Интеленс

General characteristics. Structure:

Active agent: each tablet contains 100 mg of an etravirin.

Excipients: a gipromelloza – 300 mg, cellulose microcrystallic – 194,4 mg, silicon dioxide colloid – 1,6 mg, croscarmellose sodium – 40 mg, magnesium stearate – 4 mg, lactoses monohydrate – 160 mg.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Etravirin is nenukleozidny inhibitor of the return transcriptase (NNIOT) of a human immunodeficiency virus – VICh-1. Etravirin directly contacts the return transcriptase and blocks RNA-dependent and DNA-dependent activity of a DNA polymerase, causing destruction of catalytic sites of this enzyme.

Antiviral activity of in vitro. Etravirin is active concerning laboratory strains and clinical VICh-1 isolates of wild type in sharply infected T-cellular lines, peripheral mononuclear cells of the person and in monocytes/macrophages of the person. Etravirin has antiviral activity of in vitro concerning a wide range of representatives of the VICh-1 group M (subtypes A, B, C, D, E, F, G) and primary isolates of group Oh, for which its average effective concentration (EC50) varies from 0,7 to 21,7 nanometers.

Etravirin is not an antagonist any of the studied anti-retrovirus drugs. It has the additive antiviral activity in a combination with protease inhibitors: amprenaviry, atazanaviry, darunaviry, indinaviry, lopinaviry, nelfinaviry, ritonaviry, tipranaviry and sakvinaviry; with nukleozidny or nucleotide inhibitors of the return transcriptase: zaltsitabiny, didanoziny, stavudiny, abakaviry and tenofoviry; with nenukleozidny inhibitors of the return transcriptase efavirenzy, delavirdiny and not Virapinum, in a combination with fusion inhibitor enfuvirtidy, integraza inhibitor raltegraviry and the antagonist of receptors of CCR5 maraviroky.

Etravirin gives synergistic or additive antiviral effect in a combination with nukleozidny inhibitors of the return transcriptase emtritsitabiny, lamivudiny and a zidovudine.

Resistance. Etravirin showed strong antiviral activity concerning 56 of 65 strains of VICh-1 with one amino-acid replacement in provisions of RT connected with resistance to NNIOT including the most widespread mutations of K103N and Y181C. Amino-acid replacements which cause the highest resistance to an etravirin in culture of cells are Y181I mutations (13-fold change of EC50 value) and Y181V (17-fold change of EC50 value). Antiviral activity of an etravirin in cultures of cells against 24 strains of VICh-1 with the multiple amino-acid replacements causing resistance to NNIOT and/or to protease inhibitors is similar to activity against a wild strain of VICh-1.

Selection of in vitro of strains of the wild VICh-1 type of a different origin and different subtypes, resistant to an etravirin, and also selection of strains of VICh-1, resistant to NNIOT, happened both at high, and at a low virus inoculum. Development of resistance to an etravirin usually demanded multiple mutations of the return transcriptase from which the following most often met: L100I, E138K, E138G, V179I, Y181C and M230I.

Mutations most of which often arose patients with unsuccessful virologic result of treatment by the combinations containing этравирин had V179F, V179I, Y181C.

Cross resistance. Limited cross resistance between etraviriny and efavirenzy in vitro at 3 of 65 mutant strains of VICh-1 bearing a mutation which causes resistance to NNIOT was revealed. At other strains of provision of amino acids, connected with reduced sensitivity to an etravirin and an efavirenz, were different. Etravirin keeps EC50 <the 10th nmol against 83% from 6171 clinical isolates, resistant to a delavirdin, an efavirenz and/or not Virapinum. It is not recommended to carry out treatment delavirdiny, efavirenzy and/or not Virapinum of patients who have a mode containing этравирин it was inefficient from the virologic point of view.

Pharmacokinetics. Absorption.

After intake with food the maximum concentration of an etravirin in plasma is reached during 4 h.

At healthy people absorption of an etravirin does not depend on a concomitant use in ranitidine or an omeprazol which raise рН stomach contents.

Concentration of an etravirin does not depend on a type of the eaten food (normal caloric content – 561 kcal or greasy food – 1160 kcal). Concentration of drug was lower when it was applied to food (for 17%), or on an empty stomach (for 51%) in comparison with its reception after food.

Thus, for maintenance of optimum concentration of an etravirin in plasma it is necessary to accept drug after food.

Distribution. In vitro about 99,9% of an etravirin communicates proteins of a blood plasma, is preferential with albumine (99,6%) and with α1-кислым a glycoprotein (97,66 - 99,02%). Distribution of an etravirin in other liquids (for example, in cerebrospinal liquid) at people was not studied.

Metabolism. in vitro experiments with microsomes of a liver of the person showed what этравирин generally is exposed to oxidizing metabolism under the influence of hepatic isoenzymes of the CYP3A family and, to a lesser extent, under the influence of CYP2C family isoenzymes and after this there is a glyukuronirovaniye.

Removal. After intake of a dose of a marked 14C-etravirin of 93,7% and 1,2% of the accepted dose were found in Calais and urine respectively. 81,2 - 86,4% of the accepted dose fell to the share of not changed etravirin in Calais. In urine этравирин in not changed look it is not found.

The final eliminative period of an etravirin makes about 30 - 40 h.

Special groups of patients. Children and teenagers (from 6 to 18 years). The pharmacokinetics of an etravirin was studied at 101 VICh-1-infitsirovannogo patient of this age group which received therapy against HIV earlier and had body weight not less than 16 kg. It was shown that exposure of drug at use of the dose corresponding to 5,2 mg/kg of body weight twice a day is comparable with that at use of drug of Intelens by adult patients in a dose of 200 mg twice a day.

Children (up to 6 years). Now researches of pharmacokinetics of an etravirin at patients of this age group are conducted.

Elderly patients. The pharmacokinetics of an etravirin does not depend on age investigated (from 18 to 77 years).

Men and women. Between men and women significant distinctions of pharmacokinetics of an etravirin were not revealed.

Race. It was shown that race of the patient does not influence pharmacokinetics of an etravirin.

Patients with abnormal liver functions. Etravirin is metabolized and eliminirutsya preferential by a liver. The pharmacokinetics of an etravirin did not change at patients with lungs and moderately expressed abnormal liver functions. There is no need to change a dose of drug of Intelens at this category of patients. At patients with heavy abnormal liver functions (a class C on a scale of Chayld-Pyyu) the pharmacokinetics of Intelens was not studied.

The patients infected with a virus of hepatitis B and/or a virus of hepatitis C. The clearance of an etravirin at the patients infected with VICh-1 and a virus of hepatitis B and/or a virus of hepatitis C is reduced. Proceeding from a profile of safety of an etravirin, dose adjustment is not required from this category of patients.

Patients with renal failures. At patients with a renal failure the pharmacokinetics of an etravirin was not studied. With urine less than 1,2% of the accepted dose of an etravirin eliminirutsya. Etravirin in not changed look in urine is not found, therefore, influence of renal failures on elimination of an etravirin minimum. As этравирин has very high ability to contact proteins of plasma, he can hardly leave from an organism in a little significant quantities by means of a hemodialysis or peritoneal dialysis.

Indications to use:

Treatment of the infection caused by a human immunodeficiency virus – VICh-1, at adult patients who received anti-retrovirus drugs, including patients with resistance to nenukleozidny inhibitors of the return transcriptase (NNIOT) as a part of a combination therapy.

Route of administration and doses:

Интеленс it is always necessary to apply in a combination with other anti-retrovirus drugs.

Adults: inside on 200 mg (2 tablets) 2 times a day after food. The maximum daily dose – 400 mg. Tablets should be swallowed entirely, washing down with water. The patients experiencing difficulties with a proglatyvaniye of tablets of Intelens can crush them and stir in a glass of water. In this case the patient has to drink glass contents immediately. For ensuring reception of a full dose the glass should be rinsed several times with water and to completely drink contents. At the same time it is necessary to avoid use warm (more than 40 °C) water and carbonated drinks.

Elderly patients: there is limited information on treatment by drug of Intelens of patients of this age group. Dose adjustment is not required. At this category of patients drug of Intelens needs to be used with care.

Patients with abnormal liver functions: with a lung or moderately expressed abnormal liver function (classes A or B on a scale of Chayld-Pyyu) dose adjustment is not required from patients. It is necessary to be careful at use of drug for patients with moderately expressed abnormal liver function. At patients with a heavy abnormal liver function (a class C on a scale of Chayld-Pyyu) the pharmacokinetics of drug of Intelens was not studied.

Patients with renal failures: with a renal failure of dose adjustment it is not required from patients.

If the patient forgot to accept the next dose of drug of Intelens and remembered it not later than in 6 h after usual time of administration of drug, then it has to accept as soon as possible it after food and then accept the following dose in time, usual for it. If there passed more than 6 h after usual time of administration of drug, then the patient should not accept the passed dose, and just resume administration of drug according to the usual scheme.

Features of use:

Patients need to be informed that modern anti-retrovirus drugs do not cure HIV infection and do not prevent transfer of HIV to other people with blood or at sexual contacts. During treatment by drug of Intelens patients have to continue to observe the appropriate measures of safety.

The doctor having sufficient experience of therapy of HIV infection has to carry out by drug of Intelens treatment.

At use of drug of Intelens it is necessary to be guided by the therapeutic anamnesis, and where it is possible, results of definition of sensitivity of VICh-1 to anti-retrovirus drugs. For treatment of patients at whom virologic failure at therapy of NNIOT took place and nukleozidny (NIOT) or nucleotide inhibitor of the return transcriptase (НтИОТ) Intelens is not recommended to be used in a combination only with NTIOT or NIOT.

Decrease in the virologic response to therapy etraviriny was noted at patients with the HIV infection caused by the strains having at the same time 3 or more mutations from below listed: V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V and G190A/S.

The conclusion about the importance of separate mutations or combinations of mutations has to become taking into account additional data: it is recommended to address urgent modern systems of interpretation for assessment of test results on resistance.

Skin reactions of heavy degree and reaction of hypersensitivity. At treatment by drug of Intelens emergence of skin reactions, potentially life-threatening or leading to a lethal outcome is possible; there are also messages about rare (<0,1%) cases of emergence of a syndrome of Stephens-Johnson and a toxic epidermal necrolysis. Also hypersensitivity reactions, including DRESS syndrome which is characterized by rash, fever, an eosinophilia and system manifestations were noted (including, but not only: the rash of heavy degree or rash which is followed by fervescence, a febricula, fatigue, muscle and joints pain, violent defeats, damage of a mucous membrane of a mouth konjyuktivit, hepatitis, an eosinophilia).

It is necessary to stop immediately administration of drug of Intelens at development of signs or symptoms of serious skin reactions or reactions of hypersensitivity of heavy degree and further to watch a clinical condition of the patient, including to control activity of hepatic transaminases and to appoint the corresponding therapy. Serious skin reactions or reactions of hypersensitivity of heavy degree usually develop on 3-6 week of therapy, and result in most cases favorable after the therapy termination by drug of Intelens and after the beginning of therapy by glucocorticosteroids. Patients have to be informed on need to see a doctor if there are serious skin reactions or reactions of hypersensitivity. Patients who stopped treatment because of hypersensitivity reactions should not accept drug of Intelens again.

The delay in drug withdrawal of Intelens after detection of rash of heavy degree can cause reaction, the life-threatening patient.

Rash. At treatment skin rash can arise drug of Intelens. Most often skin rash happens easy or moderately expressed, arises on the second week of therapy and is seldom observed after the 4th week. In most cases such rash does not demand special treatment and usually disappears in 1-2 weeks against the background of the continuing treatment. Cases of rash were more often observed at women.

Elderly patients.

Experience of use of drug of Intelens for elderly patients is limited: in the III phase of clinical trials of 6 patients at the age of 65 years or is more senior and 53 patients at the age of 56–64 years received therapy by drug of Intelens. The type and frequency of side effects at patients were more senior than 55 years are similar to those that were observed at younger patients.

Patients with associated diseases. Liver diseases. At patients with a lung and moderately expressed abnormal liver function (classes A or B on a scale of Chayld-Pyyu) a dose of drug of Intelens do not need to be reduced. At patients with a heavy abnormal liver function (a class C on a scale of Chayld-Pyyu) the pharmacokinetics of an etravirin was not studied.

The patients who are at the same time infected with a virus of hepatitis B and/or a virus

hepatitis C. It is necessary to be careful at use of drug of Intelens for the patients who are at the same time infected with a virus of hepatitis B and/or a virus of hepatitis C in connection with limited data on use of an etravirin for this group of patients. At this category of patients the increased risk of increase in activity of enzymes of a liver cannot be excluded.

Diseases of kidneys. Renal clearance of an etravirin it is insignificant it is small (<1,2%) and therefore at patients with renal failures the general clearance of this drug practically does not change. In this case special precautionary measures are not required, it is not necessary to reduce a dose of drug of Intelens.

Etravirin has high ability to contact proteins of plasma and therefore it is a little probable that he will be brought in significant quantities by means of a hemodialysis and peritoneal dialysis.

Redistribution of fatty tissue. At HIV-positive patients the combined anti-retrovirus therapy sopro- vozhdatsya by redistribution of fatty tissue of an organism (lipodystrophy). This redistribution includes loss of peripheral and front hypodermic fatty tissue, increase in amount of intraabdominal and visceral fat, a hypertrophy of mammary glands and accumulation of fat in dorsotservikalny area (formation of a fatty hump).

Long-term effects of this phenomenon are not known now, and its mechanisms are insufficiently studied. There is a hypothesis of communication between a visceral lipomatoz and inhibitors of protease, and also between a lipoatrophia and nukleozidny inhibitors of the return transcriptase. The increased risk is connected with such specific features of the patient as advanced age, and also with long anti-retrovirus therapy and the accompanying metabolic disturbances. Clinical inspection of HIV-positive patients has to include assessment of physical signs of redistribution of fatty tissue.

Immunity recovery syndrome. HIV-positive patients with a heavy immunodeficiency during the beginning of the combined anti-retrovirus therapy can have an inflammatory reaction to asymptomatic or latent opportunistic infections which can be shown by deterioration in a clinical state and strengthening of the available symptoms. Usually such reactions are observed in the first weeks or months after the beginning of the combined anti-retrovirus therapy. It is possible to give a Cytomegaloviral retinitis, generalized and/or focal mikobakterialny infections and the pneumonia caused by Pneumocystis jirovecii as examples. Emergence of any symptoms of an inflammation demands immediate inspection and, if necessary, treatment. There are messages on developing of autoimmune diseases, such as a diffusion toxic craw (Bazedova a disease) against the background of immunity recovery. The term of developing of these diseases widely varies; diseases can begin in many months after an initiation of treatment.

Osteonecrosis. Though the etiology of an osteonecrosis is multifactorial (emergence of an osteonecrosis can be caused including use of glucocorticosteroids, alcohol intake, strong immunosuppression, a high index of body weight), patients have messages on osteonecrosis cases especially with an advanced stage of HIV infection and/or the patients who are on the long combined anti-retrovirus therapy. Patients should recommend to see a doctor if they feel joint pains or painful restriction in the movements.

Lactose intolerance and lactose intolerance. Each tablet contains 160 mg of lactose. Интеленс patients cannot appoint with deficit of lactase, a lactose intolerance, glyukozo-galaktozny malabsorption.

Interactions with other medicines. The concomitant use of an etravirin and a combination tipranavir/ritonavir (500/200 mg 2 times a day) is not recommended because of considerable pharmacokinetic interaction (76% decrease in the area under a curve "concentration time" (AUC) of an etravirin) which can reduce considerably efficiency of treatment etraviriny.

Side effects:

The undesirable medicinal reactions revealed during clinical trials. The often being most found undesirable reactions were: rash (10% in group of drug of Intelens in comparison with 3,5% in group of placebo), diarrhea (7% in group of drug of Intelens in comparison with 11,3% in group of placebo), a gipertriglitseridemiya (6,3% in group of drug of Intelens in comparison with 4,3% in group of placebo), nausea (5,2% in group of drug of Intelens in comparison with 4,8% in group of placebo).

The uses of drug of Intelens given about safety received from clinical trials are systematized concerning each of systems of bodies depending on occurrence frequency with use of the following classification: very frequent (≥1/10), frequent (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000).

From cardiovascular system:

- often – a myocardial infarction, increase in arterial pressure;

- infrequently – fibrillation of auricles, stenocardia, a hemorrhagic stroke.

From hemopoietic and lymphatic system:

- often – thrombocytopenia, anemia.

From a nervous system:

- often – peripheral neuropathy, a headache, alarm, sleeplessness;

- infrequently – spasms, a faint, amnesia, a tremor, drowsiness, paresthesia, a hypesthesia, confusion of consciousness, a disorientation, dreadful dreams, sleep disorders, including a hypersomnia, nervousness, pathological dreams, disturbances of concentration of attention.

From sense bodys:

- infrequently – the obscured sight, вертиго.

From a respiratory organs:

- infrequently – an asthma at an exercise stress, a bronchospasm.

From digestive tract:

- often – a gastroesophageal reflux, diarrhea, vomiting, nausea, an abdominal pain, a meteorism, gastritis;

- infrequently – pancreatitis, a hematemesis, stomatitis, a lock, dryness in a mouth, desires to vomiting, abdominal distention.

From an urinary system:

- often – a renal failure.

From skin and soft tissues:

- very often – rash;

- often – night perspiration, a lipodystrophy;

- infrequently – face edemas, a hyperhidrosis, a prurigo, a xeroderma, a lipodystrophy, a Quincke's disease, a mnogoformny erythema, Stephens-Johnson's syndrome.

Disturbances of metabolism and food:

- often – a diabetes mellitus, a hyperglycemia, a hypercholesterolemia, a gipertriglitseridemiya, a lipidemia;

- infrequently – anorexia, a dislipidemiya.

Disturbances of the general character:

- often – fatigue;

- infrequently – slackness.

From immune system:

- infrequently – an immunity recovery syndrome, hypersensitivity on drug.

From gepatobiliarny system:

- infrequently – hepatitis, fatty dystrophy of a liver, cytolytic hepatitis, a hepatomegalia.

From reproductive system and mammary glands: gynecomastia.

From laboratory indicators: increase in activity of pancreatic amylase, a lipase, alaninaminotranspherase (further – ALT), aspartate aminotransferases (further – nuclear heating plant) increase in concentration of creatinine, general cholesterol, lipoproteins of low density, triglycerides, glucose, and decrease in number of neutrophils, leukocytes.

Skin rash was the most frequent cause of drug withdrawal. Rash most often was easy or moderately expressed, usually makulezny, makulo-papular or erythematic, as a rule, arose on the second week of treatment and seldom developed after the 4th week. Most often rash did not demand special treatment and usually disappeared within 1-2 weeks against the background of treatment continuation. Cases of developing of rash against the background of therapy by drug of Intelens were more often noted at women.

Moderately expressed side effects (no more than 0,5% of patients) had an acquired lipodystrophy, a Quincke's disease, a mnogoformny erythema and a hemorrhagic stroke. Seldom (<0,1%) Stephens-Johnson's syndrome (less than 0,1%) was observed and it is very rare – a toxic epidermal necrolysis (less than 0,01%).

Interaction with other medicines:

Antiarrhytmic means:

- Digoxin (0,5 mg once): the combination of digoxin and the drug Intelens® can be used without changes of doses. It is recommended to carry out monitoring of concentration of digoxin in plasma.

- Amiodaronum, bepridit, Disopyramidum, флекаинид, lidocaine (intravenously), мексилетин, пропафенон, quinidine: concentration of these antiarrhytmic means can decrease at their use along with the drug Intelens®. At simultaneous use of drug of Intelens and antiarrhytmic means it is necessary to be careful and , whenever possible, to carry out monitoring of concentration of the last in plasma.

Anticoagulants:

- Warfarin: concentration of warfarin can change at its use along with Intelens. It is recommended to carry out monitoring of the international normalized relation at simultaneous use of warfarin and drug of Intelens.

Anticonvulsants (carbamazepine, phenobarbital, Phenytoinum): are inductors of isoenzymes of the CYP450 system. Интеленс it is impossible to use along with the specified drugs as it can cause significant decrease in concentration of an etravirin in plasma which, in turn, can lead to loss of therapeutic effect of Intelens.

Antifungal means:

- Flukonazol (200 mg once a day in the morning): frequency of side effects at the patients accepting флуконазол and the drug Intelens®, is comparable with that at the patients accepting флуконазол and placebo. Simultaneous use of drug of Intelens and flukonazol can be carried out without changes of doses.

- Vorikonazol (200 mg 2 times a day): simultaneous use of drug of Intelens and vorikonazol can be carried out without changes of doses.

- Itrakonazol, кетоконазол, позаконазол: позаконазол is strong inhibitor of isoenzymes CYP3A4 and can cause increase in concentration of an etravirin in plasma.

Itrakonazol and кетоконазол also are also CYP3A4 isoenzyme substrates.

Simultaneous use of drug of Intelens and itrakonazol or ketokonazol can lead to increase in concentration of an etravirin in plasma. And along with it concentration of an itrakonazol or a ketokonazol in plasma can decrease under the influence of an etravirin. Simultaneous use of these means and drug of Intelens can be carried out without changes of doses.

Antimalarial means:

- Artemeter/lyumefantrin (80/480 mg, 6 doses according to the scheme: 0 h, 8 h, 24 h, 36 h, 48 h, 60 h): dose adjustment at a concomitant use of drug of Intelens and an artemetera/lyumefantrin is not required. Nevertheless, it is necessary to show care at a concomitant use of these drugs as it is unknown whether can lead decrease in exposure of an artemeter or his active metabolite of a digidroartemizinin to decrease in antimalarial activity.

Antitubercular drugs:

- Rifampicin, rifapentine are strong inductors of isoenzymes CYP450. Интеленс it is not necessary to apply in a combination with rifampicin and rifapentine as it can cause significant decrease in concentration of an etravirin in plasma and, therefore, lead to loss of its therapeutic effect.

- Rifabutin (300 mg once a day): if Intelens is not applied along with the protease inhibitor strengthened by a dose of a ritonavir, then Intelens and рифабутин it is possible to apply without correction of doses. At simultaneous use of drug of Intelens with darunaviry, lopinaviry or sakvinaviry with a concomitant use of a ritonavir, it is necessary to appoint with care рифабутин in connection with possible considerable decrease in concentration of an etravirin in plasma. In such cases the dose of a rifabutin has to be appointed according to instructions in instructions on a medical use of inhibitors of protease.

Antibacterial drugs:

- That azithromycin eliminirutsya with bile medicinal interactions between azithromycin and Intelens® are not expected. Simultaneous use of azithromycin and the drug Intelens® can be carried out without correction of doses of both drugs.

- Klaritromitsin (500 mg 2 times a day): этравирин reduced concentration of a klaritromitsin in plasma by 53%; at the same time, concentration of an active metabolite, 14-gidroksiklaritromitsin, increased for 46%. As 14-gidroksiklaritromitsin has reduced activity against the Mycobacterium avium complex (MAS) complex, the general activity of a klaritromitsin and its metabolite concerning this activator can change. Therefore, for treatment of the infections caused by MAS it is desirable to use the means alternative to a klaritromitsin, for example, azithromycin.

Benzodiazepines:

- Diazepam: use of an etravirin along with diazepam can increase concentration of the last in plasma.

Glucocorticosteroids:

- Dexamethasone for system use: dexamethasone induces an isoenzyme of CYP3A4 and can reduce concentration of an etravirin in plasma. Loss of therapeutic effect of Intelens can be a consequence of it. Dexamethasone should be applied (to system use) with care or to use alternative means, especially at long therapy.

Contraceptive means on the basis of estrogen (ethinylestradiol, Norethisteronum): the combination of contraceptives on the basis of estrogen and/or progesterone and Intelens can be applied without correction of doses.

Antiviral means:

• Botseprevir (800 mg 3 times a day): at simultaneous use of drug of Intelens and botseprevir of dose adjustment it is not required. At simultaneous use of drug of Intelens and botseprevir, or other drug which can reduce concentration of an etravirin in plasma, it is necessary to be careful. It is recommended to control carefully the virologic response to treatment of a virus of hepatitis C and HIV.

Apply for information to the application instruction of the corresponding drug.

- Ribavirin eliminirutsya by kidneys and therefore he, most likely, does not interact with drug of Intelens.

- Telaprevir (to 750 mg there are each 8 hours): at simultaneous use of drug of Intelens and telaprevir of dose adjustment it is not required.

The medicines containing a St. John's Wort made a hole (Hypericum perforatum): the St. John's Wort made a hole (Hypericum perforatum) is the strong inductor of isoenzymes of P450 cytochrome. Интеленс it is impossible to apply along with the drugs containing the St. John's Wort which is made a hole as it can lead to significant decrease in concentration of an etravirin in plasma and to loss of its therapeutic effect.

Inhibitors of GMG-KOA reductase (statines):

- Atorvastatin (40 mg once a day): at a concomitant use of Intelens® and an atorvastatin the dose of the last needs to be adjusted for achievement of required clinical effect (concentration of an atorvastatin decreases by 37%, concentration of a 2-gidroksiatorvastatin increases by 27%).

- Pravastatin, most likely, does not interact with Intelens.

- Lovastatin, розувастатин and симвастатин are CYP3A4 substrates and simultaneous use of these drugs with etraviriny can cause decrease in their concentration in plasma.

- Fluvastatin, розувастатин and, to a lesser extent, питавастатин are metabolized by an isoenzyme of CYP2C9 and their simultaneous use with drug of Intelens can lead to increase in plasma of concentration of statines. Correction of their dose can be required.

H2 receptors blockers:

- Ranitidine (150 mg 2 times a day): it is possible to use at the same time without correction of doses.

Immunodepressants:

- Cyclosporine, сиролимус, такролимус: it is necessary to be careful at use of drug of Intelens along with system immunodepressants as этравирин can change them to concentration in plasma.

Narcotic analgetics:

- Methadone (60 – 130 mg a day): during simultaneous use with drug of Intelens and after that there was no need for methadone dose adjustment.

Inhibitors of phosphodiesterase of the 5th type (FDE-5 inhibitors):

- Sildenafil, vardenafit, tadalafit (50 mg a day): simultaneous use of FDE-5 inhibitors and Intelens can demand dose adjustment of FDE-5 inhibitors for the purpose of achievement of desirable clinical effect (concentration sildenafit and N-desmetilsildenafila decreased by 57% and 41% respectively).

Klopidogrel. Transformation of a klopidogrel can be reduced to its active metabolite at combined use of a klopidogrel with drug of Intelens. It is necessary to consider alternative options of treatment.

Inhibitors of a proton pomp:

- Omeprazol (40 mg once a day): it is possible to use without correction of doses.

Selective serotonin reuptake inhibitors:

- Paroksetin (40 mg once a day): it is possible to use without correction of doses.

Contraindications:

Hypersensitivity to an etravirin or any component of drug. Children's age (up to 18 years). Pregnancy and period of breastfeeding. Heavy abnormal liver functions (a class C on Chayld-Pyyu). Lactose intolerance, deficit of lactase, glyukozo-galaktozny malabsorption. Simultaneous use with drugs which influence concentration of an etravirin in a blood plasma and with drugs which concentration in a blood plasma changes at combined use with etraviriny: nenukleozidny inhibitors of the return transcriptase (эфавиренз, not Virapinum, делавирдин, рилпивирин); protease inhibitors without concomitant use of a low dose of a ritonavir (нелфинавир, индинавир, саквинавир and others, except a fosamprenavir); ритонавир (at reception in a dose of 600 mg 2 times a day); combination tipranavir/ritonavir; anticonvulsants (carbamazepine, phenobarbital, Phenytoinum); antitubercular drugs (rifampicin, rifapentine); the medicines containing the St. John's Wort made a hole (Hypericum perforatum).

With care:

- elderly patients;

- the patients who are at the same time infected with a virus of hepatitis B and/or a virus of hepatitis C.

Overdose:

Data on overdose of Intelens at the person are limited. It is probable that the most often observed side effects caused by use of Intelens such as rash, diarrhea, nausea, headache will be the most frequent symptoms of overdose.

The specific antidote of an etravirin does not exist. Treatment of overdose consists in performing the general supporting symptomatic therapy including monitoring of the main physiological indicators and observation of a clinical condition of the patient.

If necessary этравирин it is possible to remove from a stomach by means of artificial vomiting or by means of a gastric lavage. For this purpose also administration of absorbent carbon is useful.

Etravirin has high ability to contact proteins of plasma and therefore dialysis , most likely, will not lead to significant removal from an organism of active substance.

Storage conditions:

At a temperature not above 30 °C. To store drug in original packaging. To store a bottle well corked for protection against moisture. Not to throw out bags of a dehumidifier. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, 100 mg.