Composition, form of production and packaging
Tablets covered with a film membrane from light pink to pink with a violet hue of color, capsular; on one side is engraved "GSI", on the cross section the core of the tablet is white.
1 tab.
rilpivirin hydrochloride 27.5 mg,
which corresponds to the content of rilpivirine 25 mg
tenofovir 300 mg
Emtricitabine 200 mg
Excipients: microcrystalline cellulose - 210 mg, lactose monohydrate - 269.8 mg, povidone - 3.25 mg, pregelatinized starch - 50 mg, polysorbate - 200.35 mg, croscarmellose sodium - 76.1 mg, magnesium stearate - 13 mg.
Composition of the membrane: hypromellose (2910 6 mPa.s) - 13.8 mg, indigo carmine dye aluminum (E132) 0.093 mg, lactose monohydrate 7.25 mg, macrogol 2.76 mg, iron oxide red oxide (E172) 0.11 mg, dye solar sunset yellow varnish aluminum (E110) - 0.02 mg, titanium dioxide (E171) - 8.4 mg, triacetin - 2.07 mg.
30 pcs. - polyethylene bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
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 to tenofovir, an analogue of the nucleoside monophosphate (nucleotide) of adenosine monophosphate. Both 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 are phosphorylated by cellular enzymes with the formation of emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine, hack 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 the termination of the synthesis of the viral DNA strand.
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerase. In vitro and in vivo data on their toxicity in relation to mitochondria is not available. Does Rilpivirin not inhibit cellular? and? Human DNA polymerase and mitochondrial? DNA polymerase.
Antiviral activity in vitro
Combination of emtricitabine. rilpivirin and tenofovir shows 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 (EC 50 ) of emtricitabine were in the range from 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 EC 50 values ​​from 0.007 to 0.075 μmol), as well as specific activity for HIV-2 strains the range of EC 50 values ​​is from 0.007 to 1.5 μmol).
In studies of the 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 rilpivirin) and protease inhibitors (amprenavir , nelfinavir, ritonavir and saquinavir) there was an additive or synergistic effect.
Rilpivirin is active against laboratory strains of wild-type HIV-1 on an acute infected T cell line with a median of EC 50 HIV-1 / IIIB 0.73 nmol (0.27 ng / ml).Although in vilro, rilpivirin demonstrated limited HIV-2 activity with EC 50 values ​​ranging from 2.510 to 10.830 nmol (920 to 3970 ng / ml), 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 EC 50 values ​​ranging from 0.07 to 1.01 nmoles (from 0.03 to 0.37 ng / ml) and primary isolates of group O with EC 50 values ​​in the range from 2.88 to 8.45 nmol (from 1.06 to 3.10 ng / ml).
The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 is assessed on lymphoblastoid cell lines, mainly on monocytes / macrophages and peripheral blood lymphocytes. The EC 50 values ​​of tenofovir were in the range from 0.04 to 8.5 μmol.
Tenofovir demonstrated antiviral activity in the cell culture for subtypes A, B, C, D, E, F, G, and O HIV-1 (range of EC 50 values ​​from 0.5 to 2.2 μmol), as well as specific activity for HIV-2 strains (range of EC 50 values ​​from 1.6 μmol to 5.5 μmol).
There was an additive or synergistic effect in studies of the combination of tenofovir with NRTI (abacavir, didanosine, emtricitabine, lamivudine, stavudine and zidovudine), NNRTI (delavirdine, efavirenz, nevirapine and rilpivirin) and IP (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir).
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 M1841 codons of reverse transcriptase (RT) for emtricitabine or the K65R reverse transcriptase codon for tenofovir. There were no other mechanisms of development of resistance to emtricitabine or tenofovir. Emtricitabine-resistant viruses with the M184V / I mutation demonstrated cross-resistance to lamivudine, but remained sensitive to didanosine, stavudip, 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, emtricitabium, and tenofovir. Tenofovir should not be used in patients with the 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 L100I, 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, Ml841, M184V, H221Y, F227C, M230I and M230L (if detected prior to treatment). These resistance-related mutations should only be considered when using the Evpler drug 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 could not be used to predict the activity of the Evipler drug in patients with virologic failure of antiretroviral therapy.
As with the use of other anti-rastroviral drugs, against the background of taking Evipler's drug, genotypic resistance testing should be conducted.
HIV-1 infected patients who had not previously received antiretroviral therapy
In a combined analysis of data from phase III clinical trials (C209 and C215), virologic failure was established in 62 patients with emtricitabine / tenofovir + rilpivirin, and 54 of 62 patients reported resistance development. Amino acid substitutions were identified that were associated with NNRTI resistance and were most commonly encountered in such patients: V90I, K101E, E138K / Q, Y181C, V189I and H221Y. However, the presence of mutations such as V90I and V189I 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. The strains of viruses with substitutions causing a decrease in sensitivity to stavudine, and mutations of resistance to zidovudia-thymidine analogues (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 HIV-1 strains with a mutation of NNRTI resistance in one OT codon, including the most common K103N and Y181C mutations, rilpivirin 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: 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, 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.
The virologic response to tenofovir has not been 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 pooled analysis of data from Phase III clinical trials (C209 and C215) among emtricitabine / tenofovir + rilpivirin patients, phenotypic resistance development information was available in 54 patients with virologic failure, 37 patients lost sensitivity to treatment 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 nevirapip. 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. After oral administration of the drug Eupler with food, emtricitabine was rapidly and intensively absorbed into the digestive tract with the attainment of Cmax in plasma for 2.5 h. C max tenofovir in plasma was observed for 2 h, and C max rilpivirin in plasma was usually achieved within 4- 5 hours. After oral administration of tenofovir, dizoproxil fumarate by HIV-infected patients, it is rapidly absorbed and converted to tenofovir. The absolute bioavailability of emtricitabine at a dose of 200 mg in the form of solid capsules was 93%. The use of hard gelatin capsules of emtricitabine at a dose of 200 mg along with fat-rich food did not affect the AUC emtricitabine. The oral bioavailability of tenofovir when administered on an empty stomach of tenofovir, dizoproxil fumarate, was approximately 25%. Simultaneous reception of tenofovir with disiproxil fumarate with fat-rich food increased oral bioavailability (an increase in the AUC of tenofovir by approximately 40% and C max by approximately 14%). There is no data on the absolute bioavailability of rilpivirin. Exposure rilpivirina was about 40% lower when taking the drug on an empty stomach than when taking with meals the usual caloric intake (533 kcal) or with food high in fat (928 kcal). When taking rilpivirin hydrochloride with a protein-enriched drink only, the exposure to rilpivirin was 50% lower than when taken with food. Receiving rilpivirin hydrochloride on an empty stomach or only with a protein-enriched drink reduces the concentration of rilpivirin in the plasma, which can potentially reduce the therapeutic effect of the drug Evpler. For an optimal level of absorption, Evipler should be taken with food.
Distribution
After intravenous administration, the volume of distribution of the individual components of emtricitabia and tenofovir was approximately 1400 ml / kg and 800 ml / kg, respectively. After oral administration, emtricitabine and tenofovir are widely distributed in the body. In vitro binding of emtricitabia to human plasma proteins was <4% and did not depend on concentration in the range from 0.02 to 200 Ојg / ml.
In vitro binding of rilpivirin to plasma proteins is approximately 99.7%, mainly due to binding to albumins. In vitro, the binding of tenofovir to plasma and serum proteins was less than 0.7% and 7.2%, respectively, in the range of tenofovir concentrations of 0.01 to 25 Ојg / ml.
Metabolism
Emtricitabine undergoes partial metabolism in the body. Biotransformation of emtricitabia involves the oxidation of the thiol group to form 3'-sulfoxide diasteromers (about 9% of the dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of the dose). In vilro experiments show that rilpivirina hydrochloride is exposed mainly to oxidative metabolism mediated by the cytochrome P450 isofermal enzyme system (CYP3A). In vilro studies have demonstrated that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 isoenzymes. Neither emtricitabine nor tenofovir inhibits the drug metabolism mediated in vilro by any of the major CYP450 isoenzymes involved in biotransformation. In addition, emtricitabine does not inhibit uridine-5-diphosphoglucuronyl transferase (the 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 emtricitabia was found in the urine as three metabolites. The systemic clearance of emtricitabia was, on average, 307 ml / min. T 1/2 after oral administration of emtricitabia is approximately 10 hours.
The final T 1/2 rilpivirin is approximately 45 hours. After applying a single oral dose of 14 C-rilpivirin, radioactive doses were detected in the feces and urine average of 85% and 6.1%, respectively. In the stool, unchanged rilpivirin averaged 25% of the dose taken. In the urine, only minor concentrations of rilpivirin (<1% of the dose) were detected.
Tenofovir is mainly excreted by the kidneys, both as a result of filtration, and with the help of the active canal transport system (human organic ion transporter 1 [hOAT1]). Approximately 70-80% of the accepted dose is excreted unchanged in urine after IV application. 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, T 1/2 of tenofovir averages between 12 and 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
Limited data from clinical studies confirm the possibility of taking Evipler's drug 1 time / day with patients with mild renal dysfunction (KK 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 the treatment exceeds the possible risk.
The drug Evpleler is contraindicated in patients with impaired renal function of medium or severe degree (KK <50 ml / min). This group of patients is required correction dosing interval emtricitabine and tenofovir that is not feasible when using a combination preparation.
Pharmacokinetic parameters were determined mainly after administration of single doses of emtricitabine 200 mg or 245 mg of tenofovir disoproxil HIV-uninfected patients with renal failure of different severity. The severity of renal function was determined in accordance with the initial CK (CrCl) normal renal function at the GHS> 80 ml / min; violation of mild renal function when CrCl = 50-79 ml / min; violation of the average degree of renal function when CrCl = 30-49 ml / min and a severe breach of renal function when CrCl = 10-29 ml / min).
The mean exposure (% CV) emtricitabine increased from 12 (25%) mcg? Hr / ml in patients with normal renal function up to 20 (6%) mcg? Hr / ml, 25 (23%) mcg? Hr / ml, and 34 ( 6%) mcg? hr / ml in patients with impaired renal function mild, moderate and severe extent, respectively.
The mean exposure (% CV) tenofovir increased from 2185 (12%) mcg? Hr / ml in patients with normal renal function up to 3064 (30%) ng? H / mL, 6009 (42%) ng? H / mL and 15985 ( 45%) ng? h / ml in patients with impaired renal function mild, moderate and severe extent, respectively.
Patients with end-stage renal failure who needed gemodiapiz, exposure between dialysis sessions steadily increased within 72 h to 53 mcg? Hr / ml (19%) of emtricitabine, and for 48 h to 42857 ng? H / ml (29 %) of tenofovir.
The pharmacokinetics of rilpivirine have not been studied in patients with impaired renal function. Rilpivirine excretion 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. Since rilpivirine has a high level of binding to plasma proteins, it is unlikely that it will be largely excreted by hemodialysis or peritoneal dialysis.
Impaired liver function
Patients with impaired liver function moderate does not require dosage adjustment of Eviplera drug, but it should be used with caution in these patients. The drug Eviplera has not been studied in patients with impaired liver function severe (class C Child-Pugh). Therefore, it is contraindicated for use in patients with liver failure and severe.
The pharmacokinetics of FTC was not studied in patients with varying degrees of liver function abnormalities.
Rilpivirine hydrochloride metabolized and eliminated primarily in the liver. The level of exposure to multiple doses rilpivirine was 47% higher in patients with hepatic mild failure patients (class A scale Child-Pyo) and 5% higher in patients with hepatic moderate failure (class B scale Child-Pyo) compared with corresponding control groups. The use of rilpivirine have not been studied in patients with severe hepatic insufficiency (class C by Child-Pugh). However, we can not exclude that the effects of pharmacologically active, non rilpivirine significantly increased in moderate hepatic insufficiency.
A single dose of 245 mg of tenofovir disoproxil used in HIV-infected patients with varying degrees of liver dysfunction, as determined in accordance with the scale of Child-Pyo. Pharmacokinetic parameters of tenofovir were not significantly altered in patients with hepatic insufficiency, indicating there is no need for dose adjustment in these patients. Mean values (% CV) C max and the AUC 0-? tenofovir totaled 223 (34.8%) ng / mL and 2050 (50.8%) ng? h / ml, respectively, in patients with normal liver function, as compared to 289 (46.0%) ng / mL and 2310 (43.5%) ng? hr / ml in patients with moderate hepatic impairment and 305 (24.8%) ng? h / mL and 2740 (44.0%) ng? h / ml in patients with severe liver failure.
Co-infection of hepatitis B and / or hepatitis C.
In general, the pharmacokinetic parameters of emtricitabine in patients with hepatitis B were similar to those nablyudachis in healthy volunteers and in HIV-infected patients.
According to the pharmacokinetic analysis populyatsnonnogo concomitant infection with hepatitis B and / or C has no significant effect on the level of impact rilpivirine.
INDICATIONS
- treatment of infection by HIV-1, as first line therapy in adult patients with HIV-1 RNA indicators within no more than 100 000 copies / ml.
DOSING MODE
Inside.
Treatment should be a doctor with experience in the treatment of HIV infection.
Adults
Preparation Eviplera applied only orally one tablet of 1 time / day together with the niche. The tablet should be proglatyzat entirely with water. Tablets should not be chewed or crush, because it can affect the absorption of the drug. In case you require removal or modification of one dose of the drug components Eviplera should apply other separate dosage forms emtritsitabiia available on the market, rilpivirine hydrochloride and tenofovir disoproxil fumarate (see. For application of these preparations instructions).
If the delay in receiving the drug was less than 12 hours, the missed dose should be taken as soon as possible with food and resume the normal dosing regimen of the drug. If the delay s taking the drug was more than 12 hours, the missed dose should not be accepted; next tablet is taken at the usual time.
If a patient has vomiting occurred during 4 hours after dosing Eviplera, together with the food to be adopted another Eviplera tablet formulation. If a patient has vomiting occurred more than 4 hours after dosing Eviplera no need for reception of another tablet formulation Eviplera until the time of obtaining the next scheduled dose.
Special patient groups
Elderly patients
The use of the drug Eviplera has not been studied in patients older than 65 years. The drug Eviplera should be used with caution in elderly patients.
Impaired Renal Function
Treatment with Eviplera cause a slight increase in the average blood concentration of creatinine in the early stages of therapy. This parameter has remained stable over time and is not considered clinically significant.
Limited data from clinical studies confirm the drug dosing regimen Eviplera 1 time / day in patients with impaired renal function mild (CC 50-80 ml / min). However, patients with mild renal insufficiency function was conducted evaluation of safety of the individual components of the preparation (emtritsitabiia and tenofovir disoproxil fumarate). Therefore, the drug should ispolzozatsya Eviplera in patients with mild impairment of renal function only if the potential benefit of treatment outweighs the possible risk.
Eviplera contraindicated drug used in patients with moderate to severe fire renal function (creatinine clearance <50 mL / min), since such patients require correction dosing interval emtricitabine and tenofovir disoproxil fumarate, that can not be done by using a combined preparation.
Impaired liver function
There is limited information regarding the use of the drug Eviplera in patients with impaired liver mild to moderate function (class A and B on the scale of Child-Pugh). Patients with impaired mild to moderate hepatic function is not required correction Eviplera dose preparation. However, the drug Eviplera should be used with caution in patients with impaired liver function moderate. The drug Eviplera has not been studied in patients with impaired liver function severe (class C on the scale of Child-Pyo). Therefore its use in this group of patients is contraindicated.
In the case of withdrawal of the drug in patients with HIV infection and with a concomitant hepatitis B patients condition should be carefully monitored for signs of worsening of hepatitis.
Children
Safety and efficacy of Eviplera use the drug in children younger than 18 years have not been established.
SIDE EFFECT
The most frequently reported adverse events probably associated with the reception rilpivirine hydrochloride, emtricitabine, tenofovir disoproxil fumarate, were nausea (9%), dizziness (8%), abnormal 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 is used with other drugs antirstrovirusnymi.
It reported rare cases of renal failure and proximal tubulopathy (including Faikoni syndrome) in patients treated with tenofovir disoproxil fumarate, sometimes leading to bone abnormalities (occasionally contributed to the development of fractures). It is recommended to monitor renal function in patients taking the drug Eviplera.
The use of tenofovir disoproxil fumarate and emtricitabine may be accompanied by the development of lactic acidosis, severe hepatomegaly with fatty infiltration of the liver and lipodystrophy.
Cancel Eviplera drug in HIV-infected patients with concomitant hepatitis B may be associated with severe exacerbations of hepatitis.
Adverse drug reactions systematic with respect 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); rare (> 1/10000, <1/1000); very rare (<1/10000), including isolated cases.
Frequency Emtricitabine rilpivirine gidrohlornd Tenofovir disoproxil fumarate
Disturbances in the blood and lymphatic system:
Common: Neutropenia Reduced number of leukocytes, decrease in hemoglobin concentration, decrease in platelet count
Uncommon: Anemia 2
Violations of the immune system:
Common: Allergic reactions
Uncommon: immune reconstitution syndrome
Metabolic and food substances:
Very often: increasing concentration of total cholesterol (fasting) iipoproteinov increased concentration of low density (LDL) (nato aa) 4 Hypophosphatemia 1
Often, hyperglycemia, hyper-triglitseridemnya decreased appetite, increased concentration triglineridov
Uncommon: Hypokalemia 1
Rare: lactic acidosis
mental disorders:
Common: insomnia, abnormal dreams depression, insomnia, abnormal dreams. sleep disorders depressed mood
disorders of the nervous system.
Very common: headache headache dizziness
Common: dizziness dizziness, somnolence Headache
Disorders of the gastrointestinal tract:
Very common: diarrhea, nausea nausea, increased activity of pancreatic amylase diarrhea, vomiting, nausea
Common: Increased amylase activity, including increased activity of pancreatic amylase; increased activity of serum lipase, vomiting, abdominal pain, dyspepsia, abdominal pain, vomiting, increased lipase activity, abdominal discomfort, dry mouth, abdominal pain, abdominal distension, flatulence
Uncommon: Pancreatitis
Violations of the hepatobiliary system:
Very common: Increase transaminases (ACT and / or ALT)
Common: Increased activity of ACT in the serum and / or an increase in ALT serum giperbnlirubinemiya Increased bilirubin Increased transaminases (ACT and / or ALT)
rare: Fatty Pec and hepatitis
Disorders of the skin and subcutaneous tissue:
Very common: Rash
Frequently: Vezikulobuleznaya rash, pustular rash, maculopapular rash, hives, itching, hives, skin discoloration (increased pigmentation) 2 Rash
Uncommon: Angioedema 3
Rare: Angioedema 3
violations by the musculoskeletal and connective tissue:
Very often: Increase creatine kinase
Uncommon: Rhabdomyolysis 1 , muscular weakness 1
rare: osteomalacia (manifested as bone pain and sometimes promotes the development of fractures) 1,3 , myopathy 1
renal dysfunction and urinary tract:
Uncommon: Increase e concentration of creatinine, proteinuria
Rare: renal failure (acute and chronic), acute tubular necrosis, proximal tubulopathy including Fanconi syndrome, nephritis (including acute interstitial nephritis) 3 , nephrogenic diabetes insipidus
Disorders general condition and reactions at the site of application:
very often: Asthenia
Frequently: Pain, asthenia fatigue
1 This adverse reaction may occur as a complication of proximal tubulopathy. In the absence of this condition is not considered related to the use of tenofovir disoproxil fumarate.
2 When using emtritsitabiia anemia in children is often observed, and changes in skin tsvsta (increased pigmentation) very often.
3This adverse reaction has been identified during post-marketing surveillance but not recorded in the randomized, controlled clinical trials. Frequency category assessed based on statistical calculations based on the total number of patients exposed emtritsitabiia in randomized, controlled clinical isslslovaniyah (n = 1563) or in randomized. controlled clinical trials of tenofovir disoproxil fumarate in the expanded access program (n = 7319).
The mean change in total cholesterol concentration (fasting) was 2 mg / dl, high density lipoproteiiov (fasting) - 4 mg / dL, low-density lipoproteiiov (fasting) - 1 mg / dl and triglyceride (fasting) - 7 mg / dl.
Creatinine concentration in the serum
During phase III clinical trials for the first four weeks of therapy rilpivirine observed increase in creatinine concentration in the serum, wherein the concentration of Creatinine remained stable until the 48 th week. After 48 weeks of treatment, average rates were 0.09 mg / dl (Range: 0.20 mg / dL to 0.62 mg / dl). In patients with impaired serum renal function, mild to moderate increases in serum creatinine concentrations were comparable to the increase in the concentration of creatinine in the blood serum in patients with normal renal function. These changes were considered to be clinically insignificant, and no patient discontinued treatment due to increase in the concentration of creatinine in serum.
Description of individual adverse reactions
Renal function
Since Eviplera drug can cause kidney damage, it is advisable to monitor renal function.
Interaction with didanosine
is contraindicated joint use of the drug Eviplera and didanosine, as it leads to 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions. It reported rare cases of pancreatitis and lactic acidosis, sometimes fatal. Dis.pipidemsh, lipodystrophy and metabolic disorders
Combination therapy is accompanied by so antirstrovirusnaya
