir were studied in HCV-negative volunteers with severe renal dysfunction (creatinine clearance less than 30 ml / min) after taking a single dose of 750 mg.The mean values ​​of the maximum concentration (C max) and the area under the concentration-time curve (AUC) telaprevir were higher by 10% and 21%, respectively, compared to the same indicators in healthy volunteers.

    Patients with impaired hepatic function

    Telaprevir is mainly metabolized in the liver. The equilibrium concentration of telprevir decreases by 15% in patients with mild violations of the liver function (class A, 5 - 6 points on the Child-Pugh scale) compared with healthy volunteers.

    The equilibrium concentration of bodyprevir decreases by 46% in patients with impaired liver function of moderate severity (grade B, 7-9 on the Child-Pugh scale) compared with healthy volunteers.

    Effect of sex

    Correction of dose depending on the patient's sex is not required.

    Race

    Data from pharmacokinetic analysis showed that race 'does not affect the concentration of telaprevir in the blood.

    Elderly patients

    At present, there is insufficient data on the efficacy and safety of telaprevir in patients older than 65 years.
    Indications:

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

    1. Previously not receiving antiviral therapy against the hepatitis C virus;

    2. Previously received interferon alfa (conventional or peginterferon) alone or in combination with ribavirin, including those who have a previous relapse or partial response to therapy or who have not responded to therapy.

    The preparation of Insivo can not be used as monotherapy or only with peginterferon alfa or only with ribavirin.

    Contraindications:
    Hypersensitivity to telaprevir or any auxiliary substance of the drug.

    The safety and efficacy of telaprevir in patients under 18 years of age and older than 65 are not currently established. therefore telaprevir Do not use in these patient groups until additional data are obtained. The preparation of INSIVO should not be taken concurrently with drugs whose clearance depends on the activity of the isoenzyme CYP3A, and an increase in the concentration in the blood plasma of which is accompanied by serious and / or life-threatening phenomena (ie having a narrow therapeutic index).

    The preparation of INSIVO should not be taken concomitantly with antiarrhythmic drugs 1a, 1c or III class, with the exception of lidocaine for intravenous administration.

    The preparation of Insivo should not be taken concomitantly with preparations that activate the isoenzyme CYP3A, since this may be accompanied by a loss of the effect of the insivo drug.

    Drugs that can not be used concurrently with Insivo are listed in Table 1. (see also "Interactions with Other Drugs").

    Table 1. Preparations that can not be used concurrently with Insivo.

    Class of drugs

    A drug

    Blockers α1-adrenoceptor

    Alfuzosin

    Antiarrhythmic drugs 1a, 1c and III classes

    Amiodarone, beprideal, flecainide, propafenone, quinidine

    Antihistamines

    Astemizole, terfenadine

    Anticonvulsants

    Carbamazepine, phenobarbital, phenytoin

    Anti-TB drugs

    Rifampicin

    Derivatives of ergot alkaloids

    Dihydroergotamine, Ershnowin, ergotamine, methylergonovine

    Means that affect the motility of the gastrointestinal tract

    Cisapride

    Herbal preparations

    Preparations on the basis of St. John's wort (Hypericum perforatum)

    Inhibitors of HMG-CoA reductase

    Lovastatin, simvastatin, atorvastatin

    Neuroleptics

    Pimozide

    Inhibitors of phosphodiesterase-5 (PDE-5)

    Sildenafil, tadalafil (only when used to treat pulmonary hypertension)

    Sedatives / hypnotics

    Oral midazolam, triazolam
    Contraindications to the use of drugs ribavirin and peginterferon alfa: Because Insivo is used only in combination with ribavirin and peginterferon alfa, the contraindications and precautions related to these drugs also apply to combination therapy, including:

    - combination therapy should not be administered during pregnancy and during lactation;

    - combination therapy should not be administered to patients with impaired renal function (creatinine clearance ≤50);

    - Combination therapy should not be administered to patients with severe liver dysfunction (Child-Pugh class B and C).

    A complete list of drugs that can not be administered concomitantly with peginterferon alfa and ribavirin, see instructions for the use of these drugs.

    Carefully:

    Insivo should be used with caution

    1. when the interval is longer QT:

    - with congenital lengthening of the interval QT;

    - with the acquired prolongation of the interval QT in the anamnesis;

    - with clinically significant bradycardia (persistent heart rate less than 50 bpm);

    - with heart failure with a drop in the left ventricular ejection fraction in the anamnesis;

    - requiring the use of drugs that are able to extend the interval QT, but do not tend to significantly increase plasma concentrations due to inhibition of the isoenzyme CYP3A4 under the action of telprevir (for example, methadone).

    2. In the presence of electrolyte disorders (hypokalemia, hypomagnesemia)

    Pregnancy and lactation:

    Pregnancy and contraceptive requirements

    Telaprevir does not have teratogenic effects in rats and mice, and is not considered toxic to the developing offspring of these animal species. Because Insivo is administered along with peginterferon alfa and ribavirin, contraindications and precautions related to these drugs also apply to combination therapy.

    Ribavirin has a pronounced teratogenic and / or embryotoxic effect in all studied animal species (see the instructions for the use of ribavirin). Therefore, extreme caution should be exercised to prevent pregnancy in female patients and in male partner partners.

    Lactation

    It is not known whether telaprevir with breast milk of women. Because of the possible adverse effects of the INSOVO preparation on infants, breast-feeding should be discontinued before treatment begins. See also the instructions for use of ribavirin.

    Dosing and Administration:
    Treatment with Insivo should be carried out by a doctor who has sufficient experience in the treatment of chronic hepatitis C.

    Dosing regimen

    Inside, two tablets 375 mg (750 mg total) every 8 hours during a meal. The total daily dose is 6 tablets (2250 mg). Tablets should be swallowed whole, not liquid, do not crumble or dissolve. Receiving Insivo drug on an empty stomach, as well as non-compliance with the dosing regimen can lead to a decrease in the concentration of telalrevir in the blood plasma, which, as a result, may reduce the therapeutic effect of the drug.

    In case of missed intake of the next dose of Insivo, if less than 4 hours have passed from the planned time of treatment, the missed dose should be taken with food as soon as possible. If more than 4 hours have passed from the planned time of reception, then the missed dose should not be taken, but the next regular dose should be taken as per the usual schedule.This recommendation is based on the fact that the half-life of telprevir is approximately 4 hours, and the recommended inter-dose interval is 8 hours.

    Duration of treatment in adult patients who had not previously received antiviral therapy, hepatitis C or having a previous relapse.

    The preparation of Insivo should be given in combination with peginterferon alfa and ribavirin / This combination of drugs should be used during the first 12 weeks of therapy (see Figure 1).

    Patients who do not have the presence of ribonucleic acid of hepatitis C virus (HCV RNA) in the blood at the 4th and 12th weeks of treatment should continue therapy with only peginterferon alfa and ribavirin for another 12 weeks. The total duration of treatment is 24 weeks.

    Patients in whom HCV RNA is detected in the blood at the 4th or 12th week of treatment should continue therapy with only peginterferon alfa and ribavirin for another 36 weeks. The total duration of treatment will be 48 weeks.

    For all patients with cirrhosis, regardless of whether HCV RNA was detected at the 4th or 12th week of treatment, it is necessary to continue therapy with only peginterferon alfa and ribavirin for an additional 36 weeks.

    The total duration of treatment will be 48 weeks.

    During treatment, the presence of HCV RNA in patients at the 4th and 12th weeks should be determined. It must be taken into account that the lack of HCV RNA in the blood test may be due to the situation that the HCV RNA content is below the quantification limit in this study. This can lead to unreasonable reduction of therapy and, as a consequence, to an increase in the percentage of relapses. Table 2 lists cases in which treatment with a combination of Insivo, peginterferon alfa and ribavirin should be discontinued.

    Duration of treatment of adult patients who had previously received antiviral therapy for hepatitis C who had a partial response to therapy or who had not responded to therapy.

    The preparation of Insivo should be prescribed in combination with peginterferon alfa and ribavirin. This combination should be used during the first 12 weeks of therapy, after which it is necessary to continue therapy only with peginterferon alfa and ribavirin for another 36 weeks. The total duration of treatment will be 48 weeks, (see Figure 2).

    Figure 2.Duration of treatment of adult patients who had previously received antiviral therapy for hepatitis C who had a partial response to therapy or who had not responded to therapy.

    During treatment with the combination of Insivo, peginterferon alfa and ribavirin, the presence of HCV RNA in patients on the 4th and 12th weeks of treatment. Table 2 lists cases in which treatment with the combination of Insivo, peginterferon alfa and ribavirin should be discontinued.

    All patients

    In patients with HCV RNA> 1000 IU / ml at the 4th or 12th week of treatment, it is recommended to cancel therapy with telaprevir, peginterferon alfa and ribavirin (see Table 2).

    Table 2. Guide to discontinuing treatment with a combination of Insivo, peginterferon alfa and ribavirin1

    A drug

    HCV RNA> 1000 IU / ml at the 4th week of treatment 2

    HCV RNA> 1000 IU / mL at the 12th week of treatment2

    Insivo

    Finish reception definitively

    The treatment of Insivo is over.

    Peginterferon alfa and ribavirin

    - Finish reception definitively

    1 This guideline is not applicable if, prior to treatment, a preliminary phase of treatment with peginterferon alfa and ribavirin was used in order to identify patients with no virologic response.

    2 Treatment with a combination of Insivo, peginterferon alfa and ribavirin.

    In patients with a history of virologic failure, additional testing for HCV RNA between 4 and 12 weeks of treatment should be considered. In the event that the HCV RNA concentration exceeds 1000 IU / ml, treatment with a combination of Insivo, peginterferon alfa and ribavirin should be discontinued.

    Patients assigned a 48-week course of treatment should stop peginterferon alfa and ribavirin therapy if they detected HCV RNA at the 24th or 36th week of treatment.

    Criteria for dose adjustment, interruption, cancellation and resumption of peginterferon alfa and ribavirin are indicated in the instructions for the use of appropriate drugs.

    Special categories of patients

    Impaired renal function

    Currently, there is no data on the use of telaprevir in patients with HCV with impaired renal function of moderate or severe degree (creatinine clearance ≤50 ml / min). In RNA HCV-negative volunteers with impaired renal function severely, there was no clinically significant change in the concentration of telaprevir in the blood. Therefore, there is no need for correction of the dose of telaprevir in patients with impaired renal function.

    Clinical data on the use of the drug Insivo in patients on hemodialysis are absent.

    The use of ribavirin is contraindicated in patients with a creatinine clearance less than 50 mL / min (see. For Ribavirin application instructions).

    Impaired liver function

    Insivo drug is not recommended for patients with impaired liver moderate or severe function (class B or C, ≥7 points on a scale Child-Pugh) or decompensated liver disease.

    Patients with mild hepatic impairment (Class A, 5-6 points on a scale Child-Pugh) dose adjustment is not required Insivo drug.

    See also the instructions for the use of ribavirin and peginterferon alfa. Both drugs are contraindicated in patients with a moderate and severe liver dysfunction (> 6 on the Child-Pugh scale).

    Elderly patients

    At present, there is insufficient data on the efficacy and safety of telaprevir in patients older than 65 years.

    Children

    Data on the efficacy and safety of the use of Insivo in children under the age of 18 are not available.

    Side effects:
    Before the drug Insivo following adverse reactions occurred with a frequency of ≥1%: anemia (chastota≥5%), rash (≥ 5%), thrombocytopenia, lymphopenia, pruritus (≥5%), nausea (≥5%), diarrhea (≥ 5%).It is important to note that, due to the need for taking Insivo in combination with peginterferon alfa and ribavirin, unwanted reactions caused by these drugs can also occur (see instructions for the use of peginterferon alfa and ribavirin). The data on the safety of the use of the INSOVO preparation obtained from clinical studies are systematized relative to each of the organ systems, depending on the frequency of occurrence using the following classification: very frequent (≥1/10), frequent (≥1 / 100, <1/10), infrequent (≥1 / 1000, <1/100), rare (≥1 / 10000, <1/1000).

    Infections and parasitic diseases:

    Frequent: candidiasis of the oral cavity.

    Violations from the blood and lymphatic system:

    Very frequent: anemia.

    Immune system disorders:

    Infrequent: hives;

    Rare: Stevens-Johnson Syndrome.

    Disorders from the endocrine system:

    Frequent: hypothyroidism.

    Disorders from the metabolism and nutrition:

    Infrequent: gout.

    Impaired nervous system:

    Frequent: faint.

    Impaired vision:

    Infrequent: retinopathy.

    Disorders from the gastrointestinal tract:

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

    Frequent: perversion of taste, rectal bleeding, anal fissure, anorectal itching;

    Infrequent: proctitis.

    Disturbances from the skin and subcutaneous tissues:

    Very frequent: itching, rash;

    Frequent: eczema, face swelling, exfoliative rash;

    Infrequent: a drug rash with eosinophilia and systemic (DRESS-) symptoms;

    General disorders:

    Infrequent: peripheral edema.

    Violations from laboratory indicators:

    Frequent: hyperbilirubinemia, thrombocytopenia, lymphopenia, hyperuricemia, hyperkalemia, decreased hemoglobin concentration in the blood, a decrease in the number of leukocytes in the blood, an increase in the level of low-density lipoproteins, an increase in the concentration of total cholesterol;

    Infrequent: an increase in the concentration of creatinine in the blood.

    It should be noted that by the 24th week of treatment, most of the laboratory parameters returned to values ​​comparable to those for the therapy with only peginterferon alfa and ribavirin. The only exception was the platelet count, which remained below the value observed with only peginterferon alfa and ribavirin therapy, until the 48th week of combination therapy.

    An increase in the concentration of uric acid in the blood plasma was very often observed during therapy with a combination of Insivo drugs, peginterferon alfa and ribavirin. The concentration of uric acid usually decreased in the course of the next 8 weeks, and was comparable to the values ​​observed in patients treated with only peginterferon alfa and ribavirin.

    Rash.

    The occurrence of rash was more common in patients; who took telaprevir with peginterferon alfa and ribavirin than in patients taking only peginterferon alfa and ribavirin. In 90% of cases, there was a mild to moderate rash, which did not require the withdrawal of Insivo. Usually, with the reception of telaprevir, there was an eczematous rash with itching, which captured less than 30% of the body surface. Some cases of rash have been described as maculopapular or erythematous. More than half of cases of unwanted skin reactions were detected during the first 4 weeks of therapy, however, the rash could appear at any period of combined therapy.

    See the "Specific guidance" section for monitoring rash and cancellation rules for insivo, ribavirin, and peginterferon alfa.Patients with mild to moderate rash should be observed for progression of the severity of skin symptoms; however, progression is rare (less than 10% of cases). To correct unwanted skin reactions, it is recommended that antihistamines and local glucocorticosteroids be prescribed. The resolution of the rash was observed after the cessation or withdrawal of the insivo. However, in some cases it may take several weeks.

    Anemia

    Reduction of hemoglobin concentration was stronger and more frequent in patients taking telaprevir in combination with peginterferon alfa and ribavirin than in patients taking only peginterferon alfa and ribavirin. Anemia of severe severity was noted in 2 - 3 % patients who received telaprevir.

    Anorectal Syndrome

    Most of the reported cases of anorectal syndrome(hemorrhoids, anorectal discomfort, anorectal pruritus and anorectal burning) were of mild or moderate severity, very rarely led to withdrawal of the drug and, as a rule, passed after the completion of combination therapy.

    Overdose:

    When taking Insivo in a dose of 1875 mg every 8 hours for 4 days, the following adverse reactions were observed: nausea, headache, diarrhea, decreased appetite, taste distortion and vomiting.

    There is no specific antidote for telaprevir. Treatment of overdose includes general supportive measures, including monitoring of vital signs and clinical status of the patient. If necessary, the non-absorbed active substance is removed by stimulating vomiting or by rinsing the stomach. Activated carbon is also effective.

    It is not known whether the telaprevir by peritoneal dialysis or hemodialysis.

    Interaction:
    Telaprevir is mainly metabolized in the liver by isoenzyme CYP3 A, and is also a substrate of P-glycoprotein. All drugs metabolized by this isoenzyme and / or P-glycoprotein or affecting its activity may alter the pharmacokinetics of telaprevir.

    Simultaneous reception of telaprevir and drugs that are inhibitors of the isoenzyme CYP3A and / or P-glycoprotein, can lead to an increase in the concentration of telaprevir in the blood plasma.The use of telaprevir can increase the systemic effect of drugs metabolized by the isoenzyme CYP3A and / or P-glycoprotein, which may enhance or prolong their therapeutic effect and undesirable drug reactions.

    Drug interactions were studied only in adult patients.

    Preparations, the reception of which is contraindicated simultaneously with the use of telaprevir

    Substrates of the isoenzyme CYP3A with a narrow therapeutic range The preparation of Insivo can not be used simultaneously with preparations that are substrates of the isoenzyme CYP3A and having a narrow therapeutic range. This can lead to an increase in the concentration of these drugs in the blood plasma and the occurrence of serious and / or life-threatening adverse reactions, including a violation of the rhythm of the heart (amiodarone, astemizole, bepridil, cisapride, pimozide, quinidine, terfenadine), spasm of peripheral vessels or ischemia (ergotamine, dihydroergotamine, ergonovine, methelergonovin), myopathies, including rhabdomyolysis (lovastatin, simvastatin, atorvastatin), prolonged or increased sedation or respiratory depression (oral midazolam, triazolam), falling blood pressure and heart rhythm disturbances (alfuzosin and sildenafil, used to treat pulmonary hypertension). Insivo should not be used concomitantly with any drug in class 1a, 1c or class III antiarrhythmic drugs, with the exception of lidocaine for intravenous administration.

    Rifampicin

    Rifampicin decreases the area under the concentration-time curve (AUC) telaprevir in blood plasma by about 92%. Therefore, the preparation of Insivo can not be used simultaneously with rifampicin.

    Drugs based on St. John's wort Perforated (Hypericum perforatum)

    Reception of herbal preparations on the basis of St. John's Wort (Hypericum perforatum) Simultaneously with the preparation, Insivo can reduce the concentration of telaprevir in the blood plasma. Therefore, herbal preparations based on St. John's wort can not be used concurrently with Insivo. Carbamazepine, phenytoin and phenobarbital

    The simultaneous use of telaprevir and inducers of hepatic enzymes can lead to a decrease in telaprevir exposure and a likely decrease in efficacy. Contraindicated potential isoenzyme inducers CYP3A, such as carbamazepine, phenytoin and phenobarbital.

    Inductors of isoenzyme CYP3A weak and moderate action

    It is necessary to avoid simultaneous application of triple therapy and isoenzyme inducers CYP3A mild to moderate in particular, in patients who have not previously had a response to therapy (partial or complete absence of response to peginterferon alfa and ribavirin therapy), except when specific dosage recommendations are given (see - Table 3 , Recommendations for the dosing of drugs exhibiting drug interaction with the drug Insivo).

    Children

    Drug interactions are studied only in adults.

    Special instructions:
    Are common

    Insivo should be used only in combination with peginterferon alfa and ribavirin, otherwise treatment will be ineffective. The dose of Insivo should not be reduced, as this can lead to ineffective therapy.

    The preparation of Insivo can not be used as monotherapy or only with peginterferon alfa or only with ribavirin.

    Before using Insivo, you should read the instructions for using peginterferon alfa and ribavirin.

    Clinical data on the use of Insivo in patients who did not have the effect of therapy, including a protease inhibitor NS3-4A HCV, or the repeated use of Insivo is not.

    If you want to stop using Insivo because of serious undesirable side reactions to the drug or an insufficient virologic response, then you can not resume treatment with Insivo once.

    Rash

    There are cases of severe rash in patients with a combination of Insivo, peginterferon alfa and ribavirin. The incidence of Stevens-Johnson syndrome was noted in less than 0.1% of patients. In all cases, the rash was resolved after discontinuation of therapy. The patient should be informed of the likelihood of developing a severe rash and the need for consultation with the doctor in case of a new rash or increased severity of the existing rash.

    Table 4 provides recommendations for assessing the degree of severity and correcting the rash.

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

    Degree of severity

    Recommendations

    Mild rash: a localized rash and / or localized - a rash with a lesion of a limited part of the body surface (can appear on several isolated areas of the body)

    It is necessary to monitor the progression of the rash until the symptoms are completely resolved.

    Rash of moderate severity: diffuse rash, covering <50% of the body surface

    Monitor the progression of the rash or systemic symptoms until the rash disappears. Consider the possibility of consulting a dermatologist.

    In case of a rash progression, consider the possibility of discontinuing the use of Insivo. If a moderate degree of rash continues to develop and no improvement occurs within 7 days after discontinuation of the INSIVO preparation, ribavirin should be discontinued.


    An earlier discontinuation of ribavirin may be required if there is a significant progression of the rash after the discontinuation of telaprevir. It is possible to continue the use of peginterferon alfa, except when medically required to stop the use of peginterferon alfa.

    In the case of progression of a moderate degree of severe rash to a severe degree (with a lesion of more than 50% of the body area), it is necessary to completely cancel the use of Insivo.

    Rash severe: rash captures more than 50 % surface of the body or is associated with significant systemic symptoms, the occurrence of ulcers on the mucous membranes, the defeat of target organs, exfoliation of the epidermis

    Immediately stop taking Insivo, consult a dermatologist, monitor the condition of the patient until the rash disappears. Therapy with ribavirin and peginterferon alfa can be continued. If there is no improvement in the patient's condition within 7 days after the discontinuation of the insivo drug, simultaneous or sequential temporary or permanent discontinuation of ribavirin and / or peginterferon alfa is recommended. For medical reasons, an earlier discontinuation or withdrawal of ribavirin and / or peginterferon alfa may be required.

    Diagnosis or suspicion of generalized bullous rash, DRESSsyndrome, Stevens-Johnson syndrome / toxic epidermal necrolysis, acute generalized exentematous pustulosis, polymorphic exudative erythema Symptoms of Stevens-Johnson syndrome: a common severe rash with skin flaking that can be accompanied by fever, flu-like symptoms, blisters in the mouth, eye area and / or on the genitals

    Immediately complete stop using Insivo, peginterferon alfa and ribavirin, consult a dermatologist.


    The treatment with insivo can not be resumed again after it has been withdrawn. See also information on the development of skin reactions in instructions for the use of ribavirin and peginterferon alfa.

    Anemia

    When using Insivo in combination with peginterferon alfa and ribavirin, the incidence of anemia, including severe, increases. It is recommended to monitor the concentration of hemoglobin before and during therapy.

    See recommendations for changing the dosage of ribavirin for patients with anemia in the instructions for the use of ribavirin. In the case of the abolition of ribavirin due to the development of anemia, it is also necessary to cancel the therapy with telaprevir. With the elimination of telaprevir due to the development of anemia, patients can continue treatment with ribavirin and peginterferon alfa during the prescribed period. Treatment with ribavirin can be resumed according to the recommendation of the ribavirin application. Do not reduce the dose of telaprevir and resume treatment with telaprevir in the event of its cancellation.

    Pregnancy and contraceptive requirements

    Because Insivo is taken with peginterferon alfa and ribavirin, the contraindications and precautions related to these drugs also apply to combination therapy.

    Ribavirin has a pronounced teratogenic and / or embryotoxic effect in all studied animal species (see the instructions for the use of ribavirin). Therefore, extreme caution should be exercised to prevent pregnancy in female patients and in male partner partners. You should use at least two effective contraceptives during treatment with a combination of Insivo, peginterferon alfa and ribavirin, and for six months after its completion.

    Treatment can begin only after receiving a negative result of the pregnancy test, conducted just before the beginning of treatment. The pregnancy test should be performed monthly during the period of combination therapy and within 6 months after completion of treatment. The use of Insivo along with hormonal contraceptives containing estrogen reduces the systemic effect of ethinylestradiol.Since hormonal contraceptives during the treatment with Insivo may not be reliable, female fertility patients should use two other effective non-hormonal contraceptives during the combination therapy, Incivo, and within 2 months after the last intake of Insivo. For example, you can use a male condom with a spermicidal gel OR a female condom with a spermicidal gel (not both at the same time), a diaphragm with a spermicidal gel, a cap on the cervix with a spermicidal gel. Two months after the end of treatment with Insivo, you can resume taking estrogen-containing hormonal contraceptives as one of the two necessary effective contraceptives, but the recommendations in the instructions for the use of appropriate drugs should be taken into account.

    Male patients whose partners are pregnant should use a condom to minimize the effects of ribavirin on the partner.

    Drug Interactions

    List of drugs that can not be taken concurrently with Insivo because of.possible life-threatening adverse events, significant drug interactions, or loss of therapeutic effect of Insivo, is given in the section "Contraindications." Other known and potentially significant drug interactions are described in the section "Interaction with other drugs".

    Interval lengthening QT

    Caution should be exercised with simultaneous prescription of the drug Insivo with drugs that are substrates of the isoenzyme CYP3 A and increasing the interval QT, such as erythromycin, clarithromycin, telithromycin, posakonazol, voriconazole, ketoconazole, tacrolimus, salmeterolIt is necessary to avoid the simultaneous administration of domperidone and telaprevir. Because the telaprevir is also a substrate of isoenzyme CYP3A, it can inhibit the metabolism of these drugs. The result of this may be an increase or prolongation of their action, including side effects from the cardiovascular system. In case the simultaneous administration of telaprevir and such preparations is necessary, careful monitoring of the patient's clinical condition, including ECG monitoring, should be carried out.It is undesirable to prescribe the drug Insivo to patients who have an inherent lengthening interval QT or congenital lengthening of the interval QT in a family history. In the event that the appointment of telprevir to such patients is necessary, careful monitoring of the patient's clinical condition, including ECG monitoring, should be carried out.

    The preparation of INSIVO should be administered with caution to the following groups of patients:

    - with the acquired prolongation of the interval QT in the anamnesis;

    - with clinically significant bradycardia (persistent heart rate less than 50 bpm)

    - with heart failure with a drop in the left ventricular ejection fraction in the anamnesis;

    - - requiring medicines, which are capable,
    lengthen the interval QT, However, they do not tend to a significant

    increase in plasma concentration due to inhibition of the isoenzyme CYP3A4 under the action of telprevir (for example, methadone).

    Electrolyte disturbances (such as hypokalemia, hypomagnesemia and hypocalcemia) are subject to control and, if necessary, correction before and throughout the treatment with Insivo.

    Laboratory indicators

    The presence of HCV RNA should be monitored at the 4th and 12th weeks, as well as in accordance with clinical indications.

    All patients before the start of combined treatment with the use of the preparation of INSOVO need to conduct the following laboratory assessments: a complete blood count with a leukocyte formula, the concentration of electrolytes, serum creatinine, TSH (thyroid-stimulating hormone), uric acid.

    Below are the recommended baseline values ​​of laboratory indicators, in which it is possible to start a combined treatment with the use of Insivo:

    - hemoglobin> 12 g / dL (women); > 13 g / dl (male);

    - thrombocytes> 90 000 / mm3;

    - absolute number of neutrophils> 1500 / mm3;

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

    - estimated creatinine clearance> 50 ml / min;

    - potassium concentration> 3.5 mmol / l.

    Conducting general blood tests (including the analysis of the leukocyte formula) is recommended at the 2nd, 4th, 8th and 12th weeks, and then on clinical indications.

    Biochemical blood test (concentration of electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, TSH) is recommended to be carried out at the same frequency as the general blood tests, or according to clinical indications.

    Cm.instructions for the use of peginterferon alfa and ribavirin, including the requirements for testing for pregnancy.

    Inadequate response to treatment

    Patients with an unsatisfactory response to antiviral therapy should be discontinued.

    Use of Insivo in combination with peginterferon alfa-2b All clinical studies of the 3 phases were conducted using peginterferon alfa-2a in combination with the preparation of Insivo and ribavirin. Data on the use of Insivo in combination with peginterferon alfa-2b in patients previously treated are not available, and data on use in patients who have not previously received treatment are limited. In patients who had not previously received treatment with peeginterferon alfa-2a / ribavirin (n = 80) or peginterferon alfa-2b ribavirin (n = 81) in combination with Insivo in an open study, a comparable frequency of persistent virologic response was noted. However, in patients treated with peginterferon alfa-2b, the increase in viral load was more frequent, and they less often met the criteria for reducing the overall duration of therapy.

    Use of Insivo in the treatment of other HCV genotypes There is insufficient clinical data on the treatment of patients with other genotypes of HCV, in addition to the 1st genotype. In this regard, the use of Insivo in patients with other genotypes of HCV, in addition to the first, is not recommended.

    Impaired renal function

    Safety and efficacy have not been established for patients with moderate or severe renal impairment (creatinine clearance <50 mL / min) or patients on hemodialysis. See also the instructions for using ribavirin for patients with creatinine clearance <50 mL / min.

    Impaired liver function

    The use of Insivo in patients with severe impairment of liver function (class C,> 10 on the Child-Pugh scale) or decompensated liver function disorder has not been studied and the use of telaprevir in such patients is not recommended.

    The use of telaprevir has also not been studied in patients with impaired liver function of moderate severity (grade B, 7-9 on the Child-Pugh scale). The recommended dose of Insivo for these patients is not established. Therefore, the use of Insivo in these patients is not recommended.

    Cm.instruction on the use of peginterferon alfa and ribavirin preparations, which should be administered concurrently with Insivo.

    Transplantation

    There are no clinical data on treatment with Insivo in combination with peginterferon alfa and ribavirin in patients before transplantation, in the near trans-transplant period, or after transplantation earlier. In this regard, the use of Insivo in patients who are candidates for transplantation or who have undergone transplantation is not recommended (see also the section "Interaction with other drugs", item "Immunodepressants").

    HCV / HIV co-infection (human immunodeficiency virus)

    Data on the treatment of patients with HCV / HIV co-infection not receiving antiretroviral therapy or being treated with efavirenz or atazanavir / ritonavir in combination with tenofovir dizoproxil fumarate and emtricitabine or lamivudine also receiving Insivo in combination with peginterferon alfa and ribavirin are limited . See section "Interaction with other drugs".

    Concomitant HCV / HBV infection (hepatitis B virus)

    There is no data on the use of Insivo in patients with concomitant HCV / HBV infection.

    Use in children

    Insivo is not recommended for use in children and adolescents under the age of 18, since its safety and efficacy in this population have not been established.

    Thyroid gland diseases

    During the combined treatment, including the preparation of INSOVO, there may be a rise in the blood of thyroid-stimulating hormone (TSH) concentration, which may indicate an aggravation or relapse of previously existing or past hypothyroidism or the occurrence of hypothyroidism de novo. The concentration of TSH in the blood should be monitored before and during treatment with a combination of Incivo. Treatment is conducted in accordance with clinical feasibility, including correction of the dose of thyroid hormone replacement therapy in patients with already existing hypothyroidism may be required.

    Important information about some of the excipients that make up the Incivo

    This medication contains 2.3 mg of sodium in one tablet, which must be taken into account when treating patients receiving a diet with a controlled sodium content.

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

    The Insivo drug has little or no effect on the ability to drive vehicles and work with machinery. No relevant studies have been carried out. Fainting and retinopathy have been reported in some patients taking Insivo, which must be considered when assessing a patient's ability to drive vehicles or work with mechanisms. See also instructions for the use of peginterferon alfa and ribavirin for more information.

    Form release / dosage:

    Tablets coated with a film coating, 375 mg.

    Packaging:For 42 tablets in a bottle of high density polyethylene with a polypropylene screw cap with a first opening control, protected from accidental opening by children. The bottle contains bags with a desiccant (silica gel). 1 or 4 bottles together with instructions for use are placed in a cardboard pack.
    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Store the drug in its original packaging. Keep the bottle well-ukuporennym for protection from moisture. Do not throw away bags of dehumidifier. Keep out of the reach of children.

    Shelf life:2 years.Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-001931
    Date of registration:14.12.2012 / 15.07.2014
    Expiration Date:14.12.2017
    Date of cancellation:2016-11-15
    The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia
    Manufacturer: & nbsp
    Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia
    Information update date: & nbsp30.10.2017
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