Eduardant® (Edurant®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRilpivirineRilpivirine
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  • Lakonivir
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    FARMASINTEZ, JSC (Irkutsk)     Russia
  • Eduardant®
    pills inwards 
    Johnson & Johnson, LLC     Russia
    • Dosage form: & nbspfilm-coated tablets
    Composition:
    Each tablet contains:

    Active substance: rilpivirin hydrochloride 27.5 mg, calculated as rilpivirin 25 mg. Excipients (core): 55.145 mg lactose monohydrate, microcrystalline cellulose 16.605 mg Croscarmellose sodium 6.05 mg, povidone (K30) 3.25 mg magnesium stearate 1.1 mg Polysorbate 20 0.35 mg.

    Excipients (coating): hypromellose (2910 6 mPa-s) 1.76 mg lactose monohydrate 0.968 mg macrogol (3000) 0.352 mg, 0.264 mg of triacetin, titanium dioxide 1.056 mg.
    Description:Round biconvex tablets, film-coated, white to almost white color engraved "TMS" on one side and "25" on the other side. On the fracture tablets from white to almost white.
    Pharmacotherapeutic group:An antiviral [HIV] agent.
    ATX: & nbsp

    J.05.A.G.   Non-nucleosides - reverse transcriptase inhibitors

    J.05.A.G.05   Rilpivirine

    Pharmacodynamics:

    Mechanism of action

    Rilpivirin is a

    diaryl pyrimidine non-nucleoside reverse transcriptase inhibitor HIV-1. The activity of rilpivirin is mediated by the non-competitive inhibition of HIV-1 reverse transcriptase. Rilpivirine does not inhibit human alpha, beta, gamma-DNA polymerase.

    Antiviral activity in vitro

    Rilpivirin is active against laboratory strains of wild-type HIV-1 in acute infected T-cell lines with an average EC50 of HIV-1 / WB of 0.77 nMol (0.27 ng / ml). Rilpivirine shows limited activity against HIV-2 in vitro with EU values50 from 2510 to 10830 nM Mechanism of action

    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. Rilpivirine does not inhibit human alpha, beta, gamma-DNA polymerase.

    Antiviral activity in vitro

    Rilpivirin is active against laboratory strains of wild-type HIV-1 in acute infected T-cell lines with an average EC50 of HIV-1 / WB of 0.77 nMol (0.27 ng / ml). Rilpivirine shows limited activity against HIV-2 in vitro with EU values50 from 2510 to 10,830 nMol (920-3970 ng / ml), however, in the absence of clinical trial data, it is not recommended to administer Eduardant ® for the treatment of HIV-2 infection. Rilpivirine has antiviral activity against a wide range of representatives of group M of HIV-1 (subtypes A, B, C, D, E, F, G, H), for which its average effective dose (EC50) varies from 0.07 to 1.01 nM (0.03-0.37 ng / ml), and the primary isolates of group O, for which its average effective dose (EC50) varies from 2.88 to 8.45 nM (1.06-3.10 ng / ml).

    Rilpivirin has additive antiviral activity in combination with nucleotide / nucleoside

    reverse transcriptase inhibitors: abacavir, didanosine, emtricitabine, stavudine, and tenofovir; with protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir and saquinavir; with non-nucleoside reverse transcriptase inhibitors: efavirenzem, etravirine and nevirapine, and also in combination with a fusion inhibitor-enfuvirtide and antagonist CCR5 co-receptor - maraviroc. Rilpivirine gives a synergistic or additive antiviral effect in combination with nucleoside reverse transcriptase inhibitors lamivudine and zidovudine, as well as an integrase inhibitor raltegravir.

    Resistance Cell culture

    When selecting wild-type HIV-1 strains of different origin and different subtypes, as well as selection of HIV-1 strains resistant to NNRTIs, the following amino acid substitutions were most often encountered: L100I, K101E, VI081, E138K, V179F, Y181C, H221Y, F227C, M230I.

    Resistance to rilpivirin was defined as a multiple change in the EC50 parameter (FC) above the biological threshold value, characteristic for the method of analysis used.

    Patients who have not previously received antiretroviral therapy Amino acid substitutions that were associated with NNRTI resistance and were most commonly encountered in such patients were: V901, K101E, E138K, E138Q, VI791, Y181C, V189I, H221Y and F227C. However, in the course of clinical trials, V901 and VI891 at the initial stage of treatment did not affect the response to rilpivirin therapy. Replacement of E138K appeared most often during rilpivirin therapy, usually in combination with replacement M184I.

    A greater number of patients with virologic failure of Aduurant® therapy compared with patients who had a virological failure of efavirenz therapy showed resistance to lamivudine / emtricitabine. With all available data in vivo and in vitro the following amino acid substitutions present at the initial stage of treatment affect the activity of rilpivirin: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I and M230L.

    Cross-resistance

    Mutant strains with resistance to HIV-1

    Of the 67 laboratory recombinant HIV-1 strains with one amino acid substitution in the reverse transcriptase gene, with a mutation resistant to NNRTI, including frequently encountered K103N and Y181C, rilpivirin demonstrated antiviral activity against 64 (96%) of these strains. At the same time it was shown that the presence of a mutation K103N in itself does not lead to a decrease in sensitivity, and in this case, the presence of a combination of mutations K103N and L100I leads to a 7-fold decrease in sensitivity. Single amino acid substitutions associated with a loss of sensitivity to rilpivirin were K101P, Y181I and Y181V.

    Isolates of recombinant strains Rilpivirin demonstrated

    sensitivity (FC < BPZ) for 62% of the 4,786 isolates of recombinant strains with resistance to efavirenz and / or nevirapine.

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

    According to the clinical study, 31 patients from 62 patients with virologic failure, against the background of treatment with Eduardant ® and phenotypic resistance, ceased to respond to rilpivirin therapy. And 28 patients had resistance to etravirine, 27 - to efavirenz and 14 - to nevirapine.

    Influence on the parameters of the electrocardiogram

    Effect of Eduardant ® on the interval QTcF when taken in the recommended dose of 25 mg once a day was studied in healthy volunteers. When taking Eduardant ® in the recommended dose of 25 mg once a day clinically significant effect on the interval QTc was not noted. When studying the use of Edurant® in doses exceeding therapeutic (75 mg once a day and 300 mg once a day) taken by healthy volunteers, the maximum average and time-matched (upper limit of the confidence interval of 95%) difference in the values ​​of the interval QTcF between the study drug and placebo and after correction values ​​were 10.7 (15.3) and 23.3 (28.4) ms, respectively. Against the background of the equilibrium state, taking the drug at doses of 75 mg once a day and 300 mg once a day led to an increase in the average value of the maximum concentration in the blood plasma (CmOh) is approximately 2.6 or 6.7 times, respectively, compared with the average value of CmOh, which was noted against the background of the equilibrium state with the introduction of the drug Edurant® in the recommended dose of 25 mg once a day.

    Pharmacokinetics:

    The pharmacokinetic properties of rilpivirin have been studied in adult healthy volunteers and adult HIV-1-infected patients who have not previously received antiretroviral therapy.The effect of rilpivirin on HIV-1 infected patients was lower than on healthy volunteers.

    Suction

    After oral administration, the maximum concentrations of rilpivirin in the blood plasma were reached within 4-5 hours. Absolute bioavailability of rilpivirin is unknown.

    Effect of food on absorption

    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 the drug Edurant® was taken with a drink enriched with proteins, the exposure was 50% lower than when it was taken with food at the same time.

    Distribution

    In vitro 99.7% of rilpivirin binds to plasma proteins, mainly albumin. Distribution rilpivirina in biological fluids (cerebrospinal fluid, secrets of the genital tract), has not been studied.

    Metabolism

    Research in vitro showed that rilpivirine is exposed to oxidative metabolism mediated by the cytochrome P450 system (CYP) BEHIND.

    Excretion

    The final half-life of rilpivirin is approximately 45 hours. After taking a single dose 14C-rilpivirin by mouth, about 85% and 6.1% of the dose of the drug containing

    radioactive label, was detected in feces and urine, respectively. The amount of rilpivirine found in the stool in unchanged form averaged 25% of the administered dose. In urine, only a small amount of unchanged rilpivirin was detected (less than 1% of the dose taken).

    Special patient groups

    Children

    The pharmacokinetics of rilpivirin in children is currently being studied. Due to insufficient study of the use of the drug in children, it is not possible to provide recommendations for the administration of Eduardant® to children.

    Elderly patients

    Pharmacokinetic analysis of data of HIV-1-infected patients showed that the pharmacokinetics of rilpivirin remains comparable for all age groups (18 to 78 years). Correction of the dose of the drug in elderly patients is not required.

    Floor

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

    Race

    Pharmacokinetic analysis of HIV-1-infected patients showed that race does not affect the effectiveness of Eduardant®. Impaired liver function

    Rilpivirin is metabolized and excreted by the liver. In a study comparing pharmacokinetic parameters in patients with mild hepatic impairment (class A on the Child-Pugh scale) and patients in the control group, as well as the pharmacokinetic parameters of patients with moderate hepatic impairment (class B on the Child-Pugh scale) and patients from the of the control group, the action of rilpivirin taken in multiple doses was 47% higher in patients with mild hepatic impairment, and 5% higher in patients with moderate impaired hepatic function. In patients with mild or moderate impairment of liver function, dose adjustment is not required. The pharmacokinetics of the Edurant® preparation in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

    Co-infection with the hepatitis B virus and / or C Pharmacokinetic analysis in populations of patients showed that co-infection with the hepatitis B virus and / or C did not have a clinically significant effect on the action of rilpivirin.

    Impaired renal function

    The pharmacokinetics of rilpivirin in patients with impaired renal function has not been studied. The kidneys show a small amount of rilpivirin.The effect of renal dysfunction on the excretion of rilpivirin is considered to be minimal. It is unlikely that hemodialysis or peritoneal dialysis can significantly accelerate the elimination of rilpivirin from the body, since rilpivirine has a high affinity for plasma proteins.

    Indications:The drug Edurant® in combination with other antiretroviral drugs as first-line therapy is indicated for the treatment of infection caused by type 1 HIV-1 (HIV-1) virus in adult patients.
    Contraindications:
    1. Hypersensitivity to rilpivirin or any other components of the drug.

    2. Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

    3. Children under 18 years.

    4. Severe violations of liver function (class C on the Child-Pugh scale).

    5. The drug Edurant® should not be used simultaneously with preparations, significantly reducing the concentration of rilpivirin in the plasma, since this can lead to loss of the virologic response or to the development of resistance to the Edurant® preparation or to the whole class of non-nucleoside inhibitors of reverse transcriptase. A significant decrease in the concentration of rilpivirin in plasma can occur in those cases,when drugs taken simultaneously with the drug Edurant® are metabolized through the isozyme CYP3A or increase the pH in the stomach (see Interactions with other drugs):

    - Anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin;

    - Anti-TB drugs rifampicin, rifapentin

    - Proton pump inhibitors-such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.

    - Glucocorticosteroid preparations of systemic action - dexamethasone (when taking more than one dose of the drug).

    - Preparations based on St. John's wort (Hypericum perforatum).
    Carefully:The drug Edurant® should be used with caution in combination with drugs that can cause a polymorphic ventricular tachycardia such as "pirouette". Data on the potential interaction of rilpivirin and drugs that extend the QT interval are limited. In a study involving healthy volunteers, it was found that high doses of rilpivirin (75 mg once a day and 300 mg once a day) prolong the QT interval on an electrocardiogram.
    Pregnancy and lactation:

    Women of reproductive age

    Due to the lack of adequate and well-controlled clinical studies of the use of Edurant® in pregnant women, women of childbearing age are recommended to use effective contraceptive during the drug intake. Pregnancy

    Adequate and well-controlled clinical or pharmacokinetic studies of the use of Edurant® with pregnant women were not conducted. There was no evidence of embryotoxicity or reproductive effects in animals. The drug Edurant® should be used during pregnancy only if the possible benefit to the mother exceeds the potential risk to the fetus.

    Lactation

    It is not known whether the rilpivirine in the breast milk of nursing women. In connection with the risk of contracting HIV infection and the possible development of adverse events in infants who are breastfeeding, it is not recommended to perform breastfeeding while taking the drug.

    Reproductive function

    Data on the effects of rilpivirin on reproductive function are not available.

    Dosing and Administration:Treatment should be performed by a doctor who has experience of HIV therapy. The drug Edurant® follows apply only in conjunction with other antiretroviral

    means. The recommended dose of the drug is one tablet (25 mg), orally once a day with meals. The tablet should be swallowed whole, not chewed, not crushed. If the delay in taking the drug is less than 12 hours, the patient should take a tablet of Eduardant ® as soon as possible with the food, the next tablet is taken at the usual time. 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. Correction of dose

    With the simultaneous use of Edurant® with rifabutin, the dose of Edurant® should be increased to 50 mg (two 25 mg tablets) once a day during meals. After the discontinuation of rifabutin therapy, the dose of Eduardant® should be reduced to 25 mg once a day during meals. Interactions with other drugs).

    Elderly patients

    Adjuvant dose adjustment in elderly patients is not required. The use of Eduardant ® in elderly patients requires caution.

    Children

    The effectiveness and safety of Eduardant ® in children under the age of 18 years is not established.

    Impaired liver function

    In patients with mild or moderate severity of liver function (class A or B on the Child-Pugh scale), dose adjustment is not required. Data on the use of the drug in patients with severe impairment of liver function (class C on the scale Child-Pugh) are absent. The use of Eduardant ® in patients with impaired liver function of moderate severity requires caution.

    Impaired renal function In patients with impaired renal function, correction of the dose of Edurant® is not required. In patients with severe renal failure or with kidney disease at the terminal stage, concurrent use of the drug Edurant® with inhibitor drugs CYP3A4 (for example, ritonavir) is only possible when the possible use of the application exceeds the potential risk.

    Side effects:
    In clinical trials, the most common adverse reactions were: depression, insomnia, headache, increased transaminase activity and rash. Among the adverse reactions of a severe degree, an increase in the activity of transaminases (1.6%), depression (0.7%), abdominal pain (0.4%), dizziness (0.3%), rash (0.3%).

    Adverse reactions of the drug are systematized relative to each of the organ systems depending on the frequency occurrence, using

    the following classification:

    Very frequent (>1/10)

    Frequent (>1/100, <1/10)

    Infrequent (>1/1000, <1/100)

    Rare (>1/10000, <1/1000)

    Very rare (<1/10000), including

    isolated cases.

    Disturbances from the gastrointestinal tract:

    Frequent: decreased appetite, abdominal pain, vomiting, nausea, dry mouth.

    Infrequent: discomfort in the abdomen.

    Disorders from the central nervous system:

    Frequent: depressive disorders (include mood worsening, depression, dysphoria, deep depression, unstable behavior, negative or suicidal thoughts, attempts at suicide), insomnia, unusual dreams, sleep disorder, dizziness, headache. Infrequent: decreased mood, drowsiness.

    Disturbances from the skin and subcutaneous tissue:

    Frequent: rash

    Influence on the results of laboratory indicators:

    Frequent: increased activity of transaminases.

    There have also been cases of a decrease in hemoglobin concentration,

    platelets, leukocytes, increased activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT), bilirubin, pancreatic amylase, lipase, total cholesterol, low-density lipoproteins, and triglycerides. The mean 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.

    Are common:

    Frequent: fatigue.

    Description of individual adverse reactions

    Redistribution of subcutaneous fatty tissue (PUFA)

    Combined antiretroviral therapy causes the redistribution of PLN (lipodystrophy) in HIV-infected patients and is manifested by the loss of subcutaneous fat on the periphery (upper and lower extremities) and the facial area, increased fatty tissue in the intraperitoneal and visceral regions, mammary hypertrophy and accumulation of subcutaneous fat in the dorsocervical region (the "buffalo hump").

    Inflammatory Syndrome restoration of immunity

    In HIV-infected patients with severe form of immunodeficiency, who only started to receive combined antiretroviral therapy, against the background of the restoration of the immune system, an inflammatory response to the presence ofopportunistic agents with the appearance or exacerbation of symptoms of a disease previously asymptomatic (inflammatory immune reconstitution syndrome). The cases of diffuse toxic goiter (Graves' disease) are registered against the background of inflammatory immune reconstitution syndrome.

    Patients co-infected hepatitis B virus and / or hepatitis C

    In patients who were co-infected with the hepatitis B virus or C receiving Eduardant®, the frequency of hepatic enzyme elevation was higher than in patients with HIV infection alone. Pharmacokinetic action Rilpivirin in co-infected patients is comparable to that in patients without co-infection.

    The level of serum creatinine

    The increase in serum creatinine was observed during the first four weeks of therapy and remained stable until the 48th week. The mean change after 48 weeks of therapy was 0.09 mg / dL (range: -0.20 mg / dL to 0.62 mg / dL). In patients with mild to moderate renal insufficiency, this increase in serum creatinine levels was comparable to an increase in serum creatinine in patients with normal renal function. These changes were regarded as as clinically insignificant, and no patient discontinued therapy due to an increase in serum creatinine levels.

    Overdose:Data on drug overdose in humans are few in number. Symptoms of overdose may include headache, nausea, dizziness, and / or unusual dreams. There is no specific antidote. Treatment includes the application of general measures of maintenance therapy, including monitoring of vital signs and ECG (QT interval), as well as monitoring the clinical state of the patient. To remove non-absorbed active substance, activated charcoal can be received. Because the rilpivirine characterized by high connectivity with plasma proteins, dialysis in the case of an overdose is ineffective.
    Interaction:Medicines that affect the metabolism of rilpivirin
    Rilpivirin is metabolized with cytochrome P450 (CYP) 3A isoenzymes, so drugs that induce or inhibit CYP3A affect the excretion of rilpivirin. Simultaneous administration of Edurant® and medications that can induce CYP3A can lead to a decrease in rilpivirin concentration in the blood plasma and reduce the therapeutic effect of rilpivirin.Simultaneous administration of Edurant® and medications that inhibit CYP3A may lead to increased rilpivirin concentration in the blood plasma.

    Simultaneous reception Edyurant® preparation and medicinal preparations raising pH in the stomach can result in lower rilpivirine plasma concentrations and possible reduction rilpivirine therapeutic action.

    The effect of rilpivirin on the metabolism of other drugs
    It is unlikely that the drug Edyurant® received a dose of 25 mg once a day, clinically significant effects on elimination of drugs metabolised by cytochrome P450 isozymes.

    The established and anticipated interactions with antiretroviral and other drugs are presented in Table 1.

    Table 1

    Drug interactions rilpivirine if concomitantly with drugs shown in Table 1 (increasing denoted as ↑, lowering both ↓, no change - <-> not applicable - NP, CI - CI, Cmax - Maximum plasma concentration, Cmin - the minimum concentration in the blood plasma, AUC - the area under the curve "concentration-time").

    Table 1: Drug interactions and recommendations for dose selection.

    Medications

    Effects on pharmacokinetic parameters of drugs

    Least square method

    Average Ratio

    (90% CI, 1.00 = no effect)

    Recommendations for simultaneous use with other drugs

    Antiviral drugs

    Antiretroviral drugs

    Nucleoside reverse inhibitors transcriptase (NRTI) / nucleotide reverse inhibitors transcriptase (HIOT)

    Didanosis in *#

    400 mg per day

    AUC didanosine 11.12 (0.99-1.27)

    Cmin Didanosine NP

    FROMmOh didanosine <-> 0.96 (0.80-1.14)

    AUC rilpivirine <-> 1.00 (0.95-1.06)

    Cmin rilpivirine <-> 1.00 (0.92-1.09)

    FROMmax rilpivirine<-> 1,00 (0,90-1,10)

    With the simultaneous administration of Eduardant ® with

    Didanosine dose adjustment is not required.

    Didanosine should be taken on an empty stomach, and at least two hours before or four hours after admission

    rilpivirin.

    Tenofovir * #

    300 mg per day

    AUC tenofovir ↑ 1,23 (1,16-1,31)

    Cmin tenofovir ↑ 1.24 (1.10-1.38)

    FROMmof tenofovir <-> 1.19 (1.06-1.34)

    AUC rilpivirin <-> 1.01 (0.87-1.18)

    Cmin rilpivirine <-> 0.99 (0.83 -1.16)

    FROMmah rilpivirin <-> 0,96 (0,81-1,13)

    With the simultaneous administration of the drug Eduardant® with tenofovir, dose adjustment is not required.

    Other NRTIs (abacavi R,

    emtricitabine, lamivudine,

    stavudine and zidovudine)

    Not studied

    Given the different ways of removing rilpivirin and other NRTIs, clinically significant drug interactions between these drugs and rilpivirin are not expected. Correction of the dose is not required.

    Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

    NNRTIs

    (delavirdine, efavirenz,

    etravirine,

    nevirapine)

    Not studied

    Not recommended

    accept

    Eduardant®

    simultaneously with other NNRTIs.

    Protease inhibitors-boosted with low-dose ritonavir

    Darunavir / riton

    avir *#

    800/100 mg per day

    AUC darunavir

    <->0,89 (0,81-0,99)

    Cmin darunavir ↓ 0.89 (0.68-1.16)

    from max darunavir <-> 0.90 (0.81-1.00)

    AUC rilpivirine ↑2,30 (1,98-2,67)

    FROMmin rilpivirine ↑ 2,78 (2,39-3,24)

    FROMmax rilpivirine ↑ 1,79 (1,56-2,06)

    With the simultaneous administration of Eduardant ® with darunavir / ritone vir, an increased concentration of rilpivirin in the blood plasma (inhibition of the isoenzyme CYP3A). With the simultaneous use of rilpivirin with darunavir / ritonavir, dose adjustment is not required.

    Lopinavir / ritonavir

    (soft gelatin

    capsules) * #

    400/100 mg twice a day

    day

    AUC lopinavir

    <->0,99 (0,89-1,10)

    Cmin lopinavir

    10,89 (0,73-1,08)

    FROMmOh lopinavir

    <-> 0,96 (0,88-1,05)

    AUC rilpivirine

    ↑ 1,52 (1,36-1,70)

    Cmin rilpivirin ↑ 1.74 (1.46-2.08)

    Cmax rilpivirine

    ↑ 1,29 (1,18-1,40)

    At simultaneous

    Adjurant® with

    lopinavir / riton

    avir can

    be observed

    rise

    concentrations

    rilpivirin in

    blood plasma

    (inhibition

    enzyme CYP3A). At simultaneous reception

    rilpivirin with lopinavir / riton

    correction avi

    dose is not required.

    Other enhanced inhibitors

    Proteases (atazanavir / ritonavir,

    fosamprenavir / ritonavir, saquinavir / ritonavir, tipranavir / ritonavir)

    Not studied

    At simultaneous

    taking the drug

    Edurant® with

    strengthened

    inhibitors

    protease can

    be observed

    rise

    concentrations

    rilpivirin in

    blood plasma

    (inhibition

    enzyme CYP3A).

    There is a low

    probability of,

    that rilpivirine

    will have an impact

    at concentration

    simultaneously

    injected protease inhibitors in blood plasma. Correction of the dose is not required.

    Protease inhibitors-without ritonavir-enhanced

    Pharmaco

    Not studied

    At simultaneous

    logically

    taking the drug

    and not

    Edurant® with

    amplified

    strengthened

    th

    inhibitors

    inhibition

    protease can

    ores

    be observed

    protease

    rise

    (atazan

    concentrations

    vir,

    rilpivirin in

    fosampr

    blood plasma

    enavir,

    (inhibition

    indian

    enzyme CYP3A).

    ir,

    There is a low

    nelfin

    probability of,

    vir)

    that rilpivirine

    will have an impact

    at concentration

    simultaneously

    of the

    inhibitors

    proteases in plasma

    blood. Corrections

    dose is not required.

    Antagonists CCR5

    Maravir

    Not studied

    At simultaneous

    OK

    admission

    rilpivirine and

    maraviroc

    clinically

    significant

    interactions

    expected.

    Dose adjustments are not

    it takes.

    HIV integrase inhibitor

    Raltegra

    AUC raltegravir

    Not required

    vir (400

    ↑9%

    dose adjustment for

    mg two

    simultaneous

    times in

    FROMmOh raltegravir

    admission to

    day)

    ↑ 10%

    raltegravir.

    FROM min raltegravir

    ↑ 27 %

    <-> AUC

    rilpivirine

    <-> Cmax rilpivirine

    <-> Cmin rilpivirine

    Other antiviral drugs

    Ribavirin

    Not studied

    At simultaneous reception

    rilpivirin with ribavirin clinically significant interactions is not expected. Correction of the dose is not required.

    Telaprevir (750 mg

    every 8 hours)

    AUC telaprevir ↓ 5%

    FROMmax telaprevir ↓ 3%

    Cmin telaprevir ↓ 11%

    AUC rilpivirin ↑ 78%

    Cmax rilpivirine ↑ 49 %

    Cmin rilpivirine ↑ 93 %

    Simultaneous reception of telaprevir with Edurant® can cause an increase in the concentration of rilpivirin in the blood plasma (counting

    inhibition of cytochrome CYP3A). Do not require correction of the doses of telaprevir and rilpivirin with simultaneous administration.

    Other medications

    Antiarrhythmics

    Digoxin

    (single dose 0.5 mg,)

    <-> AUC

    <-> Cmax

    No dosage adjustment is required when taking concomitantly with digoxin.

    Anticoagulants

    Dabigatran

    Not studied. The risk of an increase in the concentration of dabigatran in plasma can not be ruled out.

    The drug Edurant® should be used with caution at the same time as dabigatran.

    Antidiabetics

    Metformin * (single dose of 850 mg)

    <-> AUC

    <-> cmax

    No dosage adjustment is required when taking concomitantly with metformin

    Anticonvulsants

    Carbamazepine

    Oxcarbazepine

    Phenobarbital

    Phenytoin

    Not studied

    Do not take the drug Edurant® in combination with data

    anticonvulsant means, as this may lead to a decrease in the concentration of rilpivirin in the blood plasma (induction of isoenzyme CYP3A4), which can cause a decrease in the therapeutic efficacy of Eduardant ®.

    Antifungal preparations of the azole group

    Ketoconazole *

    400 mg per day

    AUC ketoconazole

    ↓0,76 (0,70-0,82)

    Cmin ketoconazole ↓ 0.34 (0.25-0.46)

    FROMmax ketoconazole

    <->0,85 (0,80-0,90)

    AUC rilpivirin ↑ 1.49 (1.31-1.70)

    Cmin rilpivirine ↑ 1,76 (1,57-1,97)

    Cmax rilpivirine

    ↑ 1,30 (1,13-1,48)

    With the simultaneous administration of Edurant® with ketoconazole, an increase in rilpivirin concentrations in the blood plasma (inhibition of the enzyme CYP3A). At simultaneous reception

    Rilpivirin with ketoconazole dose adjustment is not required.

    Fluconazole

    Itraconazole

    Posaconazole

    Voriconazole

    Not studied

    With simultaneous reception of the drug

    Edurant® with antifungal agents of the azole group may increase the concentration of rilpivirin in the blood plasma (inhibition of the enzyme CYP3A). At simultaneous reception

    Rilpivirin with such dosage adjustment preparations is not required.

    Anti-TB drugs

    Rifabutin * #

    300 mg per day↑

    AUC rifabutin <->

    Cmin rifabutin <->

    FROMmOh rifabutin <->

    AUC 25-0-deacetyl-rifabutin <->

    FROMmin 25-0-

    deacetyl rifabutin <->

    FROMmax 25-0-

    deacetyl-rifabutin

    When taking 25 mg of rilpivirin per day:

    AUC rilpivirine ↓ 42%

    Cmin rilpivirine ↓ 48%

    FROMmOh RILPIVIRINA

    ↓ 31 %

    When taking 50 mg of rilpivirin per day (compared with

    taking 25 mg rilpivirin per day):

    AUC rilpivirin ↑ 16%

    Cmin rilpivirine <->

    FROMmah rilpivirin ↑ 43%

    At simultaneous

    application of

    preparation

    Eduardant® with rifabutin a concentration of rilpivirin in the blood plasma can decrease due to induction

    Enzymes CYP3A4. This can lead to a loss of therapeutic effect

    rilpivirin. With the simultaneous use of the drug

    Eduardant® with rifabutin dose of the drug

    Adjurant® should be increased from 25 mg to 50 mg once daily. With cancellation of therapy

    rifabutin dose of the drug

    Aduarant® should be reduced to 25 mg once daily.

    Rifampicin

    600 mg per day

    AUC

    rifampicin

    <-> 0,99 (0,92-1,07)

    Cmin rifampicin NP

    FROMmrifampicin <-> 1.02 (0.93-1.12)

    AUC 25-0-deacetyl-rifampicin ↓ 0.91 (0.77-1.07)

    Cmin 25-0-deacetyl-rifabutin <-> NP

    With 25-0-deacetyl-rifampicin

    <->1,00 (0,87-1,15)

    AUC rilpivirin ↓ 0.20 (0.18-0.23)

    Cmin of rilpivirin ↓ 0.11 (0.10-0.13)

    Rlpivirin

    ↓ 0,31 (0,27-0,36)

    Do not use Eduardant ® in combination with rifampicin, as this can lead to a decrease in the concentration of rilpivirin in the blood plasma (induction of CYP3A4 enzymes) and, in turn, cause a loss

    therapeutic

    effect

    rilpivirin.

    Rifapentin

    Not studied

    Do not use Eduardant ® in combination with rifapentin, as this can lead to a decrease in the concentration of rilpivirin in the blood plasma (induction

    enzymes CYP3A4) and, in turn, cause a loss

    therapeutic

    effect

    rilpivirin.

    Antibiotics of the macrolide group

    Clariromycin

    Erythromycin

    Not studied

    With the simultaneous administration of Eduardant ® with clarithromycin, erythromycin, an increase in plasma rilpivirin concentrations (inhibition of the enzyme CYP3A). If possible, alternative drugs should be prescribed, for example azithromycin.

    Glucocorticoids

    Dexamethasone (systemic)

    Not studied

    Do not use Eduardant ® in combination with dexamethasone systemic action, as this can lead to a significant decrease in the concentration of rilpivirin in the blood plasma (induction of enzymes CYP3A4) and, in turn, cause a loss of therapeutic

    The effect of rilpivirin.

    The possibility of using alternative drugs, especially with prolonged use.

    Proton Pump Inhibitors

    Omeprazole *#

    20 mg per day

    AUC omeprazole ↓ 0.86 (0.76-0.97)

    Cmin omeprazole NP

    FROMmax omeprazole ↓ 0.86 (0.68-1.09)

    AUC rilpivirin ↓ 0.60 (0.51-0.71)

    Cmin rilpivirin ↓ 0.67 (0.58-0.78)

    FROMmRILPIVIRINA

    ↓ 0,60 (0,48-0,73)

    Do not use Eduardant ® in combination with omeprazole, as this can lead to a decrease in the concentration of rilpivirin in the blood plasma (increase in pH) and, in turn, cause a loss of therapeutic effect of rilpivirin.

    Lansoprazole

    Rabeprazole

    Pantoprazole

    Esomeprazole

    Not studied

    Do not use Eduardant ® in combination with proton pump inhibitors, as this can lead to a significant decrease in the concentration of rilpivirin in the blood plasma (increase in pH), and, in turn,cause the loss of therapeutic effect of rilpivirin.

    Blockers of H2-histamine receptors

    Famotidine *#

    Single entry

    a dose of 40 mg,

    accepted for 12 hours before

    rilpivirine

    Famotidine*#

    Single entry

    a dose of 40 mg,

    taken 2 hours before rilpivirine

    Famotidine *#

    Single entry

    a dose of 40 mg,

    taken 4 hours before rilpivirine

    Cimetidine

    Nisatidine

    Ranitid

    AUC rilpivirine ↓ 0.91 (0.78-1.07)

    Cmin rilpivirine NP

    Staph of rilpivirin <-> 0,99 (0,84-1,16)

    AUC rilpivirine ↓ 0,24 (0,20-0,28)

    Cmin rilpivirine NP

    FROMmax RILPIVIRINA

    <-> 0,15 (0,12-0,19)

    AUC rilpivirine ↑ 1,13 (1,01-1,27)

    Cmin rilpivirine NP

    FROMmOh RILPIVIRINA

    <-> 1,21 (1,06-1,39)

    Not studied

    Adjunct should be used with caution when prescribing concomitantly with H2 receptor antagonists, as this can lead to a significant decrease in the concentration of rilpivirin in the blood plasma in connection with an increase in pH in the stomach. H 2 -receptor antagonists should be taken at least 12 hours before or 4 hours after taking rilpivirin.

    Antacid agents

    Antacids

    means (hydroxide

    aluminum or magnesium, calcium carbonate)

    Not studied

    Adjunct should be used with

    caution simultaneously with antacid agents, since this

    can lead to a significant decrease in the concentration of rilpivirin in the blood plasma in connection with the increase in pH in the stomach. Antacids can be administered at least 2 hours before or 4 hours after taking rilpivirin.

    Narcotic analgesics

    Methadone *

    60-100 mg per day

    Individualvalently of theother dose

    AUC methadone R(- ) ↓ 0,84 (0,74-0,95)

    Cmin methadone R(-) ↓0,78(0,67-0,91)

    FROM max methadone R(-) ↓ 0,86 (0,78-0,95)

    AUC rilpivirine <->. *

    Cmin rilpivirine <->.*

    FROM max rilpivirine <->. *

    * Taking into account data on groups of historical control

    With the simultaneous administration of methadone with the drug Edurant®

    correction of the dose is not required. Nevertheless,

    Clinical monitoring is recommended in connection with the need for correction of the methadone maintenance regimen in some patients.

    Herbal medicines

    St. John's Wort

    hole (Hyperic um

    perforatu t)

    Not studied

    Adjurant® should be used with caution at the same time as preparations based on St. John's Wort, as this can lead to a significant decrease in the concentration of rilpivirin in the blood plasma (increase in pH), which in turn will lead to a loss of the therapeutic effect of rilpivirin.

    Analgesics

    Paracetol *#

    500 mg single dose

    AUC

    paracetamol

    <->1,03 (0,95-1,13)

    Cmin paracetamol

    NP

    FROMmParacetamol

    <-> 0,98 (0,85-1,13)

    AUC rilpivirine

    <-> 1,16 (1,10-1,22)

    Cmin rilpivirine

    <-> 1,26 (1,16-1,38)

    FROMmah rilpivirina

    <-> 1,09(1,01-1,18)

    With simultaneous reception of the drug

    Edurant® with

    paracetamol

    dose adjustment is not

    it takes.

    Estrogen-containing contraceptives

    Ethinyl

    AUC

    At simultaneous

    stridio

    ethinyl estradiol

    taking the drug

    l * #

    <->1,14 (1,10-1,19)

    Edurant® with

    contraceptive

    0.035 mg

    Cmin

    means,

    in a day

    ethinyl estradiol

    containing

    <-> 1,09 (1,03-1,16)

    estrogen and

    norethine

    progesterone,

    drone *

    FROMmOh

    dose adjustment is not

    ethinyl estradiol

    it takes.

    1 mg in

    ↑1,17 (1,06-1,30)

    day

    AUC

    norethindrone

    <->0,89 (0,84-0,94)

    Cmin norethindrone

    <->0,99 (0,90-1,08)

    FROMmOh norethindrone

    <->0,94 (0,83-1,06)

    AUC rilpivirine <-> *

    Cmin rilpivirine <-> *

    FROMmOh rilpivirine <-> *

    * Given the data

    groups

    historical

    control

    Inhibitors of HMG-CoA reductase

    Atorvastatia*#


    40 mg in day

    AUC

    atorvastatin

    <->1,04 (0,97-1,12)

    Cmin atorvastatin

    1 0,85 (0,69-1,03)

    Stach

    atorvastatin

    ↑ 1,35 (1,08-1,68)

    AUC of rilpivirine

    <-> 0,90 (0,81-0,99)

    Cmin rilpivirine

    <-> 0,90 (0,84-0,96)

    The Stalk of the Rilpivirin

    At simultaneous

    taking the drug

    Edurant® with

    atorvastatin

    dose adjustment is not

    it takes.

    4↓0,91 (0,79-1,06)

    Fluvastathen

    Lovastatin

    Pitavastatia

    Rightsathen

    Rosewastathen

    Simvastathen

    Not studied

    At simultaneous

    taking the drug

    Edurant® with

    inhibitors of HMG-

    CoA reductase

    dose adjustment is not

    it takes.

    Inhibitors of phosphodiesterase type 5 (PDE-5)

    Silden

    AUC sildenafil

    At simultaneous

    Phil*#

    <-> 0,97 (0,87-1,08)

    taking the drug

    Edurant® with

    50 mg

    Cmin sildenafil

    sildenafil

    one-off

    NP

    dose adjustment is not

    tnaya

    Cmax sildenafil

    it takes.

    dose

    <-> 0,93 (0,80-1,08)

    AUC rilpivirine

    <->0,98 (0,92-1,05)

    Cmin rilpivirine

    <->1,04 (0,98-1,09)

    Cmax RILPIVIRINA

    <->0,92 (0,85-0,99)

    Varden

    Not studied

    At simultaneous

    Phil

    taking the drug

    Tadalafil

    Edurant® with inhibitors of PDE-5 dose adjustment is not required.

    * Interaction between Edurant® and the drug

    was studied in a clinical trial. Other medicinal

    interactions are assumed.

    # This study investigates the interaction of drug drugs

    was performed when taking Edurant® in a dose exceeding the recommended dose.

    Dosing recommendations refer to the recommended dose of the drug

    Adjurant® 25 mg once a day.

    + This study investigating the interaction of drug drugs

    was performed when taking Edurant® in a dose exceeding the recommended dose.

    Male and female contraception

    The likelihood of a decrease in the effectiveness of oral contraceptives

    Simultaneous admission with the drug Edurant® is low. Dose adjustment

    contraceptives based on estrogen and / or progesterone

    Simultaneous admission with the drug Edurant® is not required.

    Medicinal products drugs, extension intervals QT

    Data on the potential interaction of rilpivirin and drugs that extend the interval QT, are limited. In a study involving healthy volunteers, it was found that high doses Rilpivirine (75 mg once a day and 300 mg once a day) lengthen the interval QT on an electrocardiogram. In this regard, the drug Edurant® should be used with caution in combination with drugs that can cause a polymorphic ventricular tachycardia such as "pirouette".


    Special instructions:
    Patients should be informed that, with current antiretroviral therapy, HIV infection can not be cured, nor can HIV infection be prevented through blood or through sexual contact. Take the necessary precautions to prevent HIV infection.

    At the moment, there is insufficient data on the safety and efficacy of Edurant® in children under 18 years of age and in patients with severe impaired liver function (grade C on the Child-Pugh scale).Therefore, until the clinical data on the safety and efficacy of the drug in children and patients with severe impairment of liver function (class C on the Child-Pugh scale) will not be obtained, it is not recommended to use Eduardant ® in these categories of patients. Before starting treatment with Eduardant®, the following should be considered: In the study participants who received Eduardant®, with an HIV-1 RNA of more than 100,000 copies / ml, the absence of a virologic response was more likely to occur at the time of initiation of therapy compared to patients on whom At the start of therapy, HIV-1 RNA levels were less than 100,000 copies / mL. The observed virological inefficiency in the treatment with Edurant® resulted in a higher incidence of resistance to NNRTIs. In patients with observed virologic failure who received therapy with Edurant®, resistance to lamivudine / emtricitabine was more likely to develop than in patients with observed virological inefficiency who received the drug efavirenz.
    Interaction with other drugs

    Caution should be exercised when administering Edurant® in combination with other medications that may decrease the therapeutic effect of rilpivirin. The drug Edurant® should be used with caution in combination with drugs that can cause tachycardia such as "pirouette". For information on the interaction of the drug with other drugs, see "Interaction with Other Drugs".
    Depressive disorders

    There are cases of depressive disorders (mood worsening, depression, dysphoria, deep depression, instability of behavior, negative thoughts, suicidal thinking, suicidal attempts) against the background of taking Eduardant ®. Most of the cases were mild to moderate. In the case of a patient experiencing symptoms of moderate depression, the patient should immediately seek medical help in order to determine whether these symptoms are associated with taking Eduardant ®. If the connection with taking the drug is proven, you should evaluate the risk compared to the benefit of continuing therapy.

    Redistribution of subcutaneous fat (FFA)
    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.

    Inflammatory immune reconstitution syndrome

    At the beginning of antiretroviral therapy, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to the presence of asymptomatic opportunistic agents with the appearance or exacerbation of the symptoms of the disease,previously occurring asymptomatically (inflammatory immune reconstitution syndrome), which may require further careful monitoring and treatment. Typically, such reactions are observed during the first weeks after the start of treatment. Examples include cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumocystis pneumonia. You should evaluate any symptoms of inflammation and, if necessary, prescribe treatment. The cases of autoimmune diseases, such as diffuse toxic goiter (Graves' disease), are registered against the background of inflammatory immune reconstitution syndrome. However, the period of occurrence of these diseases varies widely; diseases can begin many months after the start of treatment.
    Effect on the ability to drive transp. cf. and fur:The drug Edurant® has no influence or has little effect on the ability to drive vehicles and manage mechanisms.
    Form release / dosage:
    Tablets, film-coated 25 mg.

    Packaging:

    For 30 tablets in high density polyethylene bottles,ukuporennye polypropylene lid with a system of protection from opening the children and control the first autopsy.

    1 bottle with instructions for use in a cardboard box.
    Storage conditions:
    Store at a temperature not exceeding 30 ° C.

    Keep in original packaging to protect from direct sunlight. Keep out of the reach of children.
    Shelf life:3 years. Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:PL-001769
    Date of registration:02.07.2012
    Date of cancellation:2017-07-02
    The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp05.05.2016
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