Eviplera

General characteristics. Structure:

Active agents: эмтрицитабин 200 mg, a rilpivirina the hydrochloride of 27,5 mg ( in terms of рилпивирин – 25 mg), тенофовир dizoproksit the fumarating 300 mg.

Excipients (kernel): cellulose of microcrystallic 210,00 mg, lactoses monohydrate of 269,80 mg, povidone of 3,25 mg, prezhelatinizirovannny starch of 50,00 mg, polysorbate of 200,35 mg, sodium of a kroskarmelloz of 76,10 mg, magnesium stearate of 13,00 mg.

Excipients (cover): gipromelloza (2910 6 мПа.с) 13,80 mg, dye indigo carmine varnish aluminum (E132) of 0,093 mg, lactoses monohydrate of 7,25 mg, macrogoal of 2,76 mg, dye iron oxide red (E172) of 0,11 mg, dye sunset yellow varnish aluminum (E110) of 0,02 mg, titanium dioxide (E171) of 8,40 mg, triacetin of 2,07 mg.

Description: kapsuloobrazny tablets, film coated from color, light pink to pink with a violet shade. On one party "GSI" is engraved. On cross section a kernel of a tablet of white color.

Pharmacological properties:

Pharmacodynamics. Eviplera is the combined drug with the fixed dose of a rilpivirin, a tenofovir, an emtritsitabin.

Action mechanism. Emtritsitabin is a nukleozidny analog of cytidine. Tenofovira of the dizoproksil fumarating will be transformed by in vivo in тенофовир, an analog of a nukleozidmonofosfat (nucleotide) of adenosine of monophosphate". Both эмтрицитабин, and тенофовир, have specific activity concerning a human immunodeficiency virus (VICh-1 and VICh-2) and a virus of hepatitis B. Rilpivirin represents diarilpirimidinovy nenukleozidny inhibitor of the return VICh-1 transcriptase. Activity of a rilpivirin is mediated by non-competitive inhibition of the return VICh-1 transcriptase. Emtritsitabin and тенофовир are phosphorylated by cellular enzymes with formation of an emtritsitabin of triphosphate and a tenofovir of diphosphate, respectively. The researches in vitro showed that both эмтрицитабин, and тенофовир, can be phosphorylated completely at simultaneous stay in a cell. Emtritsitabina triphosphate and a tenofovira diphosphate inhibit the return VICh-1 transcriptase on the competitive mechanism, leading to termination of synthesis of a chain of virus DNA. Both an emtritsitabina triphosphate, and a tenofovira diphosphate are weak inhibitors of a DNA polymerase of mammals. In vitro and in vivo of data on their toxicity concerning mitochondrions is not available. Rilpivirin does not inhibit cellular α and β a DNA polymerase of the person and mitochondrial γ a DNA polymerase.

Antiviral activity of in vitro. The combination of an emtritsitabin, a rilpivirin and a tenofovir shows synergistic antiviral activity in cellular culture.

Antiviral activity of an emtritsitabin concerning laboratory and clinical VICh-1 isolates was estimated on the line of limfoblastoidny cells, the line of cells MAGICCR5 and on mononuclear cells of peripheral blood. Values of 50% of effective concentration (EC50) of an emtritsitabin were in the range from 0,0013 to 0,64 µmol. Emtritsitabin shows antiviral activity in cellular culture concerning the A, B, C, D, E, F subtypes, and G VICh-1 (range of EC50 values from 0,007 to 0,075 µmol), and also specific activity concerning VICh-2 strains (range of EC50 values from 0,007 to 1,5 µmol).

In researches of a combination of an emtritsitabin with the nukleozidny inhibitors of the return transcriptase (NIRT) (абакавир, диданозин, ламивудин, ставудин, тенофовир and a zidovudine), nenukleozidny inhibitors of the return transcriptase (NNIOT) (делавирдин, эфавиренз, not Virapinum and рилпивирин) and the protease inhibitors (PI) (ампренавир, нелфинавир, ритонавир and саквинавир) observed the additive or synergy effect. Rilpivirin shows activity concerning laboratory strains of VICh-1 of wild type on sharply infected T-cellular line with a median of EC50 VICh-1/IIIB value 0,73 nmol (0,27 ng/ml). Though in vitro рилпивирин showed limited activity concerning VICh-2 with EC50 values in the range from 2,510 to 10,830 nmol (from 920 to 3970 ng/ml), in lack of clinical data treatment of an infection of VICh-2 of a rilpivirin is not recommended by a hydrochloride. Rilpivirin also showed antiviral activity concerning a wide range of primary isolates of strains of VICh-1 of group M (the A, B, C, D, F, G subtype, H) with EC50 values in the range from 0,07 to 1,01 nmol (from 0,03 to 0,37 ng/ml) and primary isolates of group O with EC50 values in the range from 2,88 to 8,45 nmol (from 1,06 to 3,10 ng/ml).

Antiviral activity of a tenofovir concerning laboratory and clinical VICh-1 isolates was estimated on limfoblastoidny cellular lines, generally on monocytes/macrophages and on peripheral blood lymphocytes. EC50 values of a tenofovir were in the range from 0,04 to 8,5 µmol. Tenofovir showed antiviral activity in cellular culture concerning the A, B, C, D, E, F, G and O VICh-1 subtypes (range of EC50 values from 0,5 to 2,2 µmol), and also specific activity concerning VICh-2 strains (range of EC50 values from 1,6 µmol to 5,5 µmol). In researches of a combination of a tenofovir with NIOT (абакавир, диданозин, эмтрицитабин, ламивудин, ставудин and a zidovudine), NNIOT (делавирдин, эфавиренз, not Virapinum and рилпивирин) and SP (ампренавир, индинавир, нелфинавир, ритонавир and саквинавир) was observed the additive or synergy effect.

Resistance. Cellular culture. Resistance to an emtritsitabin or a tenofovir was observed by in vitro and at some VICh-1 of the infected patients owing to substitution in codons of M184V or M184I of the return transcriptase (RT) for an emtritsitabin or in a codon of K65R of the return транскриптазыдля a tenofovira. Other mechanisms of development of resistance to an emtritsitabin or a tenofovir were not revealed. Emtritsitabin-rezistentnye viruses with a mutation of M184V/I showed cross resistance to a lamivudin, but remained sensitive to a didanozin, a stavudin, a tenofovir, a zaltsitabin and a zidovudine. The mutation in K65R codon can be also connected with resistance to an abakavir or a didanozin and to lead to decrease in sensitivity to these drugs, and also to a lamivudin, an emtritsitabin, and a tenofovir. Tenofovir should not be applied at patients with K65R VICh-1 mutation. VICh-1 with mutations in codons of K65R, M184V and K65R+M184V remains completely sensitive to a rilpivirin. Resistant to a rilpivirin and to NNIOT strains were allocated on cellular cultures from the wild VICh-1 types of various nature and subtypes. Such mutations as L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I connected with resistance were most often observed. Taking into account all available in vitro and in vivo of data at the patients who were earlier not receiving anti-retrovirus therapy the following mutations can influence activity of drug of Evipler: K65R, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, H221Y, F227C, M230I and M230L (at their identification prior to treatment). These, connected with resistance, mutations have to be considered only when using drug of Evipler for treatment of the patients who were earlier not receiving anti-retrovirus therapy. These mutations connected with resistance were revealed according to in vivo only at the patients who were earlier not receiving treatment and therefore cannot be used for forecasting of activity of drug of Evipler at patients with virologic inefficiency of anti-retrovirus therapy. As well as when using other anti-retrovirus means, against the background of administration of drug of Evipler the research of genotypic resistance has to be conducted. VICh-1 the infected patients who were earlier not obtaining anti-retrovirus therapy In the integrated analysis of the data obtained during clinical trials of the III phase (C209 and C215) among the patients receiving emtritsitabin/tenofovir + рилпивирин at 62 patients was established virologic failure of therapy, at the same time information on development of resistance was available to 54 of 62 patients. Amino-acid replacements which were associated with resistance to NNIOT were established and most often occurred at such patients: V90I, K101E, E138K/Q, Y181C, V189I and H221Y. However existence of such mutations as V90I and V189I did not exert impact on efficiency of treatment. At more than 3 patients during therapy the mutations connected with resistance to NIOT were revealed: K65R, K70E, M184V/I and K219E.

Cross resistance. At development of resistance of VICh-1 to a rilpivirin development of cross resistance to an emtritsitabin and a tenofovir and vice versa is not noted. 

Resistance on cellular culture. Emtritsitabin: strains, resistant to an emtritsitabin, with substitution in a codon of M184V/I showed cross resistance to a lamivudin, but remained sensitive to a didanozin, a stavudin, a tenofovir and a zidovudine. Strains of viruses with the substitutions causing decrease in sensitivity to a stavudin and with resistance mutations to analogs of a zidovudine thymidine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or a didanozin (L74V), remained sensitive to an emtritsitabin. VICh-1 containing the substitution of K103N or other substitutions connected with resistance to a rilpivirin and other NNIOT remained sensitive to an emtritsitabin. Rilpivirin: in group of 67 recombinant laboratory strains of VICh-1 with a resistance mutation to NNIOT in one codon FROM, including the mutations which are most extended by K103N and Y181C, рилпивирин showed antiviral activity concerning 64 (96%) from these strains. The resistance mutations in one codon connected with an anesthesia to a rilpivirin were: K101P and Y181V/I. Tenofovir: the mutation in K65R codon can be also connected with resistance to an abakavir or a didanozin and to lead to decrease in sensitivity to these drugs, and also to a lamivudin, an emtritsitabin and a tenofovir, at preservation of sensitivity to a zidovudine. At patients with three and more mutations of resistance of VICh-1 to zidovudine analogs - thymidine, including M41L or L210W, decrease in level of response on тенофовир was noted. The virologic answer on тенофовир was not lowered at patients with VICh-1 an infection and with a mutation of M184V connected with resistance to an abakaviru/emtritsitabinu/lamivudin. Patients with mutations of K103N and Y181C, or with the substitutions connected with resistance to a rilpivirin and NNIOT were sensitive to a tenofovir. VICh-1 the infected patients who were earlier not obtaining anti-retrovirus therapy In the integrated analysis of the data obtained during clinical trials of the III phase (C209 and C215) among the patients receiving emtritsitabin/tenofovir + рилпивирин at 54 patients with virologic failure of therapy was available phenotypical information on development of resistance, 37 patients in the course of treatment lost sensitivity to an emtritsitabin, 29 – to a rilpivirin and 2 – to a tenofovir, respectively. Among these patients, 37 were steady against a lamivudin, 28 against an etravirin, 26 against an efavirenz, and 12 against not Virapinum. Decrease in sensitivity to a kabakavir and/or a didanozin was in certain cases observed. 

Pharmacokinetics. Absorption. Bioequivalence of one tablet of drug of Evipler, film coated, and combinations of one capsule of an emtritsitabin of 200 mg, one tablet, film coated, a rilpivirina (in the form of a hydrochloride) 25 mg and one tablet, film coated, a tenofovira of a dizoproksil (in the form of a fumarat) 245 mg was defined at use of single doses after food to healthy volunteers. After oral administration of drug of Evipler together with food, эмтрицитабин it was quickly and intensively soaked up in the digestive tract (DT) with achievement of the maximum concentration in plasma within 2,5 hours. The maximum concentration of a tenofovir in plasma (Cmax) is observed within 2 hours, and the maximum concentration of a rilpivirin in plasma is usually reached within 4-5 hours. After  oral administration of a tenofovir of a dizoproksil of a fumarat by HIV-positive patients, it quickly is soaked up and turns in тенофовир. Absolute bioavailability of an emtritsitabin in a dose of 200 mg in the form of solid capsules made 93%. Use of solid gelatin capsules of an emtritsitabin in a dose of 200 mg together with food rich with fats did not influence the square under a curve "concentration time" (AUC) of an emtritsitabin. Peroral bioavailability of a tenofovir at use on an empty stomach of a tenofovir of a dizoproksil of a fumarat made about 25%. The concomitant use of a tenofovir was dizoproksit by a fumarata with the food enriched with fats increased peroral bioavailability (increase in AUC of a tenofovir approximately for 40% and Cmax approximately for 14%). There are no data on absolute bioavailability of a rilpivirin. Exposure of a rilpivirin was about 40% lower at administration of drug on an empty stomach, than at a concomitant use with food of usual caloric content (533 kcal) or with food with the high content of fats (928 kcal). At reception of a rilpivirin of a hydrochloride only with the drink enriched with proteins, exposure of a rilpivirin was 50% lower, than at reception with food. Reception of a rilpivirin of a hydrochloride on an empty stomach or only with the drink enriched with proteins reduces concentration of a rilpivirin in plasma that can potentially reduce therapeutic effect of drug of Evipler. For optimum level of absorption, Evipler's drug has to be accepted together with food.

Distribution. After intravenous administration, the volume of distribution of separate components of an emtritsitabin and tenofovir, approximately made 1400 ml/kg and 800 ml/kg, respectively. After oral administration, эмтрицитабин and тенофовир are widely distributed in an organism. In vitro made linkng of an emtritsitabin with proteins of plasma of the person <4% and did not depend on concentration in the range from 0,02 to 200 mkg/ml. In vitro linkng of a rilpivirin with proteins of plasma makes about 99,7%, generally due to communication with albumine. In vitro linkng of a tenofovir with proteins of plasma and blood serum was less than 0,7% and 7,2% respectively, in the range of concentration of a tenofovir from 0,01 to 25 mkg/ml.

Metabolism. Emtritsitabin is exposed to incomplete metabolism in an organism. Biotransformation of an emtritsitabin includes oxidation of thiol group with formation of 3-sulfoksidny diastereomer (about 9% of a dose) and a konjyugirovaniye with glucuronic acid with formation of a 2-O-glucuronide (about 4% of a dose). In vitro experiments show that the rilpivirina a hydrochloride is exposed to generally oxidizing metabolism mediated by fermental system of an isoenzyme of P450 (CYP3A) cytochrome. In vitro of a research showed that the tenofovira of a dizoproksil fumarates, тенофовир are not substrates of isoenzymes CYP450. Neither эмтрицитабин, nor тенофовир do not inhibit in vitro the medicinal metabolism mediated by any of the main isoenzymes of CYP450 participating in biotransformation. Besides, эмтрицитабин uridine-5-diphosphoglucuronyl does not inhibit transferase (the enzyme responsible for a glyukuronization). 

Removal. Emtritsitabin is generally excreted by kidneys (about 86%) and through intestines (about 14%). 13% of a dose of an emtritsitabin were revealed in urine in the form of three metabolites. The system clearance of an emtritsitabin was on average equal to 307 ml/min. The elimination half-life after oral administration of an emtritsitabin makes about 10 hours. The final elimination half-life of a rilpivirin makes about 45 hours. After use of a single peroral dose of a 14C-rilpivirin, radioactive doses of a byliobnaruzhena in Calais and мочев average in 85% and 6,1%, respectively. To Calais which is not changed рилпивирин averaged 25% of the accepted dose. In urine only insignificant concentration of a rilpivirin were revealed (<1% of a dose). Tenofovir is generally excreted by kidneys, both as a result of filtering, and by means of system of active canalicular transport (the conveyor of organic ions of the person of 1 [hOAT1]). About 70-80% of the accepted dose are excreted in not changed view with urine after intravenous use. The seeming clearance of a tenofovir averaged primerno307 ml/min. The renal clearance has to make about 210 ml/min. that exceeds a glomerular filtration rate. It indicates that active canalicular secretion is an important part of process of removal of a tenofovir. After oral administration, the elimination half-life of a tenofovir averages from 12 to 18 hours.

Special groups of patients. Elderly patients. The population pharmacokinetic analysis of the given VICh-1-infitsirovannykh patients showed that the pharmacokinetics of a rilpivirin remains comparable for all age groups (from 18 to 78 years).

Floor. Clinically significant distinctions in pharmacokinetic parameters of a rilpivirin at men and women were not noted.

Race. Clinically significant distinctions in pharmacokinetic parameters at patients with various ethnic origin were not noted.

Children. In general, pharmacokinetic parameters of an emtritsitabin at newborns, children and teenagers (aged from 4 months up to 18 years) are similar to those that are observed at adults. Pharmacokinetic parameters of a rilpivirin and tenofovir at children and teenagers are studied now. Due to the insufficiency of clinical data, recommendations about dosing at children cannot be provided.

Renal failure. Limited data of clinical trials confirm a possibility of administration of drug of Evipler with patients with a renal failure of easy degree (clearance of creatinine of 50-80 ml/min.) once a day. However at patients with a renal failure of easy degree assessment of safety of separate components of drug was not carried out, the emtritsitabina and a tenofovira dizoproksit a fumarat. Therefore Evipler's drug has to be used at such patients only if the potential advantage of treatment surpasses possible risk. Evipler's drug is contraindicated to patients with a renal failure of average or heavy degree (clearance of creatinine <50 ml/min.). Correction of an interval of dosing of an emtritsitabin and tenofovir is necessary for this group of patients that is not feasible when using of the combined drug. Pharmacokinetic parameters decided in the main ambassador of use of single doses of an emtritsitabin of 200 mg or a tenofovira of a dizoproksil of 245 mg of HIV to not infected patients on a renal failure of varying severity. Severity of a renal failure was defined according to initial clearance of creatinine (CrCl) (normal function of kidneys at CrCl> 80 ml/min.; a renal failure of easy degree at CrCl = 50–79 ml/min.; a renal failure of average degree at CrCl = 30–49 ml/min. and a renal failure of heavy degree at CrCl = 10-29 ml/min.). Average exposure (% of CV) of an emtritsitabin increased with 12 (25%) мкг×ч/мл at patients with normal function of kidneys to 20 (6%) мкг×ч/мл, 25 (23%) мкг×ч/мл and 34 (6%) мкг×ч/мл at patients with a renal failure of easy, average and heavy degree, respectively. Average exposure (%CV) of a tenofovir increased since 2185 (12%) мкг×ч/мл at patients with normal function of kidneys to 3064 (30%) нг×ч/мл, 6009 (42%) нг×ч/мл and 15985 (45%) нг×ч/мл at patients with a renal failure of easy, average and heavy degree, respectively. At patients with an end-stage of a renal failure for whom the hemodialysis was required exposure between dialysis sessions steadily increased within 72 hours to 53 мкг×ч/мл (19%) at an emtritsitabin, and within 48 hours to 42857 нг×ч/мл (29%) at a tenofovir. The pharmacokinetics of a rilpivirin was not studied at patients with a renal failure. Excretion of a rilpivirin kidneys is insignificant. At patients with a renal failure heavy or an end-stage concentration of drug in plasma can increase because of secondary change of absorption, distribution and/or metabolism owing to a renal failure. As рилпивирин has the high level of linkng with proteins of plasma, it is improbable that it will be brought substantially out of an organism at a hemodialysis or at peritoneal dialysis.

Abnormal liver function. Patients with an abnormal liver function of average degree do not need dose adjustment of drug of Evipler, but this group of patients should appoint it with care. at patients with an abnormal liver function of heavy degree (a class C on a scale of Chayld-Pyyu). Therefore it is contraindicated to apply it at patients with a liver failure of heavy degree. The pharmacokinetics of an emtritsitabin was not studied at patients with various degree of an abnormal liver function. Rilpivirina a hydrochloride is metabolized and eliminirutsya generally by a liver. Level of influence of repeated doses of a rilpivirin was 47% higher at patients with a liver failure of easy degree (a class A on a scale of Chayld-Pyyu) and 5% above at patients with a liver failure of average degree (a class B on a scale of Chayld-Pyyu) in comparison with the corresponding control groups. Use of a rilpivirin was not studied at patients with a heavy liver failure (a class C on a scale of Chayld-Pyyu). However it is impossible to exclude that influence pharmacological of an active, not connected rilpivirin significantly increases at a liver failure of average degree. The single dose of a tenofovir of a dizoproksil of 245 mg was applied at HIV-positive patients with various degree of an abnormal liver function which was defined according to a scale of Chayld-Pyyu. Pharmacokinetic parameters of a tenofovir significantly did not change at patients with a liver failure, indicating lack of need of dose adjustment at these patients. Average Cmax and AUC0-values (%CV) ∞ made a tenofovir 223 (34,8%) ng/ml and 2050 (50,8%) нг×ч/мл , respectively, at patients with normal function of a liver, in comparison with 289 (46,0%) ng/ml and 2310 (43,5%) нг×ч/мл at patients with a liver failure of average degree and 305 (24,8%) нг×þ/ml and 2740 (44,0%) нг×ч/мл at patients with a liver failure of heavy degree.

The accompanying infection of hepatitis B and/or hepatitis C. In general, pharmacokinetic parameters of an emtritsitabin at patients with hepatitis B were similar with those that were observed at healthy volunteers and at HIV - the infected patients. According to data of the population pharmacokinetic analysis the accompanying infection caused by a virus of the hepatitis B and/or C does not exert significant impact on the level of influence of a rilpivirin.

Indications to use:

Treatment of the infection caused by a virus of an immunodeficiency of 1 type (VICh-1) as therapy of the first line at the adult patients having indicators of VICh-1 RNA within no more than 100 000 copies/ml.

Route of administration and doses:

Inside. Treatment has to be carried out by the doctor having experience of therapy of HIV infection.

Adults. Evipler's drug is used only orally, on one tablet together with food once a day. The tablet should be swallowed entirely, washing down with water. Tablets cannot be chewed or broken as it can influence drug absorption. If cancellation or change of a dose of one of components of drug of Evipler is required, it is necessary to apply other separate dosage forms of an emtritsitabin which are available in the market, the rilpivirina of a hydrochloride and a tenofovir dizoproksit a fumarat (see application instructions of these drugs). If delay in administration of drug made less than 12 hours, the passed dose should be accepted as soon as possible together with food and to renew the usual mode of a drug dosing. If delay in administration of drug made more than 12 hours, the passed dose should not be accepted; the following pill is taken in usual time. If the patient had a vomiting within 4 hours after administration of drug of Evipler, together with food one more pill of drug of Evipler has to be taken. If ubolny there was vomiting more than in 4 hours after administration of drug of Evipler, there is no need for reception of one more tablet of drug of Evipler until receiving the following planned dose of drug. 

Special groups of patients. Elderly patients.

Use of drug of Evipler was not studied at patients 65 years are more senior. Evipler's drug has to be used with care at elderly patients. 

Renal failure. Treatment by Evipler's drug caused small increase in average concentration of creatinine in blood at early stages of therapy. This parameter remained stable eventually and it is not considered clinically significant.

Limited data of clinical trials confirm the drug dosing mode of Evipler at patients with a renal failure of easy degree (clearance of creatinine of 50-80 ml/min.) once a day. However at patients with insufficiency of function of kidneys of easy degree assessment of safety of separate components of drug was not carried out (the emtritsitabina and a tenofovira dizoproksit a fumarat). Therefore Evipler's drug has to be used at patients with insufficiency of function of kidneys of easy degree only if the potential advantage of treatment surpasses possible risk. It is contraindicated to use Evipler's drug at patients with a renal failure of average or heavy degree (clearance of creatinine <50 ml/min.) as correction of an interval of dosing of an emtritsitabin and tenofovir of a dizoproksil of a fumarat is necessary for such patients that cannot be carried out when using combined drug.

Abnormal liver function. There is limited information concerning use of drug of Evipler for patients with an abnormal liver function of easy and average degree (a class A and B on a scale of Chayld-Pyyu). Patients with an abnormal liver function of easy and average degree do not need dose adjustment of drug of Evipler. Nevertheless, Evipler's drug should be used with care at patients with an abnormal liver function of average degree. Evipler's drug was not studied at patients with an abnormal liver function of heavy degree (a class C on a scale of Chayld-Pyyu). Therefore its use for this group of patients is contraindicated. In case of drug withdrawal at patients with HIV infection and with the accompanying hepatitis B, the condition of patients has to be controlled carefully regarding identification of signs of an exacerbation of hepatitis.

Children. Safety and efficiency of use of drug of Evipler at children is younger than 18 years is not established. 

Features of use:

Patients have to be warned that modern anti-retrovirus drugs do not cure of HIV infection, and also it is impossible to warn HIV infection - an infection through blood or by means of sexual contact. It is necessary to take necessary precautionary measures for prevention of infection with HIV infection.

Virologic inefficiency of therapy and development of resistance.

Evipler's drug was not estimated at the patients who had in the anamnesis virologic inefficiency at therapy by any anti-retrovirus means. Evipler's drug should not be appointed to patients with VICh-1 an infection having a mutation in K65R codon. It is necessary to be guided by the list of the mutations connected with rilpiviriny only at purpose of drug of Evipler to the patients who were earlier not receiving therapy. Participants have researches, over 100 000 copies/ml receiving эмтрицитабин + тенофовир in a combination with rilpiviriny with VICh-1 RNA at the time of the beginning of therapy were more often noted lack of the virologic answer, in comparison with patients who at the time of the beginning of therapy indicators of VICh-1 RNA had no more than 100 000 copies/ml. Observed virologic inefficiency at patients with indicators of VICh-1 RNA a combination эмтрицитабин + тенофовир and рилпивирин led over 100 000 copies/ml at the time of the beginning of therapy at treatment to higher frequency of formation of resistance to class NNIOT drugs. Patients with nablyudayemoyvirusologichesky failure have therapies rilpiviriny, resistance to a klamivudinu/emtritsitabin, in comparison with the patients with observed virologic inefficiency receiving drug эфавиренз developed more often. In this regard use of drug of Evipler is shown for treatment of an infection of VICh-1 as the first line of therapy at the patients having indicators of VICh-1 RNA within no more than 100 000 copies/ml. As well as for other anti-retrovirus drugs, before therapy by Evipler's drug it is necessary to analyze genotypic stability.

Influence on cardiovascular system. Purpose of a rilpivirin in supertherapeutic doses (75 mg and 300 mg once a day), is followed by lengthening of an interval of QTc on the electrocardiogram (ECG). Use of the recommended dose of a rilpivirin of 25 mg once a day not clinically significant influence on QTc interval length. Evipler's drug has to be used with care at combined use with the drugs known for the ability to cause ventricular tachycardia like "pirouette". 

Joint appointment with other medicines. Evipler's drug should not be appointed together with other medicines containing эмтрицитабин, a rilpivirina a hydrochloride, the tenofovira of a dizoproksil fumarates or other analogs of cytidine, for example, ламивудин. Evipler's drug should not be used along with an adefovir dipivoksily.

Joint purpose of drug of Evipler and didanozin. Contraindicated joint purpose of these drugs as system influence of a didanozin significantly increases after combined use from a tenofovir of a dizoproksil fumaraty that can increase risk of development of the pobochnykhreaktion connected with didanoziny. It was reported about exceptional cases of development of pancreatitis of ilaktat-acidosis, sometimes with a lethal outcome.

Renal failure. It is contraindicated to patients to appoint Evipler's drug with a renal failure of average or heavy degree (clearance of creatinine <50 ml/min.). These patients need correction of an interval of the mode of dosing of an emtritsitabin and tenofoviradizoproksil of a fumarat that cannot be carried out when using of the combined drug. Evipler's drug should not be accepted together with nefrotoksichny medicines, or soon after their cancellation. When using in clinical practice of a tenofovir of a dizoproksil of a fumarat it was reported about a renal failure, a renal failure, increase in concentration of creatinine, a hypophosphatemia and proximal tubulopatiya (including Fankoni's syndrome). It is recommended to estimate clearance of creatinine at all patients prior to treatment by Evipler's drug, and also to estimate function of kidneys (clearance of creatinine and concentration of phosphates in plasma) every 4 week during the first godaprimeneniye of drug, and then each 3 months. Patients with risk have development of a renal failure, including patients with a renal failure in the anamnesis against the background of use of an adefovir dipivoksit, the thicket should control function of kidneys. If at any patient receiving Evipler's drug, concentration of phosphates in serum makes <1,5 mg/dl (0,48 mmol/l) or the clearance of creatinine is reduced to <50 ml/min., function of kidneys has to be estimated repeatedly within one week, including definition of concentration of glucose and potassium at blood and glucose in urine. As Evipler's drug is the combined medicine, and intervals of dosing of its separate components cannot be changed, lecheniyepreparaty Eviplera it is necessary to stop at patients with confirmed a snizheniyemklirensa of creatinine to <50 ml/min. or decrease in concentration of phosphates in serum <1,0 mg/dl (0,32 mmol/l). If cancellation of one of components of a preparataevipler is shown or dose adjustment is necessary, it is possible to use the separate dosage forms of an emtritsitabin which are available in the market, the rilpivirina of a hydrochloride and a tenofovir dizoproksit a fumarat.

Influence on a bone tissue. By means of the two-power x-ray absorbtsiometriya (TPXRA) small, but statistically significant decrease in the mineral density of a bone tissue (MDBT) and content of minerals in a bone tissue (SMKT) in comparison with a reference value which was identical to group of a rilpivirin and control group was revealed. There are data on decrease in MPKT in a backbone and change of level of biomarkers of a bone tissue in comparison with a reference value for the patients receiving treatment of a terofovir of a dizoproksil fumaraty. However increase in risk of a perelomovila of signs of clinically significant bone disturbances was not noted. Bone disturbances (sometimes promoting development of changes) can be connected by a sproksimalny renal tubulopatiya. At suspicion on existence of bone disturbances it is necessary to address for the corresponding consultation the specialist doctor. 

Patients with HIV and the accompanying infection caused by a virus of the hepatitis B or C. At the patients with the chronic hepatitis B or C receiving anti-retrovirus therapy the increased risk of development of the heavy and potentially deadly undesirable reactions connected with an abnormal liver function is noted. For the choice of an optimum method of treatment of patients with HIV infection and the accompanying hepatitis B, doctors have to address the modern guides to treatment of HIV - an infection. At co-administration of drugs for treatment of hepatitis B or C see also application instructions of these drugs. Safety and efficiency of drug Eviplera at treatment of chronic hepatitis Out of was estimated. Emtritsitabin and тенофовир separately and in a combination showed activity concerning a hepatitis B virus in pharmakodinamichesky researches. At drug withdrawal of Evipler patients with HIV infection and soputstvuyushchimgepatity In can have a heavy exacerbation of hepatitis. Clinical ilaboratorny indicators of patients with HIV infection and the accompanying hepatitis B at which Evipler's drug was cancelled should be controlled carefully at least within several months after the treatment termination. In similar cases resuming of treatment of hepatitis B can be proved. At patients with a serious illness of a liver or cirrhosis it is not recommended to stop therapy as the exacerbation of hepatitis after drug withdrawal can lead to a decompensation.

Liver diseases. Safety and efficiency of drug of Evipler at patients with significant background diseases of a liver were not estimated. At patients with insufficiency of function of a liver the pharmacokinetics of an emtritsitabin was not studied. Emtritsitabin is not exposed to essential metabolism by liver enzymes therefore existence of insufficiency of function of a liver should not influence activity of drug significantly. Patients with insufficiency of function of a liver of easy or average degree (a class A and B on a scale of Chayld-Pyyu) do not need dose adjustment of a rilpivirin of a hydrochloride. Use of a rilpivirin of a hydrochloride was not studied at patients with heavy insufficiency of function of a liver (a class C on a scale of Chayld-Pyyu). Studying of pharmacokinetics of a tenofovir at patients with insufficiency of function of a liver showed that dose adjustment is not required from these patients. It is improbable that dose adjustment of drug of Evipler can be required by patients with insufficiency of function of a liver of easy average degree. Evipler's drug has to be used with care at patients with insufficiency of function of a liver of average degree (a class B on a scale of Chayld-Pyyu) and is contraindicated for appointment as the patient with insufficiency of function of a liver of heavy degree (a class C on a scale of Chayld- I Drink). At patients with an abnormal liver function in the anamnesis the increased frequency of abnormal liver functions is also noted during the combined anti-retrovirus therapy. These patients have to be under careful observation according to standard practice. If such patients have liver ukhudsheniyazabolevaniye signs, it is necessary to consider a question of suspension or cancellation of treatment. 

Lactacidemia.

When using analogs of nucleosides it was reported about development of the lactacidemia which was usually followed by fatty infiltration of a liver. Early manifestations of this state (a symptomatic giperlaktatemiya) include digestion disturbance symptoms benign (nausea, vomiting, an abdominal pain), nonspecific symptoms (an indisposition, appetite loss, decrease in body weight), respiratory symptoms (frequent and/or deep breath) or neurologic symptoms (including muscular weakness). The lactacidemia is connected with high death rate and can be followed by pancreatitis, insufficiency of function of a liver and kidneys. The lactacidemia usually arises after several months of therapy. Treatment by analogs of nucleosides has to be stopped in case of development of a symptomatic giperlaktatemiya and metabolic / лактат-ацидоза, the progressing hepatomegalia or quickly increasing activity of aminotransferases. Analogs of nucleosides have to be appointed with care to all patients (especially to women with obesity) with a hepatomegalia, hepatitis or with other izvestnymifaktor of risk (including certain medicines and alcohol). Patients with the accompanying VGS-infection, poluchayushchiyealfa-interferon and рибавирин can be subject to extra risk. Patients with the increased risk have to be under careful control. Redistribution of the hypodermic fatty tissue (HFT) the Combined anti-retrovirus therapy can cause redistribution of PZhK (lipodystrophy) in HIV-positive patients. Exact origins and the remote effects of this phenomenon are not known now. It is supposed that there is a communication between development of a visceral lipomatoz and reception of the protease inhibitors (PI), and also between a lipoatrophia and the nukleozidny inhibitors of the return transcriptase (NIRT). The increased risk of development of a lipodystrophy is connected with such individual factors as advanced age, and also the factors concerning reception of medicines, for example, longer course of anti-retrovirus therapy and the metabolism disturbances connected with it. Clinical examination of patients has to include assessment of physical signs of pereraspredeleniyapodkozhny fat. It is necessary to consider a question of need of control of concentration of lipids for serum on an empty stomach and concentration of glucose in blood. In the presence of clinical indications, treatment of lipidic disturbances has to be carried out. 

Mitochondrial disturbances. Nucleosides and analogs of nucleosides showed ability to cause in vitro and in vivo mitochondrial disturbances of various degree. It was reported about development of mitochondrial disturbances in the HIV-negative newborns who underwent pre-natal and/or post-natal influence of analogs of nucleosides. Among the main registered side reactions hematologic disturbances (anemia, a neutropenia) and metabolic disturbances (a giperlaktatemiya, a hyperlipasemia) are noted. These changes often have passing character. Some remote neurologic disturbances (a hypertension, spasms, behavioural disturbances) were registered. Now it is unknown whether neurologic disturbances are passing or constant. All children who underwent pre-natal influence of nucleosides or analogs of nucleosides, even HIV - negative newborns, in case of manifestation of the corresponding signs or symptoms have to be under careful clinical laboratory observation and undergo careful inspection regarding possible existence of mitochondrial changes.

Immunity recovery syndrome. By the beginning of anti-retrovirus therapy at HIV-positive patients with a heavy immunodeficiency the inflammatory response to existence of asymptomatic opportunistic infections in the form of emergence or an aggravation of symptoms of the disease which was earlier proceeding asymptomatically (an immunity recovery syndrome) can develop that can demand further careful observation and treatment. Usually such reactions are observed within the first weeks after an initiation of treatment. Can be examples a Cytomegaloviral retinitis, generalized and/or focal mikobakterialny infections and pneumocystic pneumonia. It is necessary to estimate any symptoms of an inflammation and , in case of need, timely to appoint treatment.

Osteonecrosis. Though the etiology of an osteonecrosis is considered multifactorial (including use of corticosteroids, alcohol intake, existence of heavy immunosuppression, higher index of body weight), cases of an osteonecrosis were registered especially often at patients with the progressing HIV infection and/or at long impact of the combined anti-retrovirus therapy. Patients should recommend to see consultation a doctor at emergence of an ache or joint pain, constraint in joints or difficulty in the movements.

Elderly patients. Evipler's drug was not studied at patients 65 years are more senior. At elderly patients the high probability of existence of reduced function of kidneys therefore drug has to be appointed with care in this group of patients is noted. 

Information on some excipients entering about composition of drug of Evipler. Evipler's drug contains lactoses monohydrate. Therefore patients with rare inborn disturbances of intolerance of a galactose, with inborn insufficiency of lactase or with a sprue of glucose and a galactose should not accept this drug.

Evipler's drug contains dye, the called aluminum varnish "a yellow sunset" (E110) which can cause allergic reactions in some patients.

Contraception at men and women. During administration of drug of Evipler effective remedies of contraception have to be applied.

Reproductive function. People do not have data on influence of drug of Evipler on fertility. Researches at animals do not indicate harmful effects of an emtritsitabin, the rilpivirina of a hydrochloride or a tenofovir dizoproksit a fumarat on fertility.

Influence on driving of the car and work with mechanisms. Evipler's drug does not influence or makes insignificant impact on ability of management of transport and work with mechanisms. Researches on studying of influence of drug on ability of management of transport and work with mechanisms were not conducted. However patients should be informed on possibility of fatigue, dizziness and drowsiness during treatment by Evipler's drug. It has to be considered at assessment of ability of the patient to manage transport and to work with mechanisms. At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

The often being most registered side reactions which are possibly connected with reception of a rilpivirin of a hydrochloride, emtritsitabin, tenofovir dizoproksit a fumarat, there were nausea (9%), dizziness (8%), unusual dreams (7%), a headache (6%), diarrhea (5%) and sleeplessness (5%). The profile of safety of an emtritsitabin and a tenofovir of a dizoproksil of a fumarat in these researches corresponded to previous experience of use of these drugs when each of them was applied with other anti-retrovirus drugs.

It was reported about exceptional cases of development of a renal failure and a proximal tubulopatiya (including Fankoni's syndrome) at the patients receiving a tenofovir of a dizoproksil fumarates that sometimes led to the bone disturbances ( which were occasionally promoting development of changes). It is recommended to observe function of kidneys at the patients receiving Evipler's drug. Use of a tenofovir was dizoproksit by a fumarata and the emtritsitabina can be followed by development of a lactacidemia, heavy hepatomegalia with fatty infiltration of a liver of an ilipodistrofiya.

Drug withdrawal of Evipler at HIV-positive patients with the accompanying hepatitis B can be followed by a heavy exacerbation of hepatitis.

Side reactions of drug are systematized concerning each of systems of bodies depending on occurrence frequency, with use of the following classification:

- Very often (≥1/10);

- Often (≥1/100, <1/10);

 - Infrequently (≥1/1000, <1/100);

- Seldom (≥1/10000, <1/1000);

- Very seldom (<1/10000), including isolated cases.

Disturbances from blood and lymphatic system:

Emtritsitabin:

- often: neutropenia;

Rilpivirina hydrochloride:

- often: decrease in quantity of leukocytes, decrease in concentration of hemoglobin, decrease in number of thrombocytes;

Emtritsitabin:

- infrequently: anemia (2).

Disturbances from immune system:

Emtritsitabin:

- often: allergic reactions;

Rilpivirina hydrochloride:

- infrequently: immunity recovery syndrome.

Disbolism and food:

Rilpivirina hydrochloride:

- very often: increase in concentration of the general cholesterol (on an empty stomach), increase in concentration of lipoproteins of the low density (LPNP) (on an empty stomach);

Tenofovir dizoproksit fumarating:

 - very often: hypophosphatemia (1);

Emtritsitabin:

- often: hyperglycemia, gipertriglitseridemiya;

Rilpivirina hydrochloride:

- often: loss of appetite, increase in concentration of triglycerides;

Tenofovir dizoproksit fumarating:

- infrequently: hypopotassemia (1);

- seldom: lactacidemia.

Disturbances of mentality:

Emtritsitabin:

- often: sleeplessness, unusual dreams;

Rilpivirina hydrochloride:

- often: a depression, sleeplessness, unusual dreams, a sleep disorder, the suppressed mood.

Disturbances from a nervous system:

Emtritsitabin:

- very often: headache;

Rilpivirina hydrochloride: 

- very often: headache;

Tenofovir dizoproksit fumarating:

- very often: dizziness.

Emtritsitabin:

- often: dizziness;

Rilpivirina hydrochloride:

- often: dizziness, drowsiness;

Tenofovir dizoproksit fumarating:

- often: headache.

Disturbances from digestive tract:

Emtritsitabin:

- very often: diarrhea, nausea

Rilpivirina hydrochloride:

- very often: nausea, increase in activity of pancreatic amylase

Tenofovir dizoproksit fumarating:

- very often: diarrhea, vomiting, nausea;

Emtritsitabin:

- often: increase in activity of amylase, including increase in activity of pancreatic amylase; increase in activity of a lipase of serum, vomiting, abdominal pain, dyspepsia;

Rilpivirina hydrochloride:

- often: an abdominal pain, vomiting, increase in activity of a lipase, discomfort in a stomach, dryness in a mouth;

Tenofovir dizoproksit fumarating:

- often: abdominal pain, abdominal distention, meteorism;

Tenofovir dizoproksit fumarating:

- infrequently: pancreatitis.

Disturbances from gepatobiliarny system:

Rilpivirina hydrochloride:

- very often: increase in activity of transaminases (nuclear heating plant and/or ALT);

Emtritsitabin:

- often: increase in activity aspartate - aminotransferases in serum (nuclear heating plant) and/or increase in activity alaninamino- transferases in serum (ALT), a hyperbilirubinemia;

Rilpivirina hydrochloride:

- often: increase in concentration of bilirubin;

Tenofovir dizoproksit fumarating:

- often: increase in activity of transaminases (ASTI/ilialt);

Tenofovir dizoproksit fumarating:

- seldom: fatty infiltration of a liver, hepatitis.

Disturbances from skin and hypodermic fabrics:

Tenofovir dizoproksit fumarating:

- very often: rash;

Emtritsitabin:

- often: vezikulobulezny rash, pustular rash, makulopapulezny rash, rash, itch, small tortoiseshell, skin discoloration ( pigmentation strengthening) (2);

Rilpivirina hydrochloride:

- often: rash;

Emtritsitabin:

- infrequently: Quincke's disease (3);

Tenofovir dizoproksit fumarating:

- seldom: Quincke's disease (3).

Disturbances from skeletal and muscular and connecting fabric:

Emtritsitabin:

- very much ччасто: increase in activity of a creatine kinase;

Tenofovir dizoproksit fumarating:

- infrequently: рабдомиолиз (1), muscular weakness (1);

Tenofovir dizoproksit fumarating:

- seldom: the osteomalacy (which is shown in the form of bone pain and sometimes promoting development of changes) (1,3), a myopathy (1).

Renal failure and urinary tract:

Tenofovir dizoproksit fumarating:

- infrequently: increase in concentration of creatinine, proteinuria;

Tenofovir dizoproksit fumarating:

- seldom: a renal failure (acute and chronic), an acute canalicular necrosis, a proximal tubulopatiya, including Fankoni's syndrome, nephrite (including acute intersticial nephrite) (3), a nephrogenic not diabetes mellitus.

Disturbances of the general state and reaction in the place of use:

Tenofovir dizoproksit fumarating:

- very often: adynamy;

Emtritsitabin:

- often: pain, adynamy;

Rilpivirina hydrochloride:

- often: fatigue.

(1). This side reaction can arise as a complication of a proximal tubulopatiya. In lack of this state it is not considered connected using a tenofovir of a dizoproksil of a fumarat.

(2). At use of an emtritsitabin for children anemia was observed often, and skin discoloration (the increased pigmentation) is very frequent.

(3). This side reaction was revealed at post-marketing observation, but was not registered in randomized, controlled clinical trials. The frequency category was estimated on the basis of statistical calculations, proceeding from total quantity of the patients who were affected by an emtritsitabin in randomized, controlled clinical trials (n=1563) or in randomized, controlled clinical trials of a tenofovir of a dizoproksil of a fumarat and in the program of expanded access (n =7319).

Average change of concentration of the general cholesterol (on an empty stomach) made 2 mg/dl, lipoproteins of high density (on an empty stomach) – 4 mg/dl, lipoproteins of low density (on an empty stomach) – 1 mg/dl and triglycerides (on an empty stomach) – 7 mg/dl.

Concentration of creatinine in blood serum. During clinical trials of the III phase within the first four weeks of therapy rilpiviriny increase in concentration of creatinine in blood serum was observed, at the same time concentration of creatinine remained stable up to the 48th week. After 48 weeks of therapy indicators averaged 0,09 mg/dl (range: from 0,20 mg/dl to 0,62 mg/dl). Patients with a renal failure of easy or average degree in blood serum had a comparable to increase in concentration of creatinine increase in concentration of creatinine in blood serum at patients with normal function of kidneys. These changes were regarded as clinically insignificant, and any patient did not stop therapy because of increase in concentration of creatinine in blood serum.

Description of separate side reactions. Renal failure. As Evipler's drug can cause injury of kidneys, it is recommended to control indicators of function of kidneys.

Interaction with didanoziny. Contraindicated combined use of drug of Evipler and a didanozin as it leads to 40–60% to increase in system influence of a didanozin that can increase risk of development of the undesirable reactions connected with didanoziny. It was reported about exceptional cases of development of pancreatitis and a lactacidemia, sometimes from the death.

Dislipidemiya, lipodystrophy and exchange disturbances. The combined anti-retrovirus therapy is followed by such metabolic disturbances as a gipertriglitseridemiya, a hypercholesterolemia, insulin resistance, a hyperglycemia and a giperlaktatemiya. The combined anti-retrovirus therapy causes redistribution of a hypodermic and fatty layer (lipodystrophy) in HIV-positive patients and is shown by loss of a hypodermic fatty tissue on the periphery (upper and lower extremities) and front area, accumulation of visceral fat, a hypertrophy of a mammary gland and accumulation of subcutaneous fat in dorsotservikalny area ("a buffalo hump").

Immunity recovery syndrome. At the beginning of the combined anti-retrovirus therapy at HIV-positive patients with a heavy immunodeficiency the inflammatory response to existence in an organism of opportunistic infections, in the form of emergence or an aggravation of symptoms of the disease which was earlier proceeding asymptomatically can develop (a syndrome of recovery of observation and additional treatment. Usually such reactions are observed within the first weeks after an initiation of treatment.

Osteonecrosis. Cases of an osteonecrosis were registered especially often at patients with the conventional risk factors, with the progressing HIV infection and/or at long impact of the combined anti-retrovirus therapy. Frequency of this undesirable reaction is not known.

Lactacidemia and heavy hepatomegalia with fatty infiltration of a liver. When using nukleozidny analogs it was reported about development of the lactacidemia which is usually followed by fatty infiltration of a liver. Treatment by nukleozidny analogs has to be cancelled in case of a giperlaktatemiya and metabolic / лактат-ацидоза, the progressing hepatomegalia or bystry rise in activity of hepatic transaminases.

Exacerbation of hepatitis after treatment cancellation. It is necessary to control carefully clinical and laboratory indicators of patients with HIV infection and the accompanying hepatitis In the ambassador of drug withdrawal of Evipler.

Coinfection of VICh/VGV or VICh/VGS. The profile of safety of an emtritsitabin, a rilpivirin and a tenofovir of a dizoproksil of a fumarat at patients with coinfection of VICh/VGV and VICh/VGS was similar to a safety profile which was observed at the patients infected with HIV without coinfection. Nevertheless, as expected, increase in activity of ALT and nuclear heating plant occurred at this group of patients more often than in the general population of HIV-positive patients.

Interaction with other medicines:

Researches of medicinal interaction with Evipler's drug were not conducted. As contains in Evipler's drug эмтрицитабин, the rilpivirina fumarates a hydrochloride and a tenofovir of a dizoproksil, all cases of medicinal interaction revealed with these active agents can arise also at use of drug of Evipler. Researches of medicinal interaction with these drugs were conducted only at adult patients. Rilpivirin is metabolized, mainly, by means of an isoenzyme of P450 (CYP3A). Therefore the medicines inducing or inhibiting activity of an isoenzyme of CYP3A can influence clearance of a rilpivirin. 

The drugs contraindicated for combined use.

Decrease in concentration of a rilpivirin in plasma at the simultaneous use of drug of Evipler and medicinal substances inducing activity of isoenzymes of CYP3A that can lead to decrease in therapeutic effect of drug of Evipler was observed.

Decrease in concentration of a rilpivirin in plasma at simultaneous use of drug of Evipler with inhibitors of a proton pomp was observed (because of increase in pH in a stomach) that can lead to decrease in therapeutic effect of drug of Evipler.

Didanozin: the concomitant use of drug of Evipler and a didanozin is contraindicated.

Eviplera – the combined medicine therefore it is contraindicated to apply it along with other drugs containing any of its components: эмтрицитабин, the hydrochloride or a tenofovira of a dizoproksil fumarates a rilpivirin.

It is contraindicated to use Evipler's drug along with other analogs of cytidine, for example, with lamivudiny. It is not necessary to appoint Evipler's drug along with adefoviry dipivoksily. Medicinal substances which are removed by kidneys: as эмтрицитабин and тенофовир are generally removed by kidneys, combined use of drug of Evipler with the medicinal substances reducing function of kidneys or competing for active canalicular secretion (for example, цидофовир), can increase concentration in serum of an emtritsitabin, tenofovir and/or jointly the appointed drugs. Evipler's drug should not be used along with nefrotoksichny medicines, or soon after their cancellation. To such drugs, along with others, aminoglycosides, B Amphotericinum belong, foskarnt, ганцикловир, pentamidine, Vancomycinum, цидофовир or interleykin-2 (also called алдеслейкин).

Others NNIOT: contraindicated combined use of drug of Evipler with others NNIOT.

The drugs recommended for combined use with care.

Inhibitors of isoenzymes of P450 cytochrome: at combined use of drug of Evipler with the medicines inhibiting activity of an isoenzyme of CYP3A increase in concentration of a rilpivirin in plasma was noted.

The drugs extending QT interval: Evipler's drug has to be used with care at combined use with the drugs known for the ability to cause ventricular tachycardia like "pirouette". There is limited information concerning a possibility of pharmakodinamichesky interaction between rilpiviriny and the medicines extending QTS interval on the electrocardiogram. In a research on healthy volunteers, use over therapeutic doses of a rilpivirin (75 mg once a day and 300 mg once a day) was followed by lengthening of an interval of QTc on an ECG.

P-glycoprotein substrates: Evipler's drug has to be appointed with care with the medicinal substances which are P-glycoprotein substrates (for example, with digoxin and dabigatrany). Rilpivirin inhibits activity of a P-glycoprotein of in vitro. The clinical importance of this inhibition is unknown. Rilpivirin can suppress activity of a P-glycoprotein in intestines and influence metabolism of the drugs transported by P-glycoproteins in intestines, for example, on concentration of a dabigatran. It can lead to increase in concentration in plasma of such drugs. Rilpivirin inhibits active canalicular secretion of creatinine in kidneys. Thanks to the same mechanism exposure of Metforminum in blood can be increased. At the beginning or after the end of combined use of a rilpivirin and Metforminum the condition of patients has to be controlled carefully.

The researches conducted with other medicines Emtritsitabin In vitro эмтрицитабин are not suppressed by the metabolism mediated by influence of any of the following isoenzymes of CYP450 of the person: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtritsitabin does not inhibit activity of the enzyme responsible for a glyukuronidation.

There is no clinically significant pharmacokinetic interrelation at joint purpose of an emtritsitabin with indinaviry, a zidovudine, stavudiny or famtsikloviry.

The dizoproksila fumarates Tenofovir. Joint purpose of the lamivudin, indinavir, efavirenz, nelfinavir or sakvinavir (strengthened ritonaviry), a ribavirina or the adefovira dipivoksit from a tenofovir dizoproksily fumaraty did not cause any significant pharmacokinetic interaction.

The combined drug эмтрицитабин + тенофовир. Joint purpose of a takrolimus from an emtritsitabinom/tenofovir of a dizoproksil fumaraty did not cause any significant pharmacokinetic interaction.

Contraindications:

1. Hypersensitivity to a rilpivirin, a tenofovir, an emtritsitabin and/or other components of drug;

2. Children's age up to 18 years;

3. Renal failure of average and heavy severity (clearance of creatinine <50 ml/min.);

4. An abnormal liver function of heavy severity (a class C on Chayld-Pyyu);

5. Breastfeeding period;

6. Deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption;

7. Evipler's drug should not be used at the same time with the following drugs:

• The drugs containing monocomponents of drug of Evipler;

• NNIOT;

• Anticonvulsants – carbamazepine, окскарбазепин, phenobarbital, Phenytoinum;

• Antituberculous remedies – рифабутин, rifampicin, rifapentine;

• Inhibitors of a proton pomp – such, as омепразол, esomeprazole, лансопразол, пантопразол, рабепразол;

• Glucocorticosteroid drugs of systemic action – dexamethasone (at reception more than one dose of drug);

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

• Didanozin;

• Cytidine analogs (ламивудин);

• Adefovira dipivoksit;

• Nefrotoksichny drugs (aminoglycosides, B Amphotericinum, foskarnt, ганцикловир, pentamidine, Vancomycinum, цидофовир or interleykin-2 (also called алдеслейкин) or soon after their cancellation.

With care:

1. An abnormal liver function of average degree (a class B on a scale of Chayld-Pyyu);

2. The age is more senior than 65 years;

3. Renal failure (clearance of creatinine of 50-80 ml/min.);

4. Simultaneous use with:

• Drugs capable to cause polymorphic ventricular tachycardia like "pirouette";

• Blockers of H2-histamine receptors;

• Antacids (for example, magnesium hydroxide or aluminum, calcium carbonate);

• Inhibitors of isoenzymes P450;

• R-glycoprotein substrates (digoxin, metformin, дабигатран).

Overdose:

At overdose emergence the condition of the patient has to be controlled carefully regarding identification of signs of toxicity. Also , if necessary, the standard maintenance therapy including observation of a clinical state, control of the main indicators of a condition of an organism and data of an ECG (QT interval length) has to be carried out. There is no specific antidote. To 30% of a dose of an emtritsitabin and about 10% of a dose of a tenofovir it can be brought out of an organism by means of a hemodialysis. There are no data on a possibility of removal of an emtritsitabin or tenofovir from an organism by means of peritoneal dialysis. As рилпивирин it is characterized by the high connecting ability with proteins of a blood plasma, dialysis in case of overdose is inefficient. For removal of the rilpivirin of a hydrochloride which is not soaked up in a GIT absorbent carbon can be also used.

Storage conditions:

To store at a temperature not above 30 °C. To store in original packaging. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, эмтрицитабин 200 mg, a rilpivirina the hydrochloride of 27,5 mg (in terms of рилпивирин –25 mg), тенофовир dizoproksit the fumarating 300 mg.

On 30 tablets in the bottles from polyethylene of high density corked by a polypropylene cover with system of protection against opening by children and control of the first opening.

On 1 bottle together with the application instruction in a cardboard pack.