Evpler - instructions for use, dose, side effects, contraindications

Active substanceEmtricitabine + Rilpivirin + TenofovirEmtricitabine + Rilpivirin + Tenofovir

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Gilead Science International Co., Ltd. United Kingdom

Dosage form: & nbspfilm-coated tablets

Composition:

Each tablet contains:

Active substances: emtricitabine 200 mg, rilpivirina hydrochloride 27.5 mg (in terms of rilpivirin - 25 mg), tenofovir disoproxil fumarate 300 mg.

Excipients (core): cellulose microcrystalline 210.00 mg, lactose monohydrate 269.80 mg, povidone 3.25 mg, pregelatinized starch 50.00 mg, polysorbate 200.35 mg, croscarmellose sodium 76.10 mg, magnesium stearate 13.00 mg. Auxiliary substances (shell): Hypromellose (2910 6 mPa.s) 13.80 mg, indigo carmine dye aluminum (E132) 0.093 mg, lactose monohydrate 7.25 mg, macrogol 2.76 mg, ferric oxide red oxide (E172) 0.11 mg, dye sunlight sunset yellow varnish aluminum (E110) 0.02 mg, titanium dioxide (E171) 8.40 mg, triacetin 2.07 mg.

Description:Capsule-shaped tablets coated with a film coat from light pink to pink with a purple hue. On one side is engraved "GSI". On the cross section, the core of a white tablet

Pharmacotherapeutic group:antiviral (HIV) agent

ATX: & nbsp

J.05.A.R.08 Emtricitabine + Tenofovir Dizoproxil + Rilpivirin

Pharmacodynamics:

Evpler is a combination drug with a fixed dose of rilpivirin,tenofovir, emtricitabine.

Mechanism of action

Emtricitabine is a nucleoside analog of cytidine. Tenofovir disoproxil fumarate is converted in vivo in tenofovir, Analogue nucleoside (nucleotide) adenosine monophosphate. "As emtricitabine, and tenofovir, have specific activity against human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.

Rilpivirin is a diaryl pyrimidine non-nucleoside inhibitor of HIV-1 reverse transcriptase. The activity of rilpivirin is mediated by the non-competitive inhibition of HIV-1 reverse transcriptase.

Emtricitabine and tenofovir phosphorylated by cellular enzymes to form tenofovir diphosphate triphosphate of FTC, respectively.

In vitro studies have shown that both emtricitabine, and tenofovir, can be completely phosphorylated while being in the cell. Emtricitabine triphosphate and tenofovir diphosphate inhibit HIV-1 reverse transcriptase by a competitive mechanism, leading to termination of viral DNA chain synthesis. Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerase. In vitro and in vivo data concerning their toxicity against mitochondria are not available. Rilpivirine does not inhibit cellular air to human DNA polymerase and mitochondrial DNA polymerase.

Antiviral activity in vitro

The combination of emtricitabine, rilpivirin and tenofovir shows a synergistic antiviral activity in the cell culture.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was evaluated on the lymphoblastoid cell line, the MAGI-CCR5 cell line and on peripheral blood mononuclear cells. The values of 50% of the effective concentration (EC50) of emtricitabine were in the range of 0.0013 to 0.64 μmol.

Emtricitabine exhibits antiviral activity in the cell culture for subtypes A, B, C, D, E, F, and G of HIV-1 (range of EC50 values from 0.007 to 0.075 μmol), as well as specific activity for HIV-2 strains of EC50 values from 0.007 to 1.5 μmol).

In studies of a combination of emtricitabine with nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, tenofovir and zidovudine), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz, nevirapine and rilpivirine) and protease inhibitors (PIs) (amprenavir, nelfinavir, ritonavir and saquinavir) an additive or synergistic effect was observed.

Rilpivirin is active against laboratory strains of wild-type HIV-1 on an acute infected T cell line with a median EC50 value of HIV-1 / WB 0.73 nmol (0.27 ng / ml). Although in vitro rilpivirine showed limited HIV-2 activity with EC50 values ranging from 2.510 to 10.830 nmol (920 to 3970 ng / ml), and in the absence of clinical data, the treatment of HIV-2 infection with rilpivirin hydrochloride is not recommended.

Rilpivirin also demonstrated antiviral activity against a wide range of primary isolates of strains of HIV-1 group M (subtypes A, B, C, D, F, G, H) with EC50 values ranging from 0.07 to 1.01 nmol (from 0 , 03 to 0.37 ng / ml) and primary isolates of group O with EC50 values ranging from 2.88 to 8.45 nmol (1.06 to 3.10 ng / ml).

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was evaluated on lymphoblastoid cell lines, mainly on monocytes / macrophages and peripheral blood lymphocytes.

The EC50 values of tenofovir were in the range of 0.04 to 8.5 μmol.

Tenofovir demonstrated antiviral activity in cell culture with respect to subtypes A, B, C, D,E, F, G and O HIV-1 (EC50 range from 0.5 to 2.2 μmol), as well as specific activity for HIV-2 strains (EC50 range from 1.6 μmol to 5.5 μmol) .

In studies of the combination of tenofovir with NRTI (abacavir, didanosine, emtricitabine, lamivudine, stavudine and zidovudine), NNRTI (delavirdine, efavirenz, nevirapine and rilpivirine) and IP (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) an additive or synergistic effect was observed.

Resistance

Cell culture

Resistance to emtricitabine or tenofovir has been observed in vitro and in some HIV-1 infected patients due to substitution in the M184V or Ml841 codons of reverse transcriptase (RT) for emtricitabine or the K65R reverse transcriptase codon for tenofovir. In addition, substitution in the K70E codon of HIV-1 reverse transcriptase causes a slight decrease in sensitivity to abacavir, emtricitabine, tenofovir and lamivudine. There were no other mechanisms of development of resistance to emtricitabine or tenofovir. Emtricitabine-resistant viruses with the M184V / I mutation showed cross-resistance to lamivudine, but remained sensitive to didanosine, stavudine, tenofovir, zalcitabine and zidovudine.

The mutation in the K65R codon can also be associated with resistance to abacavir or didanosine and lead to a decrease in sensitivity to these drugs, as well as to lamivudine, emtricitabine, and tenofovir. Tenofovir It should not be used in patients with K65R mutation of HIV-1. HIV-1 with mutations in the codons K65R, M184V and K65R + M184V remains completely sensitive to rilpivirin.

Resistant to rilpivirin and to NNRTI strains were isolated on cell cultures from wild types of HIV-1 of different nature and subtypes. The most frequently observed mutations associated with resistance were L1001, K101E, V1081, E138K, V179F, Y181C, H221Y, F227C and M230I.

Taking into account all available in vitro and in vivo data, the following mutations can influence the activity of the Evipler drug in patients who have not previously received antiretroviral therapy: K65R, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, H221Y, F227C, M230I and M230L (if detected prior to treatment).

These resistance-related mutations should only be considered when using the Evpler medication to treat patients who have not previously received antiretroviral therapy.

These resistance-related mutations were detected in vivo only in patients who had not previously received treatment,and therefore can not be used to predict the activity of the drug Evpleler in patients with virological ineffectiveness of antiretroviral therapy.

As with the use of other antiretroviral drugs, the study of genotypic resistance should be conducted against the background of taking Evipler.

HIV-1 infected patients who had not previously received antiretroviral therapy

In a combined analysis of the data obtained during phase III clinical trials (C209 and C215) among patients receiving emtricitabine / tenofovir +rilpivirine In 62 patients, virological failure of therapy was established, while information on the development of resistance was available for 54 of 62 patients. Amino acid substitutions were identified that were associated with NNRTI resistance and were most commonly encountered in such patients: V90I, K101E, E138K / Q, Y181C, VI891 and H221Y. However, the presence of mutations such as V90I and VI891 did not affect the effectiveness of treatment. More than 3 patients during the therapy had mutations associated with resistance to NRTIs: K65R, K70E, M184V / I and K219E.

Cross-resistance

With the development of HIV-1 resistance to rilpivirin, there has been no development of cross-resistance to emtricitabine and tenofovir and vice versa.

Resistance to cell culture

Emtricitabine: Emtricitabine-resistant strains with substitution in codon M184V / I demonstrated cross-resistance to lamivudine, but remained sensitive to didanosine, stavudine, tenofovir and zidovudine.

Strains of viruses with substitutions causing a decrease in sensitivity to stavudine, and resistance mutations to analogues of zidovudine thymidine (M41L, D67N, K70R, L210W, T215Y / F, K219Q / E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1, containing K103N substitution or other substitutions associated with resistance to rilpivirin and other NNRTIs, remained sensitive to emtricitabine. Rilpivirin: in a group of 67 recombinant laboratory strains of HIV-1 with a mutation of resistance to NNRTIs in one OT codon, including the most common K103N and Y181C mutations, rilpivirine demonstrated antiviral activity against 64 (96%) of these strains. Resistance mutations in one codon associated with a loss of sensitivity to rilpivirin were: K101P and Y181V / I.

Tenofovir: mutations in codons K65R and K70E cause a decrease in sensitivity to abacavir, didanosine, lamivudine, emtricitabine and tenofovir, while maintaining sensitivity to zidovudine.

In patients with three or more mutations of HIV-1 resistance to zidovudine-thymidine analogs, including M41L or L210W, there was a decrease in the response rate to tenofovir. Virological response to tenofovir was not reduced in patients with HIV-1 infection and with the M184V mutation associated with resistance to abacavir / emtricitabine / lamivudine.

Patients with mutations K103N and Y181C, or with substitutions, associated with resistance to rilpivirin and NNRTI, were sensitive to tenofovir.

HIV-1 infected patients who had not previously received antiretroviral therapy

In a combined analysis of the data obtained during phase III clinical trials (C209 and C215) among patients receiving emtricitabine / tenofovir + rilpivirine, phenotypic information on resistance development was available in 54 patients with virologic failure, 37 patients lost sensitivity to emtricitabine, 29 to rilpivirin, and 2 to tenofovir, respectively. Among these patients, 37 were resistant to lamivudine, 28 to etravirine, 26 to efavirenz, and 12 to nevirapine. In some cases, a decrease in the sensitivity of cabacavir and / or didanosine was observed.

Pharmacokinetics:

Absorption

The bioequivalence of one tablet of the film-coated Evpler formulation and the combination of one capsule of emtricitabine 200 mg, one film-coated tablet, rilpivirine (as hydrochloride) 25 mg and one film-coated tablet, tenofovir dizoproxyl (as fumarate) 245 mg was determined by the use of single doses after eating healthy volunteers.

Taking Evipler's drug along with a light meal (390 kcal, 12 g fat) or with a standard meal (540 kcal, 21 g fat) caused an increase in the concentration of rilpivirin and tenofovir in the plasma. The maximum plasma concentration (Stach) and the area under the concentration-time curve (AUC) of rilpivirin increased by 34 % and 9%, respectively, when used with light meals, and 26% and 16%, respectively, when used with a standard meal. Stax and AUC of tenofovir increased by 12% and 28% % respectively, when used with a light meal, and 32% and 38% respectively when used with a standard meal. The concentration of emtricitabine was not dependent on food intake. After oral administration of the drug Evipler together with food, emtricitabine quickly and intensively absorbed in the gastrointestinal tract (GIT) with reaching a maximum concentration in the plasma for 2.5 hours.

The maximum concentration of tenofovir in plasma (Cmax) is observed for 2 hours, and the maximum concentration of rilpivirin in plasma is usually achieved within 4-5 hours. After oral administration of tenofovir with dizoproxil fumarate by HIV-infected patients, it is rapidly absorbed and converted into tenofovir. The absolute bioavailability of emtricitabine at a dose of 200 mg in the form of solid capsules was 93%. There is no data on the absolute bioavailability of rilpivirin.

For an optimal level of absorption, Evipler should be taken with food.

Distribution

After intravenous administration, the volume of distribution of individual components of emtricitabine and tenofovir, approximately 1400 ml / kg and 800 ml / kg, respectively. After oral administration, emtricitabine and tenofovir widely distributed in the body. In vitro, the binding of emtricitabine to human plasma proteins was <4% and was independent of the concentration in the range of 0.02 to 200 μg / ml.

In vitro binding of rilpivirin to plasma proteins is approximately 99.7%, mainly due to binding to albumins. In vitro binding of tenofovir to plasma and serum proteins was less than 0.7% and 7.2%, respectively, in the range of tenofovir concentrations from 0.01 to 25 μg / ml.

Metabolism

Emtricitabine undergoes partial metabolism in the body. Biotransformation of emtricitabine includes thiol oxidation group with the formation of 3'-sulfoxide diastereomers (about 9% of the dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (about 4% of the dose). In vitro experiments show that rilpivirin hydrochloride undergoes mainly oxidative metabolism mediated by the cytochrome P450 isoenzyme enzyme system (CYP3A). In vitro studies have demonstrated that neither tenofovir disoproxil fumarate nor tenofovir They are not substrates of CYP450 isoenzymes. Neither emtricitabine, nor tenofovir do not inhibit in vitro drug metabolism mediated by any of the major CYP450 isozymes involved in biotransformation. Besides, emtricitabine does not inhibit uridine 5-diphosphoglucuronyl transferase (enzyme responsible for glucuronization).

Excretion

Emtricitabine is mainly excreted by the kidneys (about 86%) and through the intestine (about 14%). 13% of the dose of emtricitabine was found in the urine as three metabolites.The systemic clearance of emtricitabine on average was 307 ml / min. The half-life after oral administration of emtricitabine is approximately 10 hours.

The final half-life of rilpivirin is approximately 45 hours. After applying a single oral dose of 14C-rilpivirin, radioactive doses were detected in feces and urine on average in 85% and 6.1%, respectively. In the stool unchanged rilpivirine averaged 25% of the dose. In the urine, only minor concentrations of rilpivirin (<1% of the dose) were detected. Tenofovir mainly excreted by the kidneys, both as a result of filtration, and with the help of the active tubular transport system (human organic ion transport transporter [hOATl]). Approximately 70-80% of the dose taken is excreted unchanged in urine after intravenous administration. The apparent clearance of tenofovir averaged about 307 ml / min. Kidney clearance should be approximately 210 ml / min, which exceeds the rate of glomerular filtration. This indicates that active tubular secretion is an important part of the tenofovir withdrawal process. After oral administration, the half-life of tenofovir is on average 12 to 18 hours. Special patient groups

Elderly patients

Population pharmacokinetic analysis of HIV-1-infected patients showed that the pharmacokinetics of rilpivirin remained comparable for all age groups (18 to 78 years).

Floor

There were no clinically significant differences in the pharmacokinetic parameters of rilpivirin in men and women.

Race

There were no clinically significant differences in pharmacokinetic parameters in patients with different ethnic origins.

Children

In general, the pharmacokinetic parameters of emtricitabine in newborns, children and adolescents (aged 4 months to 18 years) are similar to those observed in adults. The pharmacokinetic parameters of rilpivirin and tenofovir in children and adolescents are currently being studied. Due to the lack of clinical data, recommendations for dosing in children can not be provided. Impaired renal function Emtricitabine and tenofovir are excreted mainly by the kidneys, and their plasma concentrations increase in patients with impaired renal function.The pharmacokinetics of rilpivirin have not been studied in patients with impaired renal function. Rilpivirine is slightly excreted by the kidneys. In this regard, it is not expected that impaired renal function will affect the excretion of rilpivirin. As rilpivirine it is not expected to be significantly eliminated during hemodialysis or peritoneal dialysis. Limited clinical trials confirm the possibility of taking Evipler's medication once a day with patients with mild renal dysfunction (creatinine clearance 50-80 ml / min.). However, in patients with mild renal dysfunction, safety assessments of individual components of the drug, emtricitabine, and tenofovir disoproxil fumarate were not conducted. Therefore, the preparation of Evipler should be used in such patients only if the potential benefit of treatment exceeds the possible risk.

Evpple's drug is contraindicated in patients with impaired renal function of medium or severe degree (creatinine clearance <50 mL / min, including patients requiring hemodialysis).This group of patients needs a correction of the dosing interval of emtricitabine and tenofovir, which is not feasible with the combined preparation. Pharmacokinetic parameters were determined mainly after single doses of emtricitabine 200 mg or tenofovir dizoproksil 245 mg of HIV to uninfected patients with renal insufficiency of varying severity. The degree of severity of renal dysfunction was determined in accordance with the initial clearance of creatinine (CrCl) (normal renal function with CrCl> 80 ml / min, renal dysfunction of mild degree with CrCl = 50-79 ml / min, impaired renal function of middle degree with CrCl = 30-49 ml / min and impaired renal function of severe degree with CrCl = 10-29 ml / min). The mean exposure (% CV) of emtricitabine increased from 12 (25%) μg / hr / mL in patients with normal renal function to 20 (6%) μg / hr, 25 (23%) μg / hr and 34 (6%) μg / hr / mL in patients with impaired renal function of mild, moderate and severe, respectively.

The mean exposure (% CV) of tenofovir increased from 2185 (12%) μg / hr / mL the patients with normal renal function up to 3064 (30%) ng / hr, 6009 (42%) ng / hr and 15985 (45%) ng / hr in patients with normal renal function impaired renal function of mild, moderate and severe, respectively.

Patients with end-stage renal failure who required hemodialysis, exposure between dialysis sessions steadily increased within 72 hours to 53 mkghch / ml (19%) of emtricitabine, and within 48 hours prior to 42857 nghch / ml (29%) of tenofovir . The pharmacokinetics of rilpivirin have not been studied in patients with impaired renal function. Excretion of rilpivirin by the kidneys is negligible. Patients with impaired renal function, severe or terminal stage plasma concentrations may be increased due to secondary changes in absorption, distribution and / or metabolism due to impaired renal function. Because the rilpivirine has a high level of binding to plasma proteins, it is unlikely that it will be largely excreted by hemodialysis or peritoneal dialysis.

Abnormal liver function Patients with impaired liver function moderate no dose adjustment is required drug Eviplera, but should be used with caution in these patients. Evpeler's drug was not studied in patients with severe hepatic dysfunction (class C on the Child-Pugh scale).Therefore, it is contraindicated in patients with severe hepatic insufficiency. The pharmacokinetics of emtricitabine has not been studied in patients with varying degrees of impaired hepatic function.

Rilpivirina hydrochloride is metabolized and eliminated mainly by the liver. The level of exposure to multiple doses of rilpivirin was 47% higher in patients with mild hepatic insufficiency (class A on the Child-Pugh scale) and 5% higher in patients with moderate hepatic impairment (grade B on the Child-Pugh scale) compared with relevant control groups. The use of rilpivirin has not been studied in patients with severe hepatic insufficiency (class C on the Child-Pugh scale). However, it can not be ruled out that the effect of pharmacologically active, unrelated rilpivirin significantly increases in hepatic insufficiency of medium degree. A single dose of tenofovir, dizoproxil 245 mg, was used in HIV-infected patients with varying degrees of liver function impairment, determined according to the Child-Pugh scale. The pharmacokinetic parameters of tenofovir did not change significantly in patients with hepatic impairment, indicating that there was no need for dose adjustment in these patients.The mean values (% CV) of Stax and AUCo-oo of tenofovir were 223 (34.8%) ng / ml and 2050 (50.8%) ng / hr, respectively, in patients with normal liver function, compared with 289 (46 , 0%) ng / ml and 2310 (43.5%) ng / hr in patients with moderate hepatic impairment and 305 (24.8%) ng / hr and 2740 (44.0%) ng / hr in patients with hepatic insufficiency of a serious degree.

Concomitant infection of hepatitis B and / or hepatitis C

In general, the pharmacokinetic parameters of emtricitabine in patients with hepatitis B were similar to those observed in healthy volunteers and in HIV-infected patients.

According to population pharmacokinetic analysis Concomitant infection caused by the hepatitis B virus and / or C does not have a significant effect on the level of exposure to rilpivirin.

Indications:Treatment of infection caused by type 1 HIV-1 virus (HIV-1) as first-line therapy in adult patients with HIV-1 RNA levels within a maximum of 100,000 copies / ml

Contraindications:

Hypersensitivity to rilpivirin, tenofovir, emtricitabine and / or other components of the drug;

2. Children under 18 years of age;

3. Violation of the function of the kidneys of moderate and severe severity (creatinine clearance <50 ml / min);

4.Violation of liver function in severe

severity (Child-Pugh class C);

5. The period of breastfeeding;

6. Lactase deficiency, lactose intolerance, glucose-galactose malabsorbtion;

7. Evipler should not be used concurrently with the following drugs:

- Preparations containing monocomponents of the preparation of Evipler;

- NNRTI;

- Anticonvulsants - carbamazepine, oxcarbazepine, phenobarbital, phenytoin;

- Anti-TB drugs - rifampicin, rifapentin;

- Proton pump inhibitors - such as omeprazole, esomeprazole, lansopurazole, pantoprazole, rabeprazole;

- G-corticosteroid preparations of systemic action - dexamethasone (when taking more than one dose of the drug);

- Preparations based on St. John's wort (Hypericum perforatum);

- Didanosine;

- Analogues of cytidine (lamivudine);

- Adefovir dipivoxyl;

- Nephrotoxic drugs (aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin) or soon after their cancellation.

Carefully:Treatment of infection caused by type 1 immunodeficiency virus (HIV-1),as first-line therapy in adult patients with HIV-1 RNA levels within a maximum of 100,000 copies / ml

Pregnancy and lactation:

Pregnancy

There are no clinical data on the use of the drug Evpleler in pregnant women. However, a moderate amount of data (300-1000 pregnancy outcomes) indicates the absence of congenital malformations or neonatal toxicity when using emtricitabine and tenofovir disoproxil fumarate. Studies in animals showed no reproductive toxicity (with the use of components of the preparation of Evipler), as well as a small number of cases of rilpivirin penetration through the placenta. It is not known whether the rilpivirine through the placenta in pregnant women. When rilpivirin was used in rats and rabbits, there was no evidence of teratogenicity.

The drug should not be used during pregnancy, except when the potential benefit of treatment for the mother exceeds the possible risk to the fetus.

Lactation

It was shown that emtricitabine and tenofsvir are excreted in breast milk in women.There are no data on the excretion of rilpivirin with breast milk in women. There is insufficient data on the effect of the components of the drug Evpler on newborns / children. Therefore, the drug Evpleler should not be used by women during breastfeeding.

To exclude the transmission of HIV to a newborn, it is recommended that HIV-infected women completely abandon breastfeeding

Dosing and Administration:

Inside.

Treatment should be performed by a doctor who has experience of HIV therapy.

Adult:

The drug is used only by oral route, one tablet once a day together with food. The tablet should be swallowed whole, washed down with water. Tablets can not be chewed or broken, as this can affect the absorption of the drug.

If you need to cancel or change the dose of one of the components of the drug, you should use other available on the market individual dosage forms of emtricitabine, rilpivirin hydrochloride and tenofovir dizoproxil fumarate (see instructions for use of these drugs).

If the delay in taking the drug is less than 12 hours, the missed dose should be taken as soon as possible with food and resume the usual dosage regimen.If the delay in taking the drug is more than 12 hours, the missed dose should not be taken; the next tablet is taken at the usual time.

If the patient has vomiting within 4 hours after taking Evipler's drug, another tablet of Evipler's drug should be taken with food. If the patient has vomited more than 4 hours after taking the drug, there is no need to take another tablet of the drug Evpler until the time of the next scheduled dose of the drug.

Special patient groups Elderly patients

The use of Evipler was not studied in patients older than 65 years. The drug should be used with caution in elderly patients.

Impaired renal function

Treatment with the drug Evpleler caused a slight increase in the average concentration of creatinine in the blood in the early stages of therapy. This parameter remained stable over time and is not considered clinically significant.

Limited data from clinical studies confirm the dosing regimen of the drug Evipler once a day in patients with impaired renal function of mild degree (creatinine clearance 50-80 ml / min).However, in patients with mild renal insufficiency, there was no safety assessment of the individual components of the drug (emtricitabine and tenofovir disoproxil fumarate). Therefore, the preparation of Evipler should be used in patients with mild renal fecundity deficiency only if the potential benefit of the treatment exceeds the possible risk.

The drug Evplera.plokpokazano apply in patients with impaired renal function of medium or severe degree (creatinine clearance <50 ml / min), since such patients need a correction of the dosing interval of emtricitabine and tenofovir disoproxil fumarate, which is not possible with a combination drug:

Impaired liver function

There is limited information on the use of the drug Evpleler in patients with impaired hepatic and mild liver function (class A and B on the Child-Pugh scale). Patients with a mild or moderate liver dysfunction do not need a dose adjustment for Evipler. Nevertheless, the drug Evpler should be used with caution in patients with impaired liver function of an average degree.The drug - Eviplera was not studied in patients with impaired hepatic function of a serious degree (class C on the Child-Pugh scale). Therefore, its use in this group of patients is contraindicated.

In case of withdrawal of the drug in patients with HIV infection and with concomitant hepatitis B, the condition of patients should be carefully monitored for signs of exacerbation of hepatitis.

Children

The safety and efficacy of using Evpler in children under the age of 18 years is not established.

Side effects:

The most frequently reported adverse reactions probably associated with taking rilpivirin hydrochloride, emtricitabine, -genofovir, dizoproxil fumarate, were nausea (9%), dizziness (8%), unusual dreams (7%), headache (6%), diarrhea (5 %) and insomnia (5%). The safety profile of emtricitabine and tenofovir disoproxil fumarate in these studies corresponded to previous experience of the use of these drugs, when each of them was used with other antiretroviral agents.

There have been reports of rare cases of renal failure and proximal tubulopathy (including Fanconi syndrome)who received tenofovir dizoproxil fumarate, which sometimes led to bone disorders (occasionally contributing to the development of fractures). It is recommended to monitor kidney function in patients receiving Evipler.

The use of tenofovir, dizoproxil fumarate and emtricitabine may be accompanied by the development of lactic acidosis, severe hepatomegaly with fatty liver infiltration and lipodystrophy.

The withdrawal of Evipler's drug in HIV-infected patients with concomitant hepatitis B may be accompanied by severe exacerbation of hepatitis.

Adverse reactions of the preparation are systematized relative to each of the organ systems depending on the frequency of occurrence, using the following classification: Very often (> 1/10);

Often (> 1/100, <1/10);

Infrequently (> 1/1000, <1/100);

Rarely (> 1/10000, <1/1000);

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

Frequency	Emtricitabine	Rilnivirine hydrochloride	Tenofovir disoproxil fumarate
Violations from the blood and lymphatic system:
Often:	Neutropenia	Reducing the number of leukocytes, a decrease in the concentration of hemoglobin, a decrease in the number of platelets
Infrequently:	Anemia²
Immune system disorders:
Often:	Allergic reactions
Infrequently:		Immunodeficiency Syndrome
Metabolic and nutritional disorders:
Highly often:		An increase in the concentration of total cholesterol (fasting), an increase in the concentration of low-density lipoprotein (LDL) (fasting) '	Hypophosphatemia¹
Often:	Hyperglycemia, hypertriglular isceridemia	Decreased appetite, increased concentration of triglycerides
Infrequently:			Hypokalemia¹
Rarely:			Lactate acidosis
Disorders of the psyche:

Often:	Insomnia, unusual dreams	Depression, insomnia, unusual dreams, sleep disturbance, depressed mood
Impaired nervous system:
Highly often:	Headache	Headache	Dizziness
Often:	Dizziness	Dizziness, drowsiness	Headache
Disorders from the gastrointestinal tract:
Highly often:	Diarrhea, nausea	Nausea, increased activity pancreatic amylase	Diarrhea, vomiting, nausea
Often:	Increase in amylase activity, including increased activity of pancreatic amylase; increased serum lipase activity, vomiting, abdominal pain, indigestion	Abdominal pain, vomiting, increased lipase activity, abdominal discomfort, dry mouth	Abdominal pain, bloating, flatulence
Infrequently:			Pancreatitis
Violations from the gepatobiliary system:
Highly often:		Increase the activity of trance and naming (ACT and / or ALT)
Often:	Increase in activity of aspartate- aminotransferase in serum (ACT) and / or increased serum alanine aminotransferase activity (ALT), hyperbilirubinemia	Increase concentrations bilirubin /	increased activity trapsaminase (Asti / or Alta)
rarely:			fatty liver infiltration, hepatitis
disorders of the knees and subcutaneous tissues:
highly often:			rash
often:	vesiculobuleznaya rash, pustular rash, maculopapular rash, rash, itching, hives, skin discoloration (increased pigmentation)² .	rash

infrequently:	angioedema edema³
rarely:			angioedema edema³
disorders of musculoskeletal and connective tissue:
highly often:	increased activity of creatine kinase
infrequently:			rhabdomyolysis¹, we can see why¹
rarely:		.	osteomalacia (manifested in the form of bone pain and sometimes contributing to the development of fractures)^1,3, myopathy¹
violation of kidney and urinary tract:
infrequently:			rise concentrations creatinine, proteinuria
rarely:			renal failure (acute and chronic), acute tubular necrosis, proximal tubulopathy, including fanconi syndrome, nephritis (including acute interstitial nephritis)³, nephrogenic diabetes insipidus
Disorders of general condition and reaction at the site of application:
highly often:			asthenia
often:	pain, asthenia	fatigue

'this side reaction may occur as a complication of proximal tubulopathy. in the absence of this condition, it is not considered associated with the use of tenofovir disoproxil fumarate.

²when using emtricitabine in children, anemia was observed frequently, and skin color change (increased pigmentation) is very common.

³this adverse reaction was detected in post-marketing surveillance, but was not recorded in randomized, controlled clinical trials. the frequency category was estimated based on statistical calculations based on the total number of patients exposed to emtricitabine in randomized, controlled clinical trials (n = 1563) or in randomized,controlled clinical trials of tenofovir dizoproxil fumarate and in the extended access program (n = 7319).

the average change in total cholesterol concentration (fasting) was 2 mg / dL, high-density lipoprotein (fasting) 4 mg / dL, low-density lipoprotein (fasting) 1 mg / dL, and triglyceride fasting 7 mg / dl.

serum creatinine concentration

in Phase III clinical trials, serum creatinine levels were increased during the first four weeks of rilpivirin therapy, while the creatinine concentration remained stable until the 48th week. after 48 weeks of therapy, the mean values were 0.09 mg / dl (range: 0.20 mg / dL to 0.62 mg / dL). in patients with mild or moderate renal dysfunction, an increase in serum creatinine was comparable with an increase in serum creatinine in patients with normal renal function. these changes were regarded as clinically insignificant, and no patient discontinued therapy due to an increase in serum creatinine concentration.

description of individual adverse reactions impaired renal function

since the drug euiplera can cause damage to the kidneys, it is recommended to monitor the indicators of kidney function.

interaction with didanosine

the joint use of the drug eupler and didanosine is contraindicated, as this results in a 40-60% increase in systemic exposure to didanosine, which may increase the risk of undesirable reactions associated with didanosine. reported rare cases of pancreatitis and lactic acidosis, sometimes fatal. Dyslipidemia, lipodystrophy and metabolic disorders

combined antiretroviral therapy is accompanied by metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia. combined antiretroviral therapy causes redistribution of the subcutaneous fat layer (lipodystrophy) in HIV-infected patients and is manifested by loss of subcutaneous adipose tissue on the periphery (upper and lower extremities) and facial area, visceral fat accumulation, mammary gland hypertrophy and accumulation of subcutaneous fat in the dorsocervical region "hump buffalo").

immune reconstitution syndrome

at the onset of combined antiretroviral therapy in HIV-infected patients with severe immunodeficiency, an inflammatory response may be developed to the presence of opportunistic infections in the body, in the form of the appearance or aggravation of symptoms previously asymptomatic (immunodeficiency syndrome), which may require further careful observation and additional treatment . usually such reactions are observed during the first weeks after the start of treatment.

osteonecrosis

cases of osteonecrosis have been recorded especially frequently in patients with recognized risk factors, with progressive HIV infection and / or prolonged exposure to combined antiretroviral therapy. the frequency of this undesirable reaction is not known.

lactate acidosis and severe hepatomegaly with e / siracil liver infiltration when nucleoside analogues were used, lactate acidosis, usually accompanied by fatty liver infiltration, was reported. treatment with nucleoside analogues should be abolished in the event of hyperlactatemia and metabolic / lactate-acidosis, progressive hepatomegaly, or a rapid increase in hepatic transaminase activity.

exacerbation of hepatitis after withdrawal of treatment

Clinical and laboratory parameters of patients with HIV infection and concomitant hepatitis should be closely monitored after the evapler drug is withdrawn. co-infection of HIV / HIV or HIV / CVD

the safety profile of emtricitabine, rilpivirin, and tenofovir disoproxil fumarate in patients with co-infection with HIV / VHD and HIV / VHC was similar to the safety profile observed in patients infected with HIV without co-infection. Nevertheless, as expected, the increase in activity of alt and act in this group of patients were more common than in the general population of HIV-infected patients

Overdose:

If an overdose occurs, the patient's condition should be carefully monitored for signs of toxicity. Also, if necessary, standard maintenance therapy should be conducted, including monitoring of the clinical condition, monitoring of the basic indicators of the state of the body and ECG data (the length of the interval QT).

There is no specific antidote. Up to 30% of the dose of emtricitabine and approximately 10% of the dose of tenofovir can be eliminated from the body by hemodialysis. There is no data on the possibility of excretion of emtricitabine or tenofovir from the body with peritoneal dialysis. Because the rilpivirine characterized by a high binding ability with plasma proteins, dialysis in case of an overdose is ineffective.

To remove non-absorbed rilpivirin hydrochloride in the gastrointestinal tract, it can also be used Activated carbon.

Interaction:

Studies of drug interactions with the drug Evpleler was not conducted. Since the preparation Evpplera contains emtricitabine, rilpivirin hydrochloride and tenofovir disoproxil fumarate, all cases of drug interaction found with these active substances may also occur with the use of the drug Evpler. Studies of drug interactions with these drugs were carried out only in adult patients.

Rilpivirin is metabolized mainly by the isoenzyme P450 (CYP3A). Therefore, drugs that induce or inhibit isoenzyme activity CYP3A, can affect the clearance of rilpivirin.

Drugs contraindicated for joint use

There was a decrease in the concentration of rilpivirin in plasma with the simultaneous use of the drug Evpler and drugs that induce isozyme activity CYP3A, which can lead to a decrease in the therapeutic effect of the drug Evpler.

There was a decrease in rilpivirin concentration in plasma with the simultaneous use of the drug Evipler with proton pump inhibitors (due to the increase in pH in the stomach), which may lead to a decrease in the therapeutic effect of the drug Evpleler.

Didaiosin: simultaneous administration of the drug Evpleler and didanosine is contraindicated. Evpler is a combined medicinal product, therefore it is contraindicated to apply simultaneously with other drugs containing any of its components: emtricitabine, rilpivirin hydrochloride or tenofovir disoproxil fumarate.

The drug Evpleple is contraindicated to be used simultaneously with other analogues of cytidine, for example, with lamivudine. The drug Evpler should not be prescribed simultaneously with adefovir dipivoxil.

Medicinal substances that are excreted by the kidneys: because the emtricitabine and tenofovir basically are excreted by the kidneys, the joint use of the drug Evpler with drugs that reduce kidney function or compete for active tubular secretion (eg, cidofovir), may increase serum concentrations of emtricitabine, tenofovir and / or co-administered drugs.Evpple's drug should not be used concomitantly with nephrotoxic drugs, or soon after they are withdrawn. These drugs, among others, include aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin).

Other NNRTIs: it is contraindicated joint use of the drug Evipler with other NNRTIs.

Preparations recommended for joint use with caution Inhibitors of cytochrome P450 isoenzymes: in the joint application of the drug Evpler with drugs that inhibit the activity of the isoenzyme CYP3A,an increase in the concentration of rilpivirin in plasma was noted.

Drugs that extend the interval QT: Evpple's preparation should be used with caution when combined with medications known to be capable of inducing a ventricular pirouette tachycardia. There is limited information on the possibility of pharmacodynamic interaction between rilpivirin and drugs extending the range QTc on an electrocardiogram.In a study on healthy volunteers, the use of over-therapeutic doses of rilpivirin (75 mg once daily and 300 mg once daily) was followed by an extension of the interval QTc on the ECG.

Substrates of P-glycoprotein: Evpple's preparation should be administered with caution with drugs that are substrates of the P-glycoprotein (for example, with digoxin and dabigatran). Rilpivirine inhibits the activity of P-glycoprotein in vitro. The clinical significance of this inhibition is unknown. Rilpivirine can suppress the activity of P-glycoprotein in the intestine and affect the metabolism of drugs transported by P-glycoproteins in the intestine, for example, the concentration of dabigatran. This can lead to an increase in plasma concentrations of such drugs. Rilpivirine inhibits the active tubular secretion of creatinine in the kidneys. Thanks to the same mechanism, exposure to metformin in the blood can be increased. At the beginning or after the end of the joint use of rilpivirin and metformin, the condition of patients should be carefully monitored.

Other types of interaction

Interactions between the components of the preparation of Eupler and co-applieddrugs are described below in Table 1 (the increase in the concentration of the drug is indicated by the drop arrow - "and no change -

Table 1: interaction between individual components of the preparation of Evipler and other drugs

Medicinal products drugs	Effects on pharmacokinetic parameters (AUC, FROM_tOh, minimal concentration in plasma (C_mj_n) other drugs	Recommendations for simultaneous use with other drugs
ANTI-VIRUS PRAI ARA YOU
Antiretroviral drugs
Nucleoside or nucleotide reverse transcriptase inhibitors (NRTI / H (t) IOT).
Didanosine / Emtricitabine	The interaction was not studied.	The simultaneous administration of the drug Evpler and didanosine is recommended.
Didanosine (400mg once a day) / Rilpivirin¹	Didanosine: AUC: T 12% C_min: not applicable C: <-> ^ max * Rilpivirin: AUC: <-> ^Cmin^: ^ from - ^ max^-
Didanosine / Tenofovir disoproxyl fumarate	Simultaneous reception of tenofovir with dizoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine, which may lead to an increased risk of undesirable reactions associated with didanosine.There have been reports of rare cases of pancreatitis and lactic acidosis, sometimes fatal. The combined use of tenofovir, dizoproxil fumarate and didanosine at a dose of 400 mg per day, is associated with a significant decrease in the amount CD4 cells, possibly due to intracellular interaction, which increases the concentration of phosphorylated (active) didanosine. Co-administration of a reduced dose of didanosine 250 mg with tenofovir

Medicinal products drugs	Effects on pharmacokinetic parameters (AUC, FROM_max, minimal concentration in plasma (C_mj_n) other drugs	Recommendations for simultaneous use with other drugs
	C_max: 1 23%
Other antiviral drugs
Ribavirin	Interaction with other components of the drug Evpleler has not been studied.	No clinically significant drug interaction is expected. Correction of the dose is not required.
Telaprevir / Rilpivirine	Telaprevir: AUC: \| 5 % Cmin: I 11 % Stah: \| % Rilpivirin: AUC: T 78 % C_min: T 93% С_max: T 49 %	Joint use of the drug Evpler and telaprevir can cause an increase in the concentration of rilpivirin in the plasma. Correction of the dose is not required.
ANTI-GRAPHIC TURNS YOU
Ketoconazole / Emtricitabine	The interaction was not studied	The concomitant use of the drug Evpler with azole antifungal agents can cause an increase in the concentration of rilpivirin in plasma (inhibition of isoenzymes SURZA). With a dose of rilpivirin 25 mg dose adjustment is not required.
Ketoconazole (400 mg once a day) / Rilpivirine¹ Fluconazole Itraconazole² Posaconazole² Voriconazole	Ketoconazole: AUC: \| 24% Cmi_n: 1 66% Stah: Rilpivirin: AUC: T 49% Cmin: t 76% Stah: T 30%
Ketoconazole / Tenofovir disoproxyl fumarate	The interaction was not studied.
ANTIMICOBACTERIAL PREPARATIONS YOU
Rifabutin / Emtricitabine	The interaction was not studied.	Evpple's preparation should not be used in combination with rifabutin, because when combined, it is likely that a significant decrease in rilpivirin concentration in the plasma (induction of isoenzyme activity CYP3A). This can lead to a decrease in the therapeutic efficacy of the drug Evpler.
Rifabutin (300 mg once a day) / Rilpivirin¹	Rifabutin: AUC: <- * C_min^:^ FROM :<-> ^ max 25- (9-deacetyl-rifabutin: AUC: <-> C_min^:^ Stach^-<->

Medicinal products drugs	Effects on the pharmacokinetic parameters (AUC, Sciach_? the minimum concentration in plasma (C_min) other drugs	Recommendations for simultaneous use with other drugs
	Rilpivirin: AUC: \| 46% C_rain: \| 49% С_ti435%
Rifabutin / Tenofovir disoproxyl fumarate	The interaction was not studied.
Rifampicin / Emtricitabine	The interaction was not studied.	Evpple's preparation should not be used in combination with rifampicin, since concomitant use probably results in a significant decrease in plasma rilpivirin concentration (induction of CYP3A isoenzyme activity). This can lead to a decrease in the therapeutic efficacy of the drug Evpler.
Rifampicin (600 mg once a day) / Rilpivirin¹ Rifapentin	Rifampicin: AUC: <- + C_min: not applicable C: <-> ^ max¹ 25-deacetyl-rifampicin: AUC: \| 9% C_min: not applicable Stakh-^4-* Rilpivirin: AUC: \| 80% Cmin "18 9% Stach 4 69%
Rifampicin (bOmgodin once a day) / Tenofovir disoproxil fumarate (300 mg once daily)	Rifampicin: AUC: <-> ^FROMmax^:^ Tenofovir: AUC: * -> FROM_tOh^:^
ANTIBIOTICS OF THE MACROLID GROUP
Clarithromycin Erythromycin Trolandomycin	Interaction with any component of the drug Evpleler has not been studied	The simultaneous administration of the drug Evpler with macrolide antibiotics can cause an increase in the concentration of rilpivirin in plasma (inhibition of activity isoenzymesURSA). If possible, discuss the use of alternative drugs, such as azithromycin.

Medicinal products drugs	Effects on pharmacokinetic parameters (AUC, Stach, the minimum concentration in the plasma (C_mi_n) other drugs	Recommendations for simultaneous use with other drugs
ANTI-SURPRISING YOURSELF
Carbamazepine Oxcarbazepine Phenobarbital Phenytoin	Interaction with any component of the drug Evpleler has not been studied.	Evpple's drug should not be used in combination with anticonvulsant drugs, because when combined, it is likely that a significant decrease in plasma rilpivirin concentration (induction of isoenzyme activity CYP3A). This can lead to a decrease in the therapeutic efficacy of the drug Evpler.
Glucocorticosteroids
Dexamethasone (systemic, excluding the use of single doses)	Interaction with any component of the drug Evpleler has not been studied.	The drug should not be used in combination with systemic dexamethasone, since concomitant use probably results in a significant decrease in plasma rilpivirin concentration (induction of isoenzyme activity CYP3A). This can lead to a decrease in the therapeutic efficacy of the drug Evpler. We should discuss the use of alternative drugs, especially with long-term treatment.
PROTON INHIBITORS pumps
Omeprazole / Emtricitabine	The interaction was not studied.	The drug should not be used in combination with proton pump inhibitors, since concomitant use probably results in a significant decrease in rilpivirin concentration in the plasma (decreased absorption, increased pH of the stomach). This may lead to a decrease in therapeutic effectiveness
Omeprazole (20 times every day) / Rilpivirine¹ Lansoprazole² Rabeprazole Pantoprazole Esomeprazole²	Omeprazole: AUC: \| 14% C_min: not applicable FROM_max:114% Rilpivirin: AUC: \| 40% C_mi„:\|33% FROM_max:\|40%

Medicinal products drugs	Effects on pharmacokinetic parameters (AUC, Sschach " minimal concentration in plasma (C_mi_n) other drugs	Recommendations for simultaneous use with other drugs
Omeprazole / Tenofovir Dizoproxil Fumarate	The interaction was not studied.	preparation of Evipler.
ANTHAGONISTS OF N-HISTAMIN RECEPTORS
Famotidine / Emtricitabine	The interaction was not studied.	Evpple's preparation should be used with extreme caution in combination with Hg receptor antagonists, since concomitant use probably results in a significant decrease in rilpivirin concentration in the plasma (decreased absorption, increased pH of the stomach). Only those Hg-receptor antagonists that can be used once a day should be used. The dosage regimen for Hg receptor antagonists should be closely monitored, and should be prescribed at least 12 hours before or 4 hours after the preparation of the Evipler preparation.
Famotidine (a single dose of 40 mg 12 hours before admission rilpivirine) / Rilpivirine¹ 2 Cimetidine Nisatidine Ranitidine²	Rilpivirin: AUC: \| 9% C_min: not applicable C: <-> ^ max "
Famotidine (a single dose of 40 mg 2 hours before admission rilpivirine) / Rilpivirine¹	Rilpivirin: AUC: \| 76% C_mi_n: not applicable C_max:\|85%
Famotidine (a single dose of 40 mg 4 hours before taking rilpivirin) / Rilpivirin¹	Rilpivirin: AUC: T 13% C_mj_n: not applicable Stakh: T 21%
Famotidine / Tenofovir disoproxyl fumarate	The interaction was not studied.
ANTHASIDE PRODUCTS
Antacids (for example, magnesium or aluminum hydroxide, calcium carbonate)	Interaction with any component of the drug Evpleler has not been studied.	The drug should be used with caution in combination with antacids, because concomitant use is likely the development of a significant decrease in the concentration of rilpivirin in the plasma (reduced absorption, increased pH of the stomach). Antacids should be prescribed, either at least 12 hours before or 4 hours after receiving Evipler.

Medicinal products drugs	Effects on pharmacokinetic parameters (AUC, FROM_max, minimal concentration in plasma (C_mj_n) other drugs	Recommendations for simultaneous use with other drugs
NARCOTIC ANALGETICS
Methadone / Emtricitabine	The interaction was not studied	With the simultaneous use of methadone and the drug Evpler
Methadone (60-1 Oomgodin once a day, individualized dose) / Rilpivirin	R (-) methadone: AUC: 1 16% C_min:\|22% C_max:\|14% Rilpivirin: AUC: R ■ - D * on the basis of historical control	correction of the dose is not required.However, it is recommended to monitor the clinical condition of the patient, since some patients may need a correction of a maintenance dose of methadone.
Methadone / T enofovir disoproxyl fumarate	Methadone: AUC: <-> Cmin- ^- Stah- ^- Tenofovir: AUC: ^ Cmin- ^- Stah- ^-
NON-ARCTIC ANALGETICS
Paracetamol/ Emtricitabine	The interaction was not studied.	Correction of the dose is not required.
Paracetamol (a single dose of 500 mg) / Rilpivirin¹	Paracetamol: AUC: <-> Cmi_n: not applicable Stach- * ~ * Rilpivirin: AUC: <-> C_mi_n: T26% Stah- ^-
Paracetamol/ Tenofovir disoproxyl fumarate	The interaction was not studied.
ORAL CONTRACEPTIVES
Ethinylestradiol / Norethindrone / Emtricitabine	The interaction was not studied.	Correction of the dose is not required.
Ethinyl estradiol (0.035 m once a day	Ethinyl estradiol: AUC: * ->

Medicinal products drugs	Effects on pharmacokinetic parameters (AUC, Stah? minimal concentration in plasma (C_min) other drugs	Recommendations for simultaneous use with other drugs
day) / Rilpivirine Norethindrone (1 mg once a day) / Rilpivirin	Cmin ' Stah: T 17% Norethindrone: AUC: <-> Cmin- ^ Stah: ^<r~* Rilpivirin: AUC: <-> * D - - <->* D - ^ max- * on the basis of historical control
Ethinylestradiol / Norethindrone / Tenofovir disoproxyl fumarate	Ethinyl estradiol: AUC: <-> Stach- ^5y Tenofovir: AUC: ~ Stah:
LNYTELITHMIC PRECARL OF YOU
Digoxin	Interaction with any component of the drug Evpleler has not been studied.	The concentration of digoxin in plasma may be increased (inhibition of P-glycoprotein in the intestine). It is recommended to monitor the concentration of digoxin in the blood in a joint appointment with the drug Evpler.
ANTICOAGULANTS
Dabigatran	Interaction with any component of the drug Evpleler has not been studied.	Dabigatran should be administered with caution in conjunction with the drug Evpler, because it is expected to increase the concentration of dabigatran in blood plasma (inhibition of P-glycoprotein in the intestine).
HYPOGLYCEMIC MEANS
Metformin	Interaction with any component of the drug Evpleler has not been studied.	The combined use of the drug Evpler with metformin can cause an increase in the concentration of metformin in the plasma (inhibition of P-

Medicinal products drugs	Effects on pharmacokinetic parameters (AUC, FROM_max, minimal concentration in plasma (C_mj_n) other drugs	Recommendations for simultaneous use with other drugs
		glycoprotein in the intestine). It is recommended to carefully monitor the patient's condition at the beginning and at the end of therapy.
MEDICINAL DRUGS YOU ARE PLANT ORIGIN
St. John's wort perforated {Hypericum perforatum)	There have been no studies of interactions with any of the active components of the preparation of Evipler.	The drug should not be used in combination with preparations containing Hypericum perforated, since concomitant administration is likely the development of a significant decrease in the concentration of rilpivirin in plasma. This can lead to a decrease in the therapeutic efficacy of the drug Evpler.
INHIBITORS HMG-CoA REDUCTASE
Atorvastatin / Emtricitabine	The interaction was not studied.	Correction of the dose is not required.
Atorvastatin (40 mg once a day) / Rilpivirine¹	Atorvastatin: AUC: <-> C, ™: 1 15% Stah: T 35% Rilpivirin: AUC: Cmiiv FROM_max: 1 9%	Correction of the dose is not required.
INHIBITORS OF PHOSPHODYESTERASE 5 TYPE (PDE-5)
Sildenafil / Emtricitabine	The interaction was not studied.	Correction of the dose is not required.
Sildenafil (a single dose of 50 mg) / Rilpivirin¹ l Vardenafil Tadalafil "	Sildenafil: AUC: * -> Cmi_n: not applicable Stach - * ^ Rilpivirin: AUC: <-> Cmin: ^ Stach: ^-^
Sildenafil / Tenofovir disoproxil fumarate	The interaction was not studied.

¹In the study of drug interaction, a dose exceeding the recommended maximum rilpivirin hydrochloride effect on the concentration of the co-administered drug was used. Dosing instructions are applicable to the recommended dose of rilpivirin 25 mg once daily.

²Drugs of the same class, in which it is possible to predict a similar drug interaction.

Studies conducted with other drugs Emtricitabine

In vitro Emtricitabine does not inhibit metabolism, mediated by the action of any of the following isoenzymes CYP450 human: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 4. Emtricitabine does not inhibit the activity of the enzyme responsible for glucuronidation.

There is no clinically significant pharmacokinetic relationship in the co-administration of emtricitabine with indinavir, zidovudine, stavudine, or famciclovir.

Tenofovir disoproxil fumarate

The co-administration of lamivudine, indinavir,efavirenz, nelfinavir or saquinavir (ritonavir-boosted), ribavirin or adefovir dipivoxyl with tenofovir disoproxil fumarate did not cause any significant pharmacokinetic interaction.

Combined drug emtricitabine + tenofovir

The co-administration of tacrolimus with emtricitabine / tenofovir with dizoproxil fumarate did not cause any significant pharmacokinetic interaction

Special instructions:

Patients should be warned that modern antiretroviral drugs do not cure HIV, nor can HIV infection be prevented through blood or through sexual contact. Take the necessary precautions to prevent HIV infection. Virologic therapy inefficiency and resistance development Evpler's drug was not evaluated in patients who had a history of virological inefficiency when treated with an antiretroviral agent. Evpeler's drug should not be given to patients with HIV-1 infection having a mutation in the K65R codon. A list of mutations associated with rilpivirin should be followed only whenthe appointment of Evipler's drug to patients who had not previously received therapy.

Participants in the study who received emtricitabine tenofovir in combination with rilpivirin with HIV-1 RNA of more than 100,000 copies / ml at the time of initiation of therapy, the absence of a virologic response was more likely than in patients who had no more than 100,000 copies / ml of HIV-1 RNA at the time of initiation of therapy. The observed virologic ineffectiveness in patients with HIV-1 RNA levels of more than 100,000 copies / ml at the time of initiation of therapy with combination therapy emtricitabine tenofovir and rilpivirine led to a higher incidence of resistance to NNRTIs. In patients with observed virologic failure of rilpivirin therapy, resistance to lamivudine / emtricitabine was more likely than in patients with observed virological inefficiency who received the drug efavirenz.

In this regard, the use of the drug Evpler shown for the treatment of HIV-1 infection as the first line of therapy in patients with HIV-1 RNA levels within a maximum of 100,000 copies / ml.

As with other antiretroviral drugs, genotypic resistance should be analyzed before starting therapy with Evpler.

Influence on the cardiovascular system

The administration of rilpivirin in super therapeutical doses (75 mg and 300 mg once a day) is accompanied by lengthening of the interval QTc on an electrocardiogram (ECG). The use of a recommended dose of rilpivirin 25 mg once a day is not accompanied by a clinically significant effect on the length of the interval QTc. The drug should be used with caution when combined with drugs known for its ability to cause ventricular tachycardia such as pirouette. Co-administration with other medications Evppler's drug should not be given together with other medicines containing emtricitabine, tenofovir disoproxil fumarate or other cytidine analogs, for example, lamivudine. The drug Evpler should not be used simultaneously with adefovir dipivoxil. Evpple's drug should not be used with rilpivirin, unless there is a need for dose adjustment (for example, when taken together with rifabutin).

Joint use of the drug Evpple and didanosine

Contraindicated the joint administration of these drugs, since the systemic effect of didanosine significantly increases after the joint use of tenofovir with dizoproxil fumarate, which may increase the risk of adverse reactions associated with didanosine. There have been reports of rare cases of pancreatitis and lactic acidosis, sometimes fatal.

Impaired renal function Evipel is contraindicated in patients with moderate or severe renal impairment (creatinine clearance <50 mL / min). These patients require adjustment of the interval of the dosing regimen of emtricitabine and tenofovir dizoproxil fumarate, which can not be achieved with a combination drug. Evpple's drug should not be taken with nephrotoxic drugs, or soon after they are withdrawn.

When using the tenofovir dizoproxil fumarate in clinical practice, renal impairment, renal insufficiency, increased creatinine concentration, hypophosphatemia and proximal tubulopathy (including Fanconi syndrome) were reported.

It is recommended to evaluate the creatinine clearance in all patients before starting Evipler's treatment, as well as assess kidney function (creatinine clearance and plasma phosphate concentration) in 2-4 weeks and 3 months after the start of the drug, and then every 3-6 months in patients without risk factors for the development of renal dysfunction. In patients with a risk of developing renal dysfunction, including patients with a history of kidney failure, adefovir dipivoxyl should be monitored more often.

If a patient receiving Eviler's preparation has serum phosphate concentration <1.5 mg / dl (0.48 mmol / L) or creatinine clearance decreased to <50 mL / min, renal function should be re-evaluated within one weeks, including the determination of glucose and potassium concentrations in the blood and glucose in the urine. Since the Evpler formulation is a combined drug and the dosage intervals of its individual components can not be changed, treatment with Evipler should be discontinued in patients with a confirmed decrease in creatinine clearance to <50 ml / min or a decrease in serum phosphate concentration <1.0 mg / dL (0.32 mmol / L).If you see the withdrawal of one of the components of the drug, or you need a dose adjustment, you can use the available on the market individual dosage forms of emtricitabine, rilpivirin hydrochloride and tenofovir dizoproxil fumarate.

Effect on bone tissue Using dual-energy X-ray absorptiometry (DRA), a small but statistically significant decrease in bone mineral density (BMD) and bone mineral content (CMT) was found compared to the baseline value, which was the same for the rilpivirin group and control group.

There is evidence of a decrease in BMD in the spine and a change in the level of biomarkers of bone tissue in comparison with the initial value in patients receiving the therofovir dizoproxil fumarate. However, there was no increase in the risk of fractures or signs of clinically significant bone disorders.

Bone disorders (sometimes contributing to the development of fractures) may be associated with proximal renal tubulopathy. If you suspect a bone disorder, consult a specialist doctor for advice.

Patients with HIV and concomitant infection caused by the hepatitis B or C virus

In patients with chronic hepatitis B or C receiving antiretroviral therapy, there is an increased risk of developing severe and potentially fatal undesirable reactions associated with impaired liver function.

To select the optimal method for treating patients with HIV infection and concomitant hepatitis B, doctors should refer to modern guidelines for the treatment of HIV infection.

When concurrently prescribing drugs for the treatment of hepatitis B or C, see also instructions for the use of these drugs. The safety and efficacy of the drug Evpler in the treatment of chronic hepatitis B has not been evaluated. Emtricitabine and tenofovir individually and in combination, demonstrated activity against hepatitis B virus in pharmacodynamic studies.

If Evipler is withdrawn in patients with HIV infection and concomitant hepatitis B, severe exacerbation of hepatitis may occur. Clinical and laboratory parameters of patients with HIV infection and concomitant hepatitis B who have been canceled by Evipler should be carefully monitored for at least several months after discontinuation of treatment.In such cases, the resumption of treatment of hepatitis B can be justified. In patients with severe liver disease or cirrhosis, it is not recommended to discontinue therapy, since exacerbation of hepatitis after drug cancellation can lead to decompensation.

Diseases of the liver

The safety and efficacy of the drug Evpleler in patients with significant background liver diseases were not evaluated. In patients with insufficient liver function, the pharmacokinetics of emtricitabine has not been studied. Emtricitabine is not subject to significant metabolism by liver enzymes, so the presence of liver failure should not significantly affect the activity of the drug. Patients with mild or moderate liver failure (class A and B on the Child-Pugh scale) do not need a dosage adjustment of rilpivirin hydrochloride. The use of rilpivirin hydrochloride has not been studied in patients with severe liver failure (class C on the Child-Pugh scale). The study of the pharmacokinetics of tenofovir in patients with insufficient hepatic function showed that dose correction in these patients is not required.

It is unlikely that patients with a mild or moderate liver failure may need a dose adjustment for Evipler. The drug should be used with caution in patients with moderate liver function (class B on the Child-Pugh scale) and is contraindicated for administration to patients with severe hepatic function (class C on the Child-Pugh scale).

In patients with a history of liver failure, there is also an increased incidence of liver dysfunction during combined antiretroviral therapy. These patients should be carefully monitored in accordance with standard practice. If such patients have signs of worsening liver disease, consideration should be given to the suspension or withdrawal of treatment.

Lactate acidosis

With the use of nucleoside analogues, lactate acidosis, usually accompanied by fatty liver infiltration, was reported. Early manifestations of this condition (symptomatic hyperlactatemia) include symptoms of poor digestion (nausea, vomiting, abdominal pain), nonspecific symptoms (malaise,loss of appetite, weight loss), respiratory symptoms (frequent and / or deep breathing) or neurological symptoms (including muscle weakness). Lactate acidosis is associated with a high mortality rate and may be accompanied by pancreatitis, liver and kidney failure. Lactate acidosis usually occurs after several months of therapy.

Treatment with nucleoside analogues should be discontinued if symptomatic hyperlactatemia and metabolic / lactate acidosis develop, progressive hepatomegaly or rapidly increasing aminotransferase activity.

Nucleoside analogues should be carefully administered to all patients (especially women with obesity) with hepatomegaly, hepatitis, or other known risk factors (including certain drugs and alcohol). Patients with concomitant HCV infection who receive alpha-interferon and ribavirin.

Patients with an increased risk should be carefully monitored. Redistribution of subcutaneous adipose tissue

Combined antiretroviral

therapy can cause a redistribution of PLN (lipodystrophy) in HIV-infected patients. The exact mechanism of occurrence and the long-term consequences of this phenomenon are not known at present. It is suggested that there is a link between the development of visceral lipomatosis and the intake of protease inhibitors (PI), as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs). An increased risk of lipodystrophy is associated with individual factors such as old age, as well as factors related to the use of medications, such as a longer course of antiretroviral therapy and associated metabolic disorders. Clinical examination of patients should include an assessment of the physical signs of redistribution of subcutaneous fat. Consideration should be given to the need to monitor the concentration of lipids in the fasting serum and the concentration of glucose in the blood. If there are clinical indications, lipid disorders should be treated. Mitochondrial disorders Nucleosides and nucleoside analogs have demonstrated the ability to cause in vitro and in vivo mitochondrial disorders of varying degrees.The development of mitochondrial disorders in HIV-negative neonates exposed to prenatal and / or postnatal effects of nucleoside analogues has been reported. Among the main recorded adverse reactions are hematologic disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipazemia). These changes are often transitory. Some distant neurological disorders (hypertension, seizures, behavioral disorders) have been reported. At present, it is not known whether neurological disorders are transitory or permanent. All children are subjected in utero effects of nucleoside or nucleoside analogues, even HIV-negative infants, in cases of relevant signs or symptoms should be under close clinical and laboratory supervision and undergo a thorough examination for the possible presence of mitochondrial changes. Inflammatory immune reconstitution syndrome

By the beginning of antiretroviral therapy in HIV-infected patients with severe immune deficiency may develop an inflammatory response to the presence of asymptomaticopportunistic infections in the form of the appearance or worsening of symptoms previously asymptomatic (immune reconstitution syndrome), which may require further careful observation and treatment. Typically, such reactions are observed during the first weeks after the start of treatment. Examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumocystis pneumonia. You should evaluate any symptoms of inflammation and, if necessary, prescribe treatment in a timely manner. Autoimmune diseases (such as Graves' disease) were also noted when an inflammatory immune reconstitution syndrome occurred. However, the time to onset of the disease may vary, and such diseases may begin months after initiation of therapy.

Osteonecrosis

Although the etiology is considered multifactorial osteonecrosis (including corticosteroid use, alcohol consumption, presence of severe immunosuppression, higher body mass index), cases of osteonecrosis were detected most frequently in patients with advanced HIV infection and / or prolonged exposure to combination antiretroviral therapy.Patients should be advised to seek medical advice if they develop aches or joint pain, joint stiffness, or difficulty in moving.

Elderly patients

Evpple's preparation has not been studied in patients older than 65 years. Older patients are more likely to have reduced renal function, so the drug should be administered with caution in this group of patients.

Information on some of the excipients included with the formulation of the drug Evpple

The preparation of Evpleler contains lactose monohydrate. Therefore, patients with rare congenital disorders of galactose intolerance, congenital insufficiency of lactase or with glucose malabsorption syndrome and galactose should not take this medication.

In the preparation of Evpleler contains a dye, called aluminum varnish "yellow sunset" (E110), which can cause allergic reactions in some patients.

Contraception in men and women

Effective means of contraception should be used while taking Evipler.

Reproductive function There is no evidence of the effect of Evpler on fertility in humans.Studies in animals do not indicate a harmful effect of emtricitabine, rilpivirin hydrochloride or tenofovir dizoproxil fumarate on fertility

Effect on the ability to drive transp. cf. and fur:Evpple's drug has no effect or has little effect on the ability to manage transport and work with mechanisms. Studies to study the effect of the drug on the ability to manage transport and work with mechanisms were not conducted. However, patients should be informed about the possibility of fatigue, dizziness and drowsiness during treatment with Evipler. This should be taken into account in assessing the ability of the patient to manage transport and work with mechanisms. When these undesirable phenomena appear, one should refrain from performing the specified activities

Form release / dosage:

Film-coated tablets, emtricitabine 200 mg, rilpivirin hydrochloride 27.5 mg (in terms of rilpivirin-25 mg), tenofovir disoproxil fumarate 300 mg.

Packaging:

For 30 tablets in high-density polyethylene bottles, sealed with a polypropylene lid with a system for protecting children from opening and controlling the first autopsy.

1 bottle with instructions for use in cardboard pack

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep in original packaging. Keep out of the reach of children.

Shelf life:

3 years. Do not use after expiry date

Terms of leave from pharmacies:On prescription

Registration number:LP-002324

Date of registration:09.12.2013

The owner of the registration certificate:Gilead Science International Co., Ltd. Gilead Science International Co., Ltd. United Kingdom

Manufacturer: & nbsp

PATHEON, Inc. Canada

Gilead Sciences Ireland UC Ireland

Information update date: & nbsp22.10.2015

Illustrated instructions

Instructions

Evpplera (Eviplera)