INTELENS
Active material: Etravirine
When ATH: J05AG
CCF: Viricide, active against HIV
ICD-10 codes (testimony): B24
When CSF: 09.01.04.01.02
Manufacturer: JOHNSON & JOHNSON LTD (Russia)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Pills white or nearly white, Oval, Engraved “T125” on one side and “100” – another.
| 1 tab. | |
| Etravirine | 100 mg |
Excipients: gipromelloza, microcrystalline cellulose, colloidal silicon dioxide, sodium croscarmellose, magnesium stearate, lactose monohydrate (incl. lactose 160 mg).
120 PC. – plastic bottles (1) – packs cardboard.
Pharmacological action
Viricide, non-nucleoside reverse transcriptase inhibitor (NNRTI) HIV-1. Etravirine communicates directly with reverse transcriptase and blocks RNA-dependent DNA-dependent DNA polymerase activity, causing the destruction of the catalytic sites of the enzyme.
Antiviral activity in vitro
Etravirine is active against laboratory strains and clinical isolates of HIV-1 wild type in acutely infected t-cell lines, Human peripheral mononuclear cells and in monocytes / macrophages by human.
Has antiviral activity in vitro against a broad range of representatives of the Group m HIV-1 (subtypes (A), B, C, D, IS, F, G) and primary isolates of G, for which its average effective concentration (EU50) It varies between 0.7 to 21.7 nM.
Etravirine is not an antagonist of any of the studied antiretroviral drugs. It has additive antiviral activity in combination with protease inhibitors: amprenavir, atazanavirom, darunavirom, indinavirom, lopinavir, nelfinavirom, ritonavirom, saquinavir and tipranavir; with nucleoside or nucleotide reverse transcriptase inhibitors: zalcitabine, didanozinom, stavudine, abacavir and tenofovir; with reverse transcriptase inhibitors, non èfavirenzom, delavirdine and nevirapine, as well as in combination with the fusion inhibitor enfuvirtide. Etravirine gives synergic or additive antiviral effect in combination with nucleoside analog reverse transcriptase inhibitors emtricitabine, lamivudine and zidovudine.
Resistance
Etravirine has shown strong antiviral activity against 56 from 65 strains of HIV-1 with a single amino acid substitution in position RT, associated with resistance to NNRTIS, including the most common mutations K103N and Y181C. Amino acid substitutions, that cause the highest resistance to ètravirinu in cell culture, mutations Y181I (13-45-fold changing the values of the EU50) and Y181V (17-45-fold changing the values of the EU50). Antiviral activity in cell cultures etravirine against 24 HIV-1 strains with multiple amino acid substitutions, causing resistance to NNRTIS and/or protease inhibitors, similar to the activity against the wild strain of HIV-1.
In vitro selection of resistant to ètravirinu strains of wild-type HIV-1 of different origin and different subtipov, and selection of strains of HIV-1, resistant to NNRTIS, There was as high, and with a low viral inokulâte. Development of resistance to ètravirinu usually require multiple reverse transcriptase mutations, of which the most frequent following: L100I, E138K, E138G, V179I, Y181C and M230I.
Mutations, most often encountered in patients with unfortunate results of treatment virological combinations, containing Etravirine, were V179F, V179I, Y181C and Y181I.
Cross-resistance
Was revealed limited cross-resistance between etravirine and èfavirenzom have in vitro 3 from 65 mutant strains of HIV-1, carrying the mutation, which causes resistance to NNRTIS. Other strains of amino acid positions, associated with reduced susceptibility to etravirine and efavirenz, varied. Etravirine maintains the EU50 <10 nM against 83% from 6171 clinical isolates, resistant to delavirdinu, efavirenz and / or nevirapine. It is not recommended to treat delavirdine, efavirenz and / or nevirapine patients, which mode, containing Etravirine, was inefficient with virological perspective.
Pharmacokinetics
Absorption
After intake of food (C)max Etravirine plasma achieved within 4 no.
Concentration in the plasma of Etravirine are similar when it is received after the standard food and after reception of fatty foods. Etravirine concentration when it is received after the standard food, the concentration of the drug decreased when it is received to the standard food (on 17%), or on an empty stomach (on 51%). Thus, for optimal absorption of Intelence® should be taken after meals.
In healthy people, Etravirine absorption does not depend on the simultaneous intake of ranitidine or omeprazole, which increase gastric pH.
Distribution
In vitro about 99.9% Etravirine binds to plasma proteins, mostly to albumin (99.6%) and with α1-acid glycoprotein (97.66 – 99.02%). Distribution of Etravirine in other liquids (eg, cerebrospinal fluid) people have not studied.
Metabolism
In vitro experiments with human liver mikrosomami revealed, What is Etravirine mostly undergoes oxidative metabolism under the influence of hepatic isoenzymes and CYP3A family, less, under the influence of isoenzymes CYP2C family, followed by going glukuronizatia.
Deduction
Once inside the dose of the labeled 14P-Etravirine 93.7% and 1.2% the dose found in the feces and urine, respectively. On the share unchanged Etravirine Calais had to 81.2-86.4% the dose. In the urine unchanged Etravirine is not detected. The final T1/2 Etravirine is about 30-40 no.
Pharmacokinetics in special clinical situations
Studies pharmacokinetics of Etravirine in children and adolescents.
Pharmacokinetics of Etravirine does not depend on the age of the studied (from 18 to 77 years).
There were no significant differences in pharmacokinetics of Etravirine depending on the sex of the patient.
Etravirine is metabolized and eliminated predominantly by the liver. Pharmacokinetics of etravirine has not changed in patients with mild and moderate acute human liver (dose Intelensa® lower is not required). In patients with severe violations of the liver (class on the scale Čajlda-Pew) pharmacokinetics of the drug Intelence® It has not been studied.
Etravirine clearance in patients, HIV-1 and hepatitis B and / or hepatitis C., reduced (based on the security profile of Etravirine, reduce the dose should not be).
In patients with renal insufficiency farmakokinetiku Etravirine haven't studied. With urine netted less than 1.2% the dose Etravirine. Unmodified Etravirine in urine is not found, Consequently, the impact of violations of the kidney to elimination of Etravirine minimally. Because etravirine has a very high ability to bind to plasma proteins, It hardly can be removed from the body in any significant quantities by hemodialysis or peritoneal dialysis.
Testimony
— treatment of infection, caused by the human immunodeficiency virus – HIV-1, adult patients, who received antiretroviral drugs, including patients with resistance to nenukleozidnym reverse transcriptase inhibitors in combination therapy.
Dosage regimen
Intelence® should always be used in combination with other antiretroviral drugs.
Adults appointed interior 200 mg (2 tab.) 2 times / day after meals. The maximum daily dose - 400 mg.
Patients older dose adjustments are not required. There is limited information on treating drug Intelence® patients in this age group.
Patients with easy or moderate impaired liver (classes a or b on a scale Child-Pugh) dose adjustment is required. Patients with severe hepatic impairment (class C Child-Pugh) farmakokinetiku drug Intelence® not studied.
Patients with impaired renal function dose adjustment is required.
If you forgot to take the next dose of Intelence® and remembered about it no later than one 6 hours after the usual time of dose, It must be taken as soon as possible after eating and then take the next dose at the usual time. If more than 6 hours after the usual time of dose, the patient should not take the missed dose, but simply resume taking the drug in the usual way.
Side effect
Determining the frequency of side effects: Often (≥ 10%), often (≥1%, < 10%), sometimes (≥ 0.1% and <1% ).
Cardio-vascular system: often – increased blood pressure; sometimes – myocardial infarction, Atrial fibrillation, angina, hemorrhagic stroke.
From the hematopoietic system: often – thrombocytopenia, anemia.
From the central and peripheral nervous system: often – perifericheskaya neuropathy, headache, alarm, insomnia; sometimes – convulsions, collapse, amnesia, tremor, drowsiness, paraesthesia, gipesteziya, hypersomnia, confusion, disorientation, nightmares, sleep disorders, nervousness, unusual dreams.
From the senses: sometimes – blurred vision, vertigo.
On the part of the respiratory system: sometimes – bronchospasm, shortness of breath on exertion.
From the digestive system: often – hastroэzofahealnыy reflux, diarrhea, vomiting, nausea, abdominal pain, flatulence, gastritis; sometimes – pancreatitis, hematemesis, stomatitis, constipation, dry mouth, vomiturition, hepatitis, fatty degeneration of the liver, cytolytic hepatitis, gepatomegaliya.
From the urinary system: often – renal failure.
Metabolism: often – diabetes, giperglikemiâ, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, dyslipidaemia; sometimes-anorexia; ≤ 5% – moderate acquired lipodystrophy.
Dermatological reactions: often – skin rash (the most common cause of drug withdrawal); sometimes – facial swelling, lipohypertrophy, night sweat, hyperhidrosis, prurigo, xerosis, lipodystrophy.
On the part of the immune system: sometimes – immune reconstitution syndrome, Hypersensitivity to the drug.
Allergic reactions: no more 0.5% – moderately expressed angioedema, erythema multiforme; rarely (<0.1%) – Stevens-Johnson syndrome.
From the laboratory parameters: increasing levels of amylase, lipase, total cholesterol, LDL, Glucose, GOLD, AST and a reduction in the number of neutrophils.
Other: often – fatigue; sometimes-sluggish, gynecomastia.
Additional information on specific patient populations
Patients, simultaneously infected with hepatitis b and/or hepatitis c virus (HCV), there was an increase in activity of AST and ALT.
Contraindications
- Childhood and adolescence up 18 years;
- Pregnancy;
- Lactation (breast-feeding);
- Galactose intolerance, lactose or glucose-Galactose malabsorption;
- Hypersensitivity to the drug.
Pregnancy and lactation
Adequate and well-controlled clinical studies safety of Etravirine during pregnancy did not take place.
IN experimental studies the animals have been detected direct or indirect negative impact on Etravirine during pregnancy, prenatal development, rodы and development postnatalynoe.
There are currently no data on the impact of Etravirine on fertility in humans.
Unknown, whether allocated Etravirine with breast milk in humans. Due to the risk of HIV transmission from mother to baby during breastfeeding and breastfeeding women themselves have the potential side effects of Etravirine, HIV-infected women should refrain from breastfeeding, If they take Intelence®.
Cautions
Patients should be informed that, that modern antiretroviral drugs do not cure HIV infection and do not prevent the transmission of HIV to other people with blood or sexual contacts. During treatment with Intelence® patients should continue to observe appropriate security measures.
Treatment with Intelence® must be treated by a doctor, with sufficient experience of treatment for HIV-infection.
In applying the drug Intelence® should be guided by therapeutic history, and, where it is possible, results of susceptibility testing HIV-1 antiretroviral drugs. For the treatment of patients, which took place virologic failure in therapy and nukleozidnym NNRTI or proliferation of reverse transcriptase inhibitor (NtIOT), Not recommended to appoint Intelence in combination only with NtIOT.
When treated with Intelence® skin rashes may occur, most often mild or moderate, generally macular, maculo-papular erythematous or. Usually, rash appeared on the 2-nd week of treatment and rarely appeared after 4 weeks. In most cases, special treatment is not required: the rash usually disappear within 1-2 weeks with continued therapy.
Patients, simultaneously infected with hepatitis b and/or hepatitis c virus (HCV) treatment was needed to stop because of side effects from the liver or bile ducts. In patients with chronic hepatitis b are recommended standard clinical monitoring.
Kidney klirens Etravirine is negligible (<1.2%), and therefore, in patients with the human kidney total klirens Etravirine practically does not change. Such patients do not need special precautions, and they did not require lower doses of the drug Intelence®.
Etravirine highly associated with the plasma protein, so its withdrawal with the help of haemodialysis and peritoneal dialysis, probably, inconsequential.
In HIV-infected patients combination antiretroviral therapy accompanied by a redistribution of adipose tissues (lipodystrophy). This redeployment includes loss of peripheral and facial subcutaneous adipose tissue, the increase in the number of intraabdominal′nogo and visceral fat, hypertrophy of the mammary glands and fat accumulation in dorsocervikal′noj area (the formation of fatty hump). The long-term consequences of this phenomenon are not currently known, and its inadequate study of the mechanisms. There is a hypothesis about the relationship between visceral Lipomatosis and protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors. The increased risk associated with such individual characteristics of the patient, as the old age, as well as long-term antiretroviral therapy and related metabolic disorders. Clinical examination of HIV-infected patients should include an evaluation of the physical attributes of the redistribution of adipose tissue.
In HIV-infected patients with severe immunodeficiency during the beginning of combination antiretroviral therapy may occur on the inflammatory reaction of asymptomatic or residual opportunistic infections, which may be deteriorating clinical condition and the enhancement of existing symptoms. Such reactions usually occur in the first weeks or months after the initiation of combination antiretroviral therapy. As examples of CMV retinitis, generalized and/or focal infection and Mycobacterial pneumonia, caused by Pneumocystis jiroveci. The appearance of any symptoms of inflammation needs immediate examination and, if necessary, treatment.
Each tablet contains 160 Lactose mg. This quantity is unlikely can cause symptoms of lactose intolerance. Intelence® do not assign patients with congenital lactose Galactose, lactase or malabsorbziei glucose-Galactose.
Effects on ability to drive vehicles and management mechanisms
Currently, there is no evidence, that Intelence® may affect these functions. Nonetheless, should take into account the profile of the side effects of the drug.
Overdose
The drug overdose Intelence® in humans are limited.
Treatment: General supportive symptomatic therapy, including monitoring of key physiological indicators and monitoring the clinical condition of the patient. If necessary, you can remove the stomach of Etravirine using artificial vomiting or by gastric lavage. To this end, effectively introducing activated charcoal. Etravirine has expressed the ability to bind to plasma proteins, Therefore, dialysis, probably, will not remove significant amounts of the drug from the body. Specific antidote Etravirine does not exist.
Drug Interactions
Medications, influence on the concentration of plasma Etravirine
Etravirine is metabolized by CYP3A4 isoenzymes, CYP2C9 and CYP2C19, and its metabolites are subjected to glucuronidation influenced by enzyme uridindifosfatglûkuronoziltransferazy. Medications, inducing CYP3A4, CYP2C9 or CYP2C19, can accelerate the clearance of Etravirine, thereby reducing its concentration in plasma.
Simultaneous application of Intelence® and preparations, which inhibit CYP3A4, CYP2C9 or CYP2C19, can slow clearance etravirine and its concentration in plasma.
Medications, on the metabolism which affects Etravirine
Etravirine is a weak inducer of CYP3A4. Simultaneous application of Intelence® and preparations, that is metabolized primarily by CYP3A4, can lead to a decrease in the concentrations of these drugs in plasma and, Consequently, weaken or shorten their therapeutic effects.
Besides, Etravirine is a weak inhibitor of CYP2C9 and CYP2C19 Isoenzymes. Simultaneous application of etravirine and preparations, which is metabolized mainly CYP2C9 or CYP2C19, can increase the concentration of drug in plasma and, Consequently, enhance or prolong their therapeutic or side effects.
Prescribed drug interaction Etravirine with other antiretroviral drugs
Intelence is not recommended® simultaneously with other NNRTI.
Nucleoside or nucleotide reverse transcriptase inhibitors (NNRTI/NtIOT):
Didanosine (400 mg 1 time / day): combination can be used without correction doses. DDI, take on an empty stomach, so you must be 1 hours before or after 2 h after administration of the drug Intelence® (which must be taken after a meal). Tenofovir (300 mg 1 time / day): combination can be used without correction doses. Other (eg, Abacavir, эmtricitabin, lamivudine, stavudine and zidovudine) net off the news, Therefore, it is considered, What is Etravirine does not interact with these drugs.
Protease inhibitors without ritonavir in low dose
Atazanavir (400 mg 1 time / day): It is not recommended to simultaneously with the drug Intelence® apply without ritonavir atazanavir in low dose (concentration of atazanavir is reduced by 47%, Etravirine concentration increases by 58%). Ritonavir: When the combination drug Intelence® with ritonavir in full dose (600 mg 2 times / day) Perhaps clinically significant decrease in the concentration of plasma Etravirine. This can lead to the loss of therapeutic effect drug Intelence®. Therefore, it is not recommended to simultaneously appoint Intelence® and ritonavir in full dose. Nelfinavir: While use may increase the concentrations of nelfinavir in plasma. Fosamprenavir: While use may increase the concentrations of amprenavir in plasma. Other: Intelence is not recommended® with other protease inhibitors without ritonavir in low dose (including as saquinavir).
Protease inhibitors while taking ritonavir
Tipranavir/ritonavir (500/200 mg 2 times / day): It is not recommended to simultaneously apply a combination of tipranavir/ritonavir and Intelence® (tipranavir concentration increases by 24%, Etravirine concentration decreases by 82%). Fosamprenavir/ritonavir (700/100 mg 2 times / day): While applying the drug Intelence® and combinations of Fosamprenavir/ritonavir may require correction doses of these drugs. Atazanavir/ritonavir (300/100 1 time / day): Intelence® can be used in conjunction with a combination of atazanavir/ritonavir dose without correction. Darunavir/ritonavir (600/100 mg 2 times / day): Intelence® can be used in conjunction with a combination of darunavir/ritonavir dose without correction. Lopinavir/ritonavir (soft gel capsules) (400/100 mg 2 times / day): Intelence® can be used in conjunction with a combination of lopinavir/ritonavir dose without correction. Saquinavir/ritonavir (1000/100 mg 2 times / day): Intelence® can be used in conjunction with a combination of saquinavir/ritonavir dose without correction.
A combination of two protease inhibitors while taking ritonavir
Lopinavir/ritonavir/saquinavir (400/800-1000/100 mg 2 times / day): Intelence® can be used in conjunction with a combination of lopinavir/ritonavir/saquinavir without correction doses.
Inhibitors
Enfuvirtid (90 mg 2 times / day): It assumed, that while applying the drug Intelence® and enfuvirtide interaction does not occur.
Integrase inhibitors
Raltegravir (400 mg 2 times / day): combination drug Intelence® and raltegravira can be used without correction doses.
Patient interaction drug Intelence® with other drugs
Antiarrhythmics (Amiodarone, bepridil, disopyramide, flekainid, lidocaine/in, mexiletine, propafenone, quinidine): the concentration of these complications may decrease when used simultaneously with the drug Intelence®. While applying the drug Intelence® and complications with caution and, possibly, monitor the latest concentrations in plasma.
Antykoahulyantы (warfarin): warfarin concentration can vary when applied simultaneously with the drug Intelence®. It is recommended that you monitor the INR while appointing the drug warfarin and Intelence®.
Anticonvulsants (Carbamazepine, phenobarbital, phenytoin): are inducers of isoenzymes CYP450 system. Intelence® You cannot assign simultaneously with these drugs, because it can cause a significant reduction in concentrations of Etravirine in plasma, which, in turn, can lead to the loss of therapeutic effect drug Intelence®.
Antifungals (fluconazole, itraconazole, ketoconazole,Posaconazole, voriconazole): fluconazole, itraconazole, ketoconazole, posaconazole are potent inhibitors of CYP3A4 isoenzymes and may cause increased concentrations of Etravirine in plasma. On the other hand, etravirine is able to reduce the concentration of ketoconazole and itraconazole plasma, since they are also substrates for CYP3A4. Voriconazole is a substrate and inhibitor of CYP3A4 and CYP2S19 CYP2S. Application of vorikonazola simultaneously with the drug Intelence®may lead to increased plasma concentrations of both drugs.
Antiinfectives: Azithromycin is naturally excreted kidneys, and so he, probably, It does not interact with the drug Intelence®. Clarithromycin (500 mg 2 times / day): Etravirine reduces the concentration == in plasma 53%; at the same time, concentration of the active metabolite, 14-hydroxy-clarithromycin, increased to 46%. Since 14-gidroksiklaritromicin has reduced activity against Mycobacterium avium complex (MAS), total activity of clarithromycin and its metabolite in regard to MAS can change. Hence, to treat infections, caused by MAS, It is advisable to use drugs, alternative clarithromycin, such as azithromycin.
Anti-TB drugs: rifampicin, rifapentin are strong inducers of CYP450 Isoenzymes. Intelence®It should not be used in combination with rifampicin and rifapentinom, because it can cause a significant reduction in concentrations in plasma and Etravirine, Consequently, the loss of its therapeutic effect. Rifabutin (300 mg 1 time / day): combination can be used without correction doses.
Antiviral agents (Ribavirin) eliminates the kidneys, and so he, probably, does not interact drug Intelence®.
Benzodiazepines (diazepam): application of Etravirine simultaneously with diazepam may increase the concentration of plasma.
GCS (dexamethasone orally or parenterally): dexamethasone induces CYP3A4 and CYP may reduce concentration in plasma Etravirine. The consequence of this could be loss of therapeutic effect drug Intelence®. Dexamethasone (except for external use) It should be administered with caution or use alternative drugs, especially when long-term therapy.
Estrogen-based contraceptives (ethinylestradiol, norethisterone): combination contraceptives based on estrogen and/or progesterone and Intelence® It can be used without dose adjustment.
Medications, containing St. John's wort (Hypericum perforatum): St. John's wort (Hypericum perforatum) is a strong inducer of CYP450 system, izofermentov. Intelence® cannot be used in conjunction with drugs, containing Hypericum perforatum, because this can lead to significant reduction of concentrations of Etravirine in plasma and the loss of its therapeutic effect.
Inhibitors of HMG-Ingibitsii KOA-reduktaza (Statins): while receiving the drug Intelence® and atorvastatin (40 mg 1 time / day) last dose must be adjusted to achieve the desired clinical effect (Atorvastatin concentration decreases by 37%, the concentration of 2-gidroksiatorastatina increases by 27%).
Pravastatin, probably, It does not interact with the drug Intelence®.
Lovastatin, rosuvastatin and simvastatin are CYP3A4 substrates, Therefore, the simultaneous use of these drugs with Etravirine can cause a decline in their concentrations in plasma.
Fluvastatin, rosuvastatin and, less, pitavastatin metabolized by CYP2C9 izofermentom and their simultaneous application with the drug Intelence® may lead to increased plasma concentrations of Statins. It may be necessary to adjust their doses.
Histamine H2-receptors (ranitidine 150 mg 2 times / day): You can assign simultaneously without correction doses.
Immunosuppressive: Use caution when prescribing the drug Intelence® at the same time with system immunodepressantami (cyclosporine, sirolimus, tacrolimus), etravirine may change as concentrations in plasma.
Opioid analgesics: (methadone 60-130 mg / day): amid simultaneous application with the drug Intelence® and then there was no need for dose adjustment of methadone.
PDE5 inhibitors: (sildenafil, Vardenafil, tadalafil 50 mg): If you are applying to FDÈ5 inhibitors and drug Intelence® may require dose adjustment FDÈ5 with a view to achieving the desired clinical effect (concentrations of sil′denafila and N-desmetil-sil′denafila declined by 57% and 41% respectively).
Protone pump inhibitors: (omeprazole 40 mg 1 time / day): correction dose is not required.
Selktivnye serotonin reuptake inhibitors (paroxetine 40 mg 1 time / day): correction dose is not required.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children at or above 30 ° C. Shelf life - 2 year.
The drug should be stored in its original packaging. Bottle store good ukuporennym to protect from moisture. Do not throw away bags with desiccant.
