Etravirine - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Means for the treatment of HIV infection

Included in the formulation

Intelence®

pills inwards

Johnson & Johnson, LLC Russia

Intelence®

pills inwards

Johnson & Johnson, LLC Russia

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

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

J.05.A.G.04 Etravirine

Pharmacodynamics:

An antiviral (HIV) agent. Non-nucleoside inhibitor of HIV-1 reverse transcriptase. Directly binds to reverse transcriptase and blocks RNA and DNA-dependent activity of DNA polymerase, causing destruction of the catalytic sites of this enzyme. It is active against laboratory strains and clinical isolates of wild-type HIV-1 in acute infected T-cell lines, human peripheral mononuclear cells and human monocytes / macrophages. It is active against 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 50% effective concentration varies from 0.7 to 21.7 nM . Has a pronounced antiviral activity against 56 (of 65) HIV-1 strains with one amino acid substitution at RT positions associated with resistance to the non-nucleoside reverse transcriptase inhibitor, including the most common mutations K103N and Y181C. Amino acid substitutions,which cause high resistance to etravirine in cell culture, are mutations of Y181I (13-fold change in the value of 50% effective concentration) and Y181V (17-fold change in the value of 50% effective concentration). The antiviral activity of etravirine in cell cultures against 24 HIV-1 strains with multiple amino acid substitutions inducing resistance to a non-nucleoside reverse transcriptase inhibitor and / or to protease inhibitors is similar to that of wild-type HIV-1 strain. The selection of HIV-1 wild-type HIV-1 strains of different origin and different subtypes, as well as the selection of HIV-1 strains resistant to the non-nucleoside reverse transcriptase inhibitor, occurs with a high and low viral inoculum. The development of resistance to etravirine requires a multitude of mutations of reverse transcriptase, of which the following were most commonly encountered: L100I, E138K, E138G, V179I, U181C and M2301. The most common mutations (with an unsuccessful virological result in the case of etravirine treatment) were V179F, VI791, Y181C and Y1811. A limited cross-resistance between etravirine and efavirenz in 3 (out of 65) mutant HIV-1 strains bearing a mutation that causes resistance to a non-nucleoside reverse transcriptase inhibitor has been identified.In other strains, the amino acid positions associated with reduced sensitivity to etravirine and efavirenz were different. Etravirine retains a 50% effective concentration of less than 10 nM against 83% of the 6171 clinical isolates resistant to delavirdine, efavirenz and / or nevirapine.

Pharmacokinetics:

Absorption of the drug (in healthy people) does not depend on the simultaneous intake of ranitidine or omeprazole, which increase the pH of the contents of the stomach. The concentrations of etravirin in plasma are similar when taking ordinary and fatty foods. Compared with the concentration at reception after eating, the concentration at reception of a preparation before meal decreases by 17% and on 51% - at reception on an empty stomach so optimum absorption of a preparation is reached at its reception after meal. Time to reach the maximum concentration in the plasma4 hours. The connection with proteins - 99,9% (mainly with albumin - 99,6% and with alpha₁acid glycoprotein - 97.66-99.02%). Etravirine is subjected to oxidative metabolism in liver microsomes under the influence of hepatic isoenzymes CYP3A and CYP2C (to a lesser extent) followed by glucuronation. The decrease in etravirin clearance in patients infected with HIV-1 and hepatitis B virus and / or hepatitis C virus has no clinical significance. Final half-lifeis 30-40 hours. It is excreted by the kidneys - 1,2% and intestines - 93,7% (81,2-86,4% - unchanged). Sex, age and mild and moderate hepatic impairment do not affect pharmacokinetics.

Indications:

Treatment of HIV-1 infection in adults who received antiretroviral drugs, including patients with resistance to non-nucleoside reverse transcriptase inhibitors as part of a combination therapy.

ICD-10

I.B20-B24.B24 Disease caused by human immunodeficiency virus [HIV], unspecified

Contraindications:

Children and adolescence under 18, pregnancy, lactation (breastfeeding), hypersensitivity to etravirine.

Carefully:

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

Pregnancy and lactation:

Category by FDA not determined. Do not use during pregnancy and lactation.

Dosing and Administration:

Etravirine is always used in combination with other antiretroviral drugs.

Apply inside 200 mg (2 tablets) 2 times a day after meals at the same time. The maximum daily dose is 400 mg.

If you missed taking the next dose of the drug (no more than 6 hours), you need to take this dose as soon as possible, take the next dose at the usual time.

If more than 6 hours have elapsed after the required time of taking the drug, the patient should not take the missed dose, but simply resume taking the drug as usual.

The combination of etravirine with didanosine can be used without dose adjustment. Didanosine should be taken on an empty stomach (1 hour before or 2 hours after taking etravirine, which is taken after meals) 400 mg once a day.

Side effects:

From the side of cardio-vascular system: often - increased blood pressure; sometimes - myocardial infarction, atrial fibrillation, stenocardia, hemorrhagic stroke.

From the side hematopoiesis system: often - thrombocytopenia, anemia.

From the side CNS and peripheral nervous system: often - peripheral neuropathy, headache, anxiety, insomnia; sometimes - convulsions, collapse, amnesia, tremor, drowsiness, paresthesia, hypesthesia, hypersomnia, confusion, disorientation, nightmares, sleep disorders, nervousness, unusual dreams.

From the side sense organs: sometimes - blurred vision, vertigo.

From the side respiratory organs: sometimes - bronchospasm, shortness of breath with physical activity.

From the side digestive system: often - gastroesophageal reflux, diarrhea, vomiting, nausea, abdominal pain, flatulence, gastritis; sometimes - pancreatitis, bloody vomiting, stomatitis, constipation, dry mouth, desires for vomiting, hepatitis, fatty liver degeneration, cytolytic hepatitis, hepatomegaly.

From the side urinary system: often - kidney failure.

From the side metabolism: often - diabetes, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, dyslipidemia; sometimes anorexia; ≤ 5% is a moderate acquired lipodystrophy.

Dermatological reactions: often - skin rash (the most common cause of drug withdrawal); Sometimes - swelling of the face, lipogypertrophy, night sweats, hyperhidrosis, pruritus, dry skin, lipodystrophy.

From the side immune system: sometimes - a syndrome of restoration of immunity, hypersensitivity to the drug.

Allergic reactions: not more than 0.5% - moderately expressed angioedema, erythema multiforme; rarely (<0.1%) is Stevens-Johnson syndrome.

From the side laboratory indicators: increased levels of amylase, lipase, total cholesterol, LDL, glucose, ALT, AST and a decrease in the number of neutrophils.

Other: often fatigue; sometimes - lethargy, gynecomastia. In patients who were simultaneously infected with the hepatitis B virus and / or hepatitis C virus, an increase in the activity of AST and ALT was observed.

Overdose:

Data on overdose 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 the drug, 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.

Etravirin 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:

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

Simultaneous use of etravirine with inhibitors of CYP3A4, CYP2C9, CYP2C19 slows its clearance and increases plasma concentration.

Etravirine is a weak inducer of the isoenzyme CYP3A4. Its simultaneous use with drugs metabolized with the participation of CYP3A4, can lead to a decrease in their concentrations in the plasma and, consequently, to weaken or shorten their therapeutic effects.

Etravirine is a weak inhibitor of CYP2C9 and CYP2C19 isoenzymes. Its simultaneous use with drugs metabolized with the participation of CYP2C9 or CYP2C19 can increase their concentration in the plasma and, therefore, enhance or prolong their therapeutic or side effects.

It is not recommended to apply etravirine simultaneously with other non-nucleoside reverse transcriptase inhibitors.

With simultaneous use with tenofovir, the doses of the drugs do not require correction; tenofovir should be taken at 300 mg once a day. Abacavir, emtricitabine, lamivudine, stavudine, zidovudine are mainly excreted by the kidneys, which is probably why etravirine, which is excreted mainly by the intestine, does not interact with these drugs.

It is not recommended to apply simultaneously atazanavir (400 mg once a day) without simultaneous reception of a low dose of ritonavir and etravirine (atazanavir concentration is reduced by 47%, etravirin concentration is increased by 58%).

It is not recommended to simultaneously use the full dose of ritonavir (600 mg 2 times a day) with etravirine, since it is possible to significantly reduce the plasma etravirin concentration, which will lead to a decrease in its therapeutic effect.

With the simultaneous use of etravirine with nelfinavir, the concentration of nelfinavir in plasma is increased.

Simultaneous use with fosamprenavir can increase the concentration of amprenavir in plasma.

It is not recommended to apply etravirine with other protease inhibitors (including saquinavir) without simultaneous reception of a low dose of ritonavir.

Simultaneously apply a combination of tipranavir / ritonavir (500/200 mg 2 times a day) and etravirine is not recommended, as the concentration of tipranavir is increased by 24%, and the concentration of etravirine is reduced by 82%.

With the simultaneous use of etravirine and a combination of fosamprenavir / ritonavir (700/100 mg 2 times a day), dosage adjustments of these drugs may be required.

Etravirine can be used concomitantly with atazanavir / ritonavir (300/100 mg once a day), darunavir / ritonavir (600/100 mg twice daily), lopinavir / ritonavir (400/100 mg twice daily), saquinavir / ritonavir (1000/100 mg 2 times a day) without dose adjustment.

Etravirine can be used concurrently with a combination of lopinavir / saquinavir / ritonavir (400 / 800-1000 / 100 mg 2 times a day) without dose adjustment.

With simultaneous use of etravirine and enfuvirtide (90 mg 2 times a day) it is assumed that they will not interact with each other.

The combination of etravirine and raltegravir (400 mg 2 times a day) can be used without dose adjustment.

With the simultaneous use of etravirine with antiarrhythmic drugs (amiodarone, bepridil, disopyramid, flecainide, lidocaine (intravenously), mexiletine, propafenone, quinidine), their concentration may decrease. Care should be taken and, if possible, monitoring of antiarrhythmic drug concentrations in plasma.

With the simultaneous use of etravirine with warfarin, concentrations of warfarin may vary,therefore it is recommended to monitor the indicator of the international normalized relationship.

Etravirine is not recommended to be used concomitantly with carbamazepine, phenobarbital, phenytoin (inductors of CYP450 system isoenzymes), since this can cause a significant decrease in its plasma concentration and, accordingly, the therapeutic effect.

Fluconazole, itraconazole, ketoconazole, posaconazole are potent inhibitors of CYP3A4 isoenzymes and can increase the concentration of etravirin in plasma. On the other hand, etravirine is able to reduce the concentrations of itraconazole and ketoconazole in plasma, because they are also substrates of CYP3A4.

Voriconazole is a substrate of CYP2C19 and an inhibitor of CYP3A4 and CYP2C. The use of voriconazole simultaneously with etravirine can lead to an increase in plasma concentrations of both drugs.

Azithromycin is excreted by the kidneys, and therefore, apparently, does not interact with etravirine.

Etravirin reduces the concentration of clarithromycin (500 mg twice daily) in plasma by 53%; However, the concentration of its active metabolite (14-hydroxy-clarithromycin) increases by 46%. 14-hydroxyclarithromycin has a decreased activity against Mycobacterium avium complex,therefore the total activity of clarithromycin and its metabolite with respect to this pathogen may change. Therefore, for the treatment of infections caused by Mycobacterium avium complex, it is desirable to use other medicaments, for example, azithromycin.

Rifampicin, rifapentin are powerful inductors of CYP450 isoenzymes. Etravirine should not be used in combination with rifampicin and rifapentin, as this significantly reduces the concentration of etravirin in the plasma and, accordingly, the therapeutic effect.

The use of etravirin simultaneously with diazepam may increase the concentration of the latter in plasma.

Dexamethasone (inward or parenterally) induces the CYP3A4 isoenzyme and can reduce plasma etravirin concentrations and, accordingly, the therapeutic effect. Dexamethasone (except for external use) should be used with caution or use alternative drugs, especially with prolonged therapy.

Hypericum perforatum (Hypericum perforatum) is a powerful inducer of the CYP450 isoenzymes. It is not recommended simultaneous use of preparations containing St. John's wort perforated with etravirine, since this leads to a significant decrease in its plasma concentrations and, accordingly, the therapeutic effect.

With simultaneous administration of etravirine and atorvastatin (40 mg once a day), the dose of the latter must be adjusted to achieve the desired clinical effect (atorvastatin concentration is reduced by 37%, the concentration of 2-hydroxy-atorvastatin is increased by 27%).

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

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

With simultaneous use of etravirine with systemic immunosuppressants (ciclosporin, sirolimus, tacrolimusCare must be taken since etravirine can change their concentration in the plasma.

With the simultaneous use of etravirine with sildenafil, vardenafil, tadalafil (50 mg), their dose may need to be adjusted to achieve the desired clinical effect (the concentrations of sildenafil and N-desmethyl-sildenafil decreased by 57% and 41%, respectively).

Etravirin has additive antiviral activity in combination with protease inhibitors: 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, and in combination with an enfuvirtide fusion inhibitor.

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

Special instructions:

Treatment should be performed by a doctor who has sufficient experience in HIV therapy.

Modern antiretroviral drugs do not cure or prevent the transmission of HIV to other people with blood or during sexual intercourse. During treatment, patients should follow appropriate safety measures.

In the treatment with etravirine, an anamnesis should be taken into account, and, if possible, the results of determining the sensitivity of HIV-1 to antiretroviral drugs.For the treatment of patients with virological failure occurred in the therapy of non-nucleoside reverse transcriptase inhibitor and the nucleoside or nucleotide reverse transcriptase inhibitor, etravirine It is not suitable for use in combination only with a nucleotide reverse transcriptase inhibitor.

Among patients infected with both HBV and / or HCV treatment was stopped due to side effects from the liver or biliary tract. Patients with chronic hepatitis are recommended to undergo standard clinical monitoring.

Renal clearance etravirine - less than 1.2%, so patients with impaired renal function, the total clearance of the drug is practically not change, so is not required to reduce the dose etravirine.

Combination antiretroviral therapy is accompanied lipodystrophy, reduced peripheral and facial subcutaneous fat tissue, increase in the number of intra-abdominal and visceral fat, mammary gland hypertrophy, fat accumulation in dorsotservikalnoy region (formation of lipid humps).There is evidence of a link between visceral lipomatosis and the intake of protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy is associated with the individual characteristics of the patient (old age, long-term antiretroviral therapy and concomitant metabolic disorders). Clinical examination of patients should include an assessment of visual signs of fat tissue redistribution.

In patients with severe immunodeficiency, at the beginning (in the first weeks or months) of combined antiretroviral therapy, asymptomatic or residual opportunistic infections may worsen, which may lead to a worsening of the clinical condition. Possible development of cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumonia caused by Pnewnocystis jiroveci. The appearance of symptoms of inflammation requires immediate examination and, if necessary, treatment.

It is not recommended to conduct therapy with delavirdine, efavirenz and / or nevirapine in patients who have etravirine proved to be ineffective from the virological point of view.

Instructions

Etravirine (Etravirinum)