Intelence® (Intelence®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceEtravirineEtravirine
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  • Intelence®
    pills inwards 
    Johnson & Johnson, LLC     Russia
  • Intelence®
    pills inwards 
    Johnson & Johnson, LLC     Russia
    • Dosage form: & nbspPills.
    Composition:

    Active substance: each tablet contains 200 mg of etravirine. Excipients: hypromellose - 600 mg, silicon dioxide colloid - 2,8 mg, croscarmellose sodium - 70 mg, magnesium stearate - 7 mg, microcrystalline silicon cellulose - 450.2 mg, microcrystalline cellulose - 70 mg.

    Description:

    White or almost white oblong biconvex tablets with engraving "T200" on one side.

    Pharmacotherapeutic group:An antiviral [HIV] agent.
    ATX: & nbsp

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

    J.05.A.G.04   Etravirine

    Pharmacodynamics:

    Mechanism of action

    Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus - HIV-1. Etravirine directly binds to reverse transcriptase and blocks RNA-dependent and DNA-dependent activity of DNA polymerase, causing destruction of catalytic sites of this enzyme.

    Antiviral activity in vitro

    Etravirine is active against laboratory strains and clinical isolates of wild-type HIV-1 in acute infected T-cell lines, peripheral human mononuclear cells and human monocytes / macrophages.

    Etravirine has antiviral activity in vitro for a wide range of representatives of group M of HIV-1 (subtypes A, B, C, D, E, F, G) and primary isolates of group O, for which its average effective concentration (EC50) varies from 0.7 to 21.7 NM. Etravirine is not an antagonist of any of the antiretroviral drugs studied. It has additive antiviral activity in combination with inhibitors proteases: amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir and saquinavir; with nucleoside or nucleotide reverse transcriptase inhibitors: zalcitabine, didanosine, stavudine, abacavir, and tenofovir; with non-nucleoside reverse transcriptase inhibitors efavirenz, delavirdine and nevirapine, in combination with an enfuvirtide fusion inhibitor, integrase inhibitor raltegravir and a CCR5 receptor antagonist maraviroc.

    Etravirine provides a synergistic or additive antiviral effect in combination with nucleoside reverse transcriptase inhibitors emtricitabine, lamivudine and zidovudine.

    Resistance

    Etravirine demonstrated strong antiviral activity against 56 of the 65 HIV-1 strains with one amino acid substitution at the RT positions associated with NNRTI resistance,including the most common mutations K103N and Y181C. Amino acid substitutions that cause the highest resistance to etravirine in cell culture are mutations Y181I (13-fold change in EC50 value) and Y181V (17-fold change in EC50 value). The antiviral activity of etravirine in cell cultures against 24 HIV-1 strains with multiple amino acid substitutions that cause resistance to NNRTI and / or protease inhibitors is similar to that of wild-type HIV-1 strain.

    Selection in vitro etravirine-resistant wild-type strains of HIV-1 of different origin and different subtypes, and selection of HIV-1 strains resistant to NNRTI occurred both at high and low viral inoculum. The development of resistance to etravirin usually required multiple mutations of reverse transcriptase, of which the following were most commonly encountered: L100I, E138K, E138G, V179I, Y181C and M230I.

    Mutations that most often occurred in patients with an unsuccessful virological result of treatment with combinations containing etravirine, were V179F, V179I, Y181C.

    Cross-resistance

    There was a limited cross-resistance between etravirine and efavirenz in vitro in 3 of 65 mutant HIV-1 strains carrying a mutation that causes resistance to NNRTIs. In other strains, the amino acid positions associated with reduced sensitivity to etravirine and efavirenz were different. Etravirine saves EC50 <10 nmol against 83% of the 6171 clinical isolates resistant to delavirdine, efavirenz and / or nevirapine. It is not recommended to perform treatment with delavirdine, efavirenz and / or nevirapine in patients in whom the regimen containing etravirine, was ineffective from the virological point of view.

    Pharmacokinetics:

    Suction

    After ingestion with food, the maximum concentration of etravirin in the plasma is reached within 4 hours.

    In healthy people, the absorption of etravirine does not depend on the simultaneous intake of ranitidine or omeprazole, which increase the pH of the contents of the stomach.

    The concentration of etravirine does not depend on the type of food taken (normal caloric content is 561 kcal or fatty food is 1160 kcal). The concentration of the drug was lower when it was applied before meals (by 17%), or on an empty stomach (51%) compared with its intake after eating. Thus, to maintain the optimal concentration of etravirin in plasma, it is necessary to take the drug after eating.

    Distribution

    In vitro about 99.9% of etravirine is bound by plasma proteins, mainly with albumin (99.6%) and with α1-acid glycoprotein (97.66 - 99.02%). The distribution of etravirine in other fluids (for example, in cerebrospinal fluid) in humans has not been studied.

    Metabolism

    Experiments in vitro with microsomes of human liver showed that etravirine is mainly subjected to oxidative metabolism under the action of hepatic isozymes of the CYP3A family and, to a lesser extent, under the action of the CYP2C family isozymes, followed by glucuronation.

    Excretion

    After ingestion of the dose of labeled 14C-etravirine, 93.7% and 1.2% of the dose were detected in feces and urine, respectively. The proportion of unchanged etravirine in the feces accounted for 81.2 - 86.4% of the dose. In the urine etravirine unchanged is not detected. The final elimination period of etravirine is about 30 to 40 hours.

    Special patient groups

    Children and adolescents (6 to 18 years)

    The pharmacokinetics of etravirine was studied in 101 HIV-1 infected patients of this age group who previously received anti-HIV therapy and had a body weight of at least 16 kg. It was shown that the exposure of the drug when applying a dose corresponding to 5.2 mg / kg of body weight twice a day,comparable to that of the use of the drug Intelens® by adult patients at a dose of 200 mg twice a day.

    Children (up to 6 years)

    At present, studies of the pharmacokinetics of etravirine in patients of this age group are being conducted.

    Elderly patients

    The pharmacokinetics of etravirine does not depend on the age of the subjects (18 to 77 years).

    Men and women

    Between men and women, there were no significant differences in the pharmacokinetics of etravirine.

    Race

    It was shown that the race of the patient does not affect the pharmacokinetics of etravirine.

    Patients with hepatic impairment

    Etravirine is metabolized and eliminated mainly by the liver. The pharmacokinetics of etravirine did not change in patients with mild or moderate impairment of liver function. There is no need to change the dose of the drug Intelence ® in this category of patients. In patients with severe impairment of liver function (class C on the Child-Pugh scale), the pharmacokinetics of Intelence® were not studied.

    Patients infected with hepatitis B virus and / or hepatitis C virus

    Etrravirin clearance in patients infected with HIV-1 and hepatitis B virus and / or hepatitis C virus is reduced.Based on the etravirin safety profile, dose adjustment in this category of patients is not required.

    Patients with impaired renal function

    Patients with renal insufficiency did not study the pharmacokinetics of etravirine. With urine, less than 1.2% of the dose of etravirine is eliminated. Etravirine in the unchanged form in the urine is not detected, therefore, the effect of renal dysfunction on the elimination of etravirine is minimal. Because the etravirine has a very high ability to bind to plasma proteins, it can hardly be removed from the body in any significant amounts by hemodialysis or peritoneal dialysis.

    Indications:

    Treatment of human immunodeficiency virus-HIV-1 infection in adult patients who received antiretroviral drugs, including those with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in combination therapy.

    Contraindications:

    • Hypersensitivity to etravirine or any component of the drug.
    • Children's age (up to 18 years).
    • Pregnancy and the period of breastfeeding.
    • Severe liver dysfunction (Child-Pugh class C).
    • Simultaneous use with drugs that affect the concentration of etravirin in blood plasma and with drugs, whose concentration in the blood plasma changes when combined with etravirine: non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine, delavirdine, rilpivirine); protease inhibitors without concurrent administration of low-dose ritonavir (nelfinavir, indinavir, saquinavir and others, except fosamprenavir); ritonavir (when taken in a dose of 600 mg 2 times a day); combination of tipranavir / ritonavir; anticonvulsants (carbamazepine, phenobarbital, phenytoin); anti-tuberculosis drugs (rifampicin, rifapentin); medicines containing St. John's wortHypericum perforatum).

    Carefully:

    • Elderly patients.
    • Patients who are simultaneously infected with hepatitis B virus and / or hepatitis C virus.

    Pregnancy and lactation:

    Pregnancy

    Adequate and well-controlled studies of the use of etravirine in pregnant women have not been conducted. Studies in animals have not shown a direct or indirect adverse effect of etravirine on the course of pregnancy, intrauterine development, childbirth and postnatal development.

    Breastfeeding period

    It is not known whether etravirine penetrate into breast milk. Because of the potential for mother-to-child transmission of HIV during breastfeeding and the occurrence of potential side effects of etravirine in nursing women themselves, HIV-infected women should refrain from breastfeeding if they take Intelence®.

    Fertility

    At present, there is no evidence of the effect of etravirine on human fertility.

    Dosing and Administration:

    Intellens® should always be used in combination with other antiretroviral drugs.

    Adults: inside by 200 mg (1 tablet) 2 times a day after meals. The maximum daily dose is 400 mg. Tablets should be swallowed whole, washed down with water. Patients experiencing difficulty in swallowing Intelence® tablets, can grind them and stir in a glass of water. In this case, the patient should immediately drink the contents of the glass. To ensure the reception of a full dose, the glass should be rinsed several times with water and completely drunk the contents. It should avoid the use of warm (more than 40 ° C) water and carbonated drinks.

    Elderly patients: there is limited information on the treatment with the drug Intelence® patients of this age group. Correction of the dose is not required.

    Intellens® should be used with caution in this category of patients.

    Patients with hepatic impairment: in patients with mild or moderate liver function disorder (Class A or B on the Child-Pugh scale), dose adjustment is not required. Caution should be exercised when using the drug in patients with moderate impairment of liver function. In patients with severe impairment of liver function (class C on the Child-Pugh scale), the pharmacokinetics of Intelence® were not studied.

    Patients with impaired renal function: in patients with impaired renal function, dose adjustment is not required.

    If the patient forgot to take another dose of the drug Intelence® and remembered about it no later than 6 hours after the usual time of taking the drug, he should take it as soon as possible after eating and then take the next dose at the usual time for it. If it is more than 6 hours after the usual time of taking the drug, the patient should not take the missed dose, but simply resume taking the drug as usual.

    Side effects:

    Unwanted drug reactions detected during clinical trials

    The most common adverse events were: a rash (10% in the Intelence® group compared with 3.5% in the placebo group), diarrhea (7% in the Intelens® group compared with 11.3% in the placebo group), hypertriglyceridemia (6.3% in the Intelence® group compared with 4.3% in the placebo group), nausea (5.2% in the Intelence® group compared with 4.8% in the placebo group).

    Data on the safety of the use of the preparation Intellens ®, obtained from clinical studies, are systematized relative to each of the organ systems depending on the frequency of occurrence using the following classification: very frequent (≥1 / 10), frequent (≥1 / 100, <1/10) , infrequent (≥1 / 1000, <1/100), rare (≥1 / 10000, <1/1000).

    From the cardiovascular system:

    Often - myocardial infarction, increased blood pressure;

    Infrequently - atrial fibrillation, stenocardia, hemorrhagic stroke.

    From the hematopoietic and lymphatic system:

    Often - thrombocytopenia, anemia.

    From the nervous system:

    Often - peripheral neuropathy, headache, anxiety, insomnia;

    Infrequent - convulsions, fainting, amnesia, tremor, drowsiness, paresthesia, hypesthesia, confusion, disorientation, nightmares, sleep disturbances, incl.hypersomnia, nervousness, pathological dreams, impaired concentration.

    From the sense organs:

    Infrequently - blurred vision, vertigo.

    On the part of the respiratory system:

    Infrequently - dyspnea with exercise, bronchospasm.

    From the gastrointestinal tract:

    Often - gastroesophageal reflux, diarrhea, vomiting, nausea, abdominal pain, flatulence, gastritis;

    Infrequently - pancreatitis, bloody vomiting, stomatitis, constipation, dry mouth, urge to vomit, bloating.

    From the urinary system:

    Often - kidney failure.

    From the skin and soft tissues:

    Very often - a rash;

    Often - night sweats, lipodystrophy;

    Infrequent - facial swelling, hyperhidrosis, pruritus, dry skin, lipodystrophy, angioedema, erythema multiforme, Stevens-Johnson syndrome.

    Metabolic and nutritional disorders:

    Often - diabetes, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia;

    Infrequently - anorexia, dyslipidemia.

    Violations of a general nature:

    Often - fatigue;

    Infrequent - lethargic.

    From the immune system:

    Infrequent is the immune reconstitution syndrome, hypersensitivity to the drug.

    From the hepatobiliary system:

    Infrequently - hepatitis, fatty liver, cytolytic hepatitis, hepatomegaly.

    On the part of the reproductive system and mammary glands: gynecomastia.

    From the laboratory indicators: increase in the activity of pancreatic amylase, lipase, alanine aminotransferase (hereinafter - ALT), aspartate aminotransferase (hereinafter - AST) increase in the concentration of creatinine, total cholesterol, low density lipoproteins, triglycerides, glucose, and a decrease in the number of neutrophils and leukocytes.

    The most common cause of drug withdrawal was skin rash. The rash most often was mild or moderately severe, usually macular, maculopapular or erythematous, usually occurred in the second week of treatment and rarely appeared after the 4th week. Most often, the rash did not require special treatment and usually disappeared within 1-2 weeks while continuing treatment. The occurrence of rash against the background of therapy with the drug Intelens® was more often observed in women.

    Moderate side effects (not more than 0.5% of patients) were acquired lipodystrophy, angioedema, erythema multiforme and hemorrhagic stroke.Rarely (<0.1%) there was Stevens-Johnson syndrome (less than 0.1%) and very rarely - toxic epidermal necrolysis (less than 0.01%).

    Additional information about specific populations of patients

    In patients who are simultaneously infected with hepatitis B virus and / or hepatitis C virus, increased activity of AST and ALT. Intellens® should be used with caution in this group of patients.

    Side effects registered in the postmarketing period: hypersensitivity reactions including DRESS symptom characterized by rash, fever, eosinophilia and systemic manifestations (including, but not limited to: severe rash or rash accompanied by fever, general malaise, fatigue, pain in muscles and joints , bullous lesions, damage to the oral mucosa, conjunctivitis, hepatitis, eosinophilia).

    From the side of musculoskeletal tissue: rhabdomyolysis.

    Overdose:

    Data on the overdose of Intelence® in humans are limited. It is likely that the most frequent symptoms of overdose are the most frequently observed side effects caused by the use of Intelence®, such as rash, diarrhea, nausea, headache. There is no specific antidote of etravirine.Treatment of an overdose consists in conducting general maintenance symptomatic therapy, including monitoring of basic physiological parameters and monitoring the clinical condition of the patient. If necessary etravirine can be removed from the stomach with artificial vomiting or by washing the stomach. For this purpose, the introduction of activated carbon is also useful. Etravirine has a high ability to bind to plasma proteins, and therefore dialysis is unlikely to result in significant removal of the active substance from the body.

    Interaction:

    Drugs affecting the concentration of etravirin in plasma

    Etravirine is metabolized by isoenzymes CYP3A4, CYP2C9 and CYP2C19, and its metabolites undergo glucuronation under the influence of the enzyme uridine diphosphate glucuronosyl transferase. Drugs that induce isoenzymes CYP3A4, CYP2C9 or CYP2C19, can accelerate the etravirin clearance, resulting in a decrease in its plasma concentration.

    The simultaneous use of the preparation of Intelence® and preparations that inhibit the isoenzymes CYP3A4, CYP2C9 or CYP2C19, can slow the etravirin clearance and increase its plasma concentration.

    Medicines, the metabolism of which is affected by etravirine

    Etravirine is a weak inducer of the isoenzyme CYP3A4. The simultaneous use of the preparation of Intelence® and preparations that are metabolized mainly by the isoenzyme CYP3A4, can lead to a decrease in the concentrations of such drugs in the plasma and, consequently, to weaken or shorten their therapeutic effects.

    Besides, etravirine is a weak inhibitor of the isoenzymes CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein, but is not its substrate.

    The simultaneous use of etravirine and preparations that are metabolized mainly by CYP2C9 or CYP2C19 isoenzymes or transported by P-glycoprotein can increase the concentration of such drugs in plasma and, therefore, enhance or prolong their therapeutic or side effects.

    Drug interactions of etravirine with other antiretroviral drugs Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (eg, efavirenz, nevirapine, delavirdine, rilpivirine)

    It is not recommended to use Intelence® at the same time as other non-nucleoside reverse transcriptase inhibitors.

    Nucleoside reverse transcriptase inhibitors (NRTIs)

    - Didanosine (400 mg once a day): the combination can be used without dose adjustment.

    Didanosine is taken on an empty stomach, and therefore it must be taken 1 hour before or 2 hours after taking the drug Intelence® (which should be taken after meals).

    - Tenofovir (300 mg once a day): the combination can be used without dose adjustment.

    - Others (for example: abacavir, emtricitabine, lamivudine, stavudine and zidovudine) are eliminated mainly by the kidneys, and therefore it is considered that etravirine does not interact with these drugs. These combinations can be used without dose adjustment.

    Protease inhibitors without concurrent administration of low-dose ritonavir

    - Atazanavir (400 mg once a day): not recommended at the same time atazanavir without simultaneous administration of low-dose ritonavir and Intelence® (atazanavir concentration decreases by 47%, etravirin concentration increases by 58%).

    - Ritonavir: a combination of the drug Intelens® with a full dose of ritonavir (600 mg twice daily) can cause a significant decrease in plasma etravirine.This can lead to a loss of the therapeutic effect of the drug Intelence®. Given this, it is not recommended to simultaneously use the full dose of ritonavir and Intelence®.

    - Nelfinavir: simultaneous use can cause an increase in the concentration of nelfinavir in the plasma. It is not recommended simultaneous use of the drug Intelens® with nelfinavir.

    - Indinavir: simultaneous use can cause a significant decrease in the concentration of indinavir in the blood plasma and a decrease in the therapeutic effect of indinavir. It is not recommended simultaneous use of the preparation of Intelence® with indinavir.

    - Fosamprenavir: simultaneous use may cause an increase in the concentration of amprenavir in plasma.

    - Others: It is not recommended to use the preparation of Intelence ® with other protease inhibitors without simultaneous reception of a low dose of ritonavir (including saquinavir).

    Protease inhibitors with simultaneous administration of ritonavir

    - Tipranavir / ritonavir (500/200 mg twice daily): it is not recommended to simultaneously use the combination of tipranavir / ritonavir and Intelence® (the concentration of tipranavir is increased by 24%, the concentration of etravirine is reduced by 82%).

    - Fosamprenavir / ritonavir (700/100 mg twice daily): with the simultaneous use of the drug Intelens® and fosamprenavir / ritonavir combination, dosage adjustment of these drugs may be required.

    - Atazanavir / ritonavir (300/100 mg once a day): Intelence® can be used concomitantly with the combination of atazanavir / ritonavir without dose adjustment.

    - Darunavir / ritonavir (600/100 mg twice daily): Intelence® can be used concomitantly with the darunavir / ritonavir combination without dose adjustment.

    - Lopinavir / ritonavir (soft gelatin capsules, tablets) (400/100 mg twice daily): Intelence® can be used concurrently with a combination of lopinavir / ritonavir without dose adjustment.

    - Saquinavir / ritonavir (soft gelatin capsules) (1000/100 mg twice daily): Intellans® can be used concomitantly with a combination of saquinavir / ritonavir without dose adjustment.

    Combination of two protease inhibitors with simultaneous administration of ritonavir

    - Lopinavir / saquinavir / ritonavir (400/800 - 1000/100 mg twice daily): Intellans® can be used concomitantly with a combination of lopinavir / saquinavir / ritonavir without dose adjustment.

    CCR5 receptor antagonists

    - Maraviroc (300 mg 2 times a day): with the simultaneous use of the drug Intelens® and maraviroc, a significant decrease in the concentration of maraviroc in plasma may occur.

    With the simultaneous administration of Intelence® with maraviroc in the absence of a potent CYP3A isoenzyme inhibitor (eg, protease inhibitors with simultaneous ritonavir administration), the recommended dose of maraviroc is 600 mg twice daily. No changes in the Intellence® dose are required.

    - Maraviroc / darunavir / ritonavir (150/600/100 mg twice daily): In the case of using Intelens® and maraviroc together with a potent inhibitor of CYP3A isoenzymes (eg with a protease inhibitor with simultaneous ritonavir intake), to change the dose of maraviroc, refer to the appropriate instructions for medical use, given that Intelence® exhibits the properties of an inducer of CYP3A isoenzymes (similar to efavirenz). No changes in the Intellence® dose are required.

    Inhibitors of fusion

    - Enfuvirtide (90 mg 2 times a day): it is assumed that with the simultaneous use of Intelence® and enfuvirtide they will not interact with each other.

    Integrase inhibitors

    - Dolutegravir (50 mg once daily), dolutegravir / darunavir / ritonavir (50 mg once daily +

    600/100 mg twice daily), dolutegravir / lopinavir / ritonavir (50 mg once daily + 400/100 mg twice daily): etravirine significantly reduces the concentration of dolutegravir in plasma. Based on a comparison of the data obtained with the data of pharmacokinetic studies of etravirine, it can be assumed that dolutegravir does not affect the pharmacokinetics of etravirine. The effect of etravirine on the concentration of dolutegravir in plasma is reduced with the simultaneous use of darunavir / ritonavir or lopinavir / ritonavir combinations, and is likely to decrease with atazanavir / ritonavir combination. Dolutegravir can be used concomitantly with the preparation of Intelence® only in case of simultaneous application of the combination atazanavir / ritonavir, darunavir / ritonavir or lopinavir / ritonavir.

    - Elvitegravir / ritonavir (150/100 mg once a day): a combination of Intelence® and elvitegravir / ritonavir can be used without dose adjustment.

    - Raltegravir (400 mg twice daily): the combination of Intelence® and raltegravir can be used without dose adjustment.

    Drug Interactions Intelence® with other drugs

    Antiarrhythmics

    - Digoxin (0.5 mg once): a combination of digoxin and Intelence® preparation can be used without dose changes.It is recommended to monitor the concentration of digoxin in plasma.

    - Amiodarone, bepridil, disopyramid, flecainide, lidocaine (intravenously), mexiletine, propafenone, quinidine: concentrations of these antiarrhythmic agents may decrease when they are used concomitantly with the preparation of Intelence®. With the simultaneous use of the drug Intelens ® and antiarrhythmic drugs should be careful and, if possible, monitor the concentrations of the latter in the plasma.

    Anticoagulants

    - Warfarin: the concentrations of warfarin may vary with its application at the same time as Intelence®. It is recommended to monitor the international normalized ratio while using warfarin and Intelence®.

    Anticonvulsants (carbamazepine, phenobarbital, phenytoin): are inducers of isoenzymes of the CYP450 system. Intelence® can not be used concomitantly with these drugs, as this can cause a significant decrease in plasma etravirin concentrations, which in turn can lead to a loss of the therapeutic effect of Intelence®.

    Antifungal means:

    - Fluconazole (200 mg once daily in the morning): the incidence of side effects in patients taking fluconazole and the preparation of Intelence®, is comparable to that of patients receiving fluconazole and placebo. Simultaneous use of the preparation Intellens® and fluconazole can be carried out without changes in the doses.

    - Voriconazole (200 mg twice a day): the simultaneous use of the drug Intelens® and voriconazole can be carried out without changing the dose.

    - Itraconazole, ketoconazole, posaconazole: posaconazole is a potent inhibitor of CYP3A4 isoenzymes and can cause an increase in plasma etravirin concentrations. Itraconazole and ketoconazole also are the substrates of the isoenzyme CYP3A4. Simultaneous use of the preparation of Intelence® and itraconazole or ketoconazole may lead to an increase in the concentration of etravirin in the plasma. And concurrently, the concentrations of itraconazole or ketoconazole in plasma may decrease under the influence of etravirine. Simultaneous application of these agents and the preparation of Intelence® can be carried out without changes in the doses.

    Antimalarials

    Artemether / lumefantrine (80/480 mg, 6 doses according to the schedule: 0 h, 8 h, 24 h, 36 h, 48 h, 60 h): no dose adjustment is required while taking Intellens® and artemether / lumefantrine.Nevertheless, caution should be exercised while taking these medications at the same time, since it is not known whether a decrease in the exposure of artemether or its active metabolite dihydroartemisinin can lead to a decrease in antimalarial activity.

    Anti-TB drugs:

    - Rifampicin, rifapentin are strong inducers of CYP450 isoenzymes.

    Intelence® should not be used in combination with rifampicin and rifapentin, as this can cause a significant decrease in plasma etravirin concentrations and, therefore, lead to a loss of its therapeutic effect.

    - Rifabutin (300 mg once a day): if Intelence® is not used concomitantly with a protease inhibitor, an enhanced dose of ritonavir, then Intelence® and rifabutin can be used without dose adjustment. If you simultaneously use Intelens® with darunavir, lopinavir or saquinavir with simultaneous administration of ritonavir, caution should be exercised rifabutin in connection with the possible significant reduction in the concentration of etravirin in plasma. In such cases, the dose of rifabutin should be given in accordance with the instructions in the instructions for the medical use of protease inhibitors.

    Antibacterials:

    - Proceeding from the fact that azithromycin Eliminated with bile, no drug interactions between azithromycin and Intelence® are expected. Simultaneous use of azithromycin and Intelence® preparation can be carried out without correction of the doses of both drugs.

    - Clarithromycin (500 mg twice daily): etravirine decreased the concentration of clarithromycin in plasma by 53%; At the same time, the concentration of the active metabolite, 14-hydroxyclarithromycin, increased by 46%. Since 14-hydroxyclarithromycin has a reduced activity against the complex Mycobacterium avium complex (MAS), the overall activity of clarithromycin and its metabolite against this pathogen can change. Therefore, for the treatment of infections caused by MAS, it is desirable to use a means alternative to clarithromycin, for example, azithromycin.

    Benzodiazepines

    Diazepam: the use of etravirine simultaneously with diazepam may increase the concentration of the latter in plasma.

    Glucocorticosteroids

    Dexamethasone for systemic use: dexamethasone induces the isoenzyme CYP3A4 and can reduce plasma etravirin concentrations. A consequence of this may be the loss of the therapeutic effect of Intelence®. Dexamethasone (for systemic use) should be used with caution or alternatives, especially with prolonged therapy.

    Contraceptives based on estrogens (ethinyl estradiol, norethisterone): a combination of contraceptives based on estrogen and / or progesterone and Intelence® can be used without dose adjustment.

    Antiviral drugs

    - Boceprevir (800 mg 3 times a day): with the simultaneous use of the preparation of Intelence® and boceprevira, dose adjustment is not required. With the simultaneous use of the drug Intelence® and boceprevir, or another drug that can reduce the concentration of etravirin in plasma, caution should be exercised. It is recommended to carefully monitor the virologic response to the treatment of the hepatitis C virus and HIV.

    Refer for information on the instructions for use of the drug.

    - Ribavirin is eliminated by the kidneys, and therefore it most likely does not interact with the preparation of Intelence®.

    - Telaprevir (750 mg every 8 hours): no simultaneous use of Intelence® and telaprevir is required.

    Drugs containing St. John's wortHypericum perforatum): St. John's wort (Hypericum perforatum) is a strong inducer of cytochrome P450 isoenzymes. Intelence® should not be used concomitantly with preparations containing St. John's wort, as this can lead to a significant decrease in plasma etravirin concentrations and a loss of its therapeutic effect.

    Inhibitors of reductase HMG-KoA (statins):

    - Atorvastatin (40 mg once a day): with the simultaneous administration of Intelence® and atorvastatin, the dose of the latter must be adjusted to achieve the desired clinical effect (atorvastatin concentration decreases by 37%, the concentration of 2-hydroxyorthovastatin increases by 27%).

    - Pravastatin, most likely, does not interact with Intelence®.

    - Lovastatin, rosuvastatin and simvastatin are substrates of CYP3A4 and simultaneous use of these drugs with etravirine can cause a decrease in their concentrations in the plasma.

    - Fluvastatin, rosuvastatin and, to a lesser extent, Pitavastatin is metabolized by the CYP2C9 isoenzyme and their simultaneous use with the preparation of Intelence® can lead to an increase in the plasma concentrations of statins. You may need to adjust their dose.

    Blockers of H2 receptors

    Ranitidine (150 mg 2 times a day): can be used simultaneously without dose adjustment.

    Immunosuppressive drugs:

    Cyclosporine, sirolimus, tacrolimus: caution should be exercised when using Intelence® concurrently with systemic immunosuppressants, since etravirine can change their concentration in the plasma.

    Narcotic analgesics:

    Methadone (60-130 mg per day): during simultaneous use with the preparation of Intelence® and after that there was no need to correct the dose of methadone.

    Inhibitors of phosphodiesterase type 5 (inhibitors PDE-5)

    Sildenafil, vardenafil, tadalafil (50 mg per day): concomitant use of PDE5 and Intelence® inhibitors may require correction of the dose of PDE5 inhibitors in order to achieve the desired clinical effect (sildenafil and N-desmethyl-sildenafil concentrations decreased by 57% and 41%, respectively).

    Clopidogrel

    The conversion of clopidogrel to its active metabolite can be reduced by the combined use of clopidogrel with Intelence®. Alternative treatment options should be considered.

    Proton Pump Inhibitors:

    Omeprazole (40 mg once a day): can be used without dose adjustment.

    Selective serotonin reuptake inhibitors:

    Paroxetine (40 mg once a day): can be used without dose adjustment.

    Special instructions:

    Patients should be advised that modern antiretroviral drugs do not cure HIV infection and do not prevent the transmission of HIV to other people with blood or during sexual intercourse. Patients should continue to follow appropriate safety measures during treatment with Intelence®.

    Treatment with the drug Intelens® should be performed by a doctor who has sufficient experience in the therapy of HIV infection.

    When using the drug Intelens ® should be guided by a therapeutic history, and, where possible, the results of determining the sensitivity of HIV-1 to antiretroviral drugs. To treat patients who have had a virological failure with NNRTI therapy and a nucleoside (NRTI) or nucleotide reverse transcriptase inhibitor (HTiOT), Intelence® is not recommended for use in combination with either HMRI or NRTI.

    A decrease in the virologic response to etravirine therapy has been observed in patients with HIV infection caused by strains having simultaneously 3 or more mutations from the following: V90I, A98G, L100I, K101E / P, V106I, V179D / F, Y181C / I / V and G190A / S.Conclusion on the significance of individual mutations or combinations of mutations should be made with additional data taken into account: it is recommended to refer to actual modern interpretation systems for evaluating the results of the resistance test.

    Severe skin reactions and hypersensitivity reactions

    In the treatment of Intelence®, skin reactions potentially potentially life-threatening or lethal may occur; There are also reports of rare (<0.1%) cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. There were also hypersensitivity reactions, including DRESS syndrome, characterized by rash, fever, eosinophilia and systemic manifestations (including, but not limited to: severe rash or rash accompanied by fever, general malaise, fatigue, muscle pain and joints, bullous lesions, damage to the oral mucosa, conjunctivitis, hepatitis, eosinophilia).

    It should immediately stop taking the drug Intelence ® in the development of signs or symptoms of serious skin reactions, or severe hypersensitivity reactions and then monitor the clinicalpatient's condition, incl. Control the activity of hepatic transaminases, and prescribe appropriate therapy. Severe skin reactions or severe hypersensitivity reactions usually develop at week 3-6 of therapy, and the result is in most cases favorable after discontinuing therapy with Intelence® and after initiating glucocorticosteroid therapy. Patients should be informed of the need to see a doctor if serious skin reactions or hypersensitivity reactions occur. Patients who discontinued treatment due to hypersensitivity reactions should not again take Intelence®. Delay in the withdrawal of the drug Intelence® after the detection of severe rash can cause a reaction that threatens the life of the patient.

    Rash

    When treating with the drug Intelens ® can occur skin rash. Most often, a skin rash is mild or moderate, occurs in the second week of therapy and is rarely seen after the 4th week. In most cases, such a rash does not require special treatment and usually disappears in 1-2 weeks on the background of ongoing treatment. Cases of rash were more common in women.

    Elderly patients

    Experience with the use of the drug Intelens ® in elderly patients is limited: in phase III clinical trials, 6 patients aged 65 years or older, and 53 patients aged 56-64 years received therapy with the drug Intelens ®. The type and frequency of side effects in patients older than 55 years were similar to those observed in younger patients

    Patients with concomitant diseases

    Diseases of the liver

    In patients with mild and moderately severe impaired liver function (classes A or B on the Child-Pugh scale), the dose of Intelence® should not be reduced. In patients with severe impairment of liver function (class C on the Child-Pugh scale), the pharmacokinetics of etravirine have not been studied.

    Patients who are simultaneously infected with hepatitis B virus and / or hepatitis C virus

    Caution should be exercised when using Intelence® in patients who are simultaneously infected with hepatitis B virus and / or hepatitis C virus, due to limited data on the use of etravirine in this group of patients. This category of patients can not exclude an increased risk of increased activity of liver enzymes.

    Kidney Diseases

    The renal clearance of etravirine is negligible (<1.2%), and therefore in patients with impaired renal function the overall clearance of this drug is virtually unchanged. In this case, no special precautions are necessary, do not reduce the dose of the drug Intelence®. Etravirine has a high ability to bind to plasma proteins, and therefore it is unlikely that it will be excreted in significant amounts by hemodialysis and peritoneal dialysis.

    Redistribution of adipose tissue

    In HIV-infected patients, combined antiretroviral therapy is accompanied by redistribution of adipose tissue (lipodystrophy). This redistribution includes loss of peripheral and facial subcutaneous fat tissue, an increase in the amount of intra-abdominal and visceral fat, hypertrophy of the mammary glands and fat accumulation in the dorso-cervical region (formation of the fatty hump). The long-term consequences of this phenomenon are not known at present, and its mechanisms are not sufficiently studied. There is a hypothesis about the relationship between visceral lipomatosis and protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors.Increased risk is associated with such individual characteristics of the patient as the elderly, as well as with long-term antiretroviral therapy and concomitant metabolic disorders. Clinical examination of HIV-infected patients should include an assessment of physical signs of fat tissue redistribution.

    Immunodeficiency Syndrome

    In HIV-infected patients with severe immunodeficiency during the onset of combined antiretroviral therapy, an inflammatory response to asymptomatic or latent opportunistic infections may occur, which may manifest as a worsening of the clinical condition and an increase in existing symptoms. Typically, such reactions are observed in the first weeks or months after the onset of combined antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii. The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment. There are reports of the occurrence of autoimmune diseases, such as diffuse toxic goiter (Bazedova disease) against the background of restoration of immunity.The time of occurrence of these diseases varies widely; diseases can begin many months after the start of treatment.

    Osteonecrosis

    Although the etiology of osteonecrosis is multifactorial (the appearance of osteonecrosis may be caused by, including the use of corticosteroids, alcohol consumption, severe immunosuppression, higher body mass index), have been reported cases of osteonecrosis particularly in patients with advanced HIV infection and / or patients who are on long-term combined antiretroviral therapy. Patients should be advised to see a doctor if they experience joint pain or painful movement restriction.

    Interactions with other drugs

    The simultaneous administration of etravirine and the combination of tipranavir / ritonavir (500/200 mg twice daily) is not recommended due to significant pharmacokinetic interaction (76% reduction in the area under the etravirin concentration-time curve (AUC)), which can significantly reduce the effectiveness of treatment etravirine.

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

    At present, there is no evidence that the preparation of Intelence® can adversely affect these functions.Nevertheless, the profile of side effects of this drug should be considered.

    Form release / dosage:

    Tablets, 200 mg.

    Packaging:

    For 60 tablets in white bottles of high-density polyethylene, covered with aluminum film, polypropylene lid, protecting from accidental opening by children; the vial contains bags with a desiccant (silica gel) at the rate of 3 bags of 2 g per 60 tablets. One bottle with instructions for medical use in a cardboard box. On the cardboard bundle, the first opening can be applied in the form of stickers (one on each side of the cardboard bundle).

    Storage conditions:

    At a temperature of no higher than 30 ° C.

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

    Shelf life:

    2 years. Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002399
    Date of registration:17.03.2014
    The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp24.10.2015
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