Etravirin (Tablets) Instructions for Use

ATC Code

J05AG04 (Etravirine)

Active Substance

Etravirine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; non-nucleoside reverse transcriptase inhibitors

Pharmacological Action

Etravirine is an antiviral agent, a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Etravirine binds directly to reverse transcriptase and inhibits RNA-dependent and DNA-dependent DNA polymerase activity, causing destruction of the catalytic sites of this enzyme.

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

It has antiviral activity in vitro against a wide range of HIV-1 group M representatives (subtypes A, B, C, D, E, F, G) and primary group O isolates, for which its mean effective concentration (EC₅₀) ranges from 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, 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, as well as in combination with the fusion inhibitor enfuvirtide. Etravirine exhibits synergism or an additive antiviral effect in combination with nucleoside reverse transcriptase inhibitors emtricitabine, lamivudine, and zidovudine.

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

In vitro selection of etravirine-resistant strains of wild-type HIV-1 of different origins and subtypes, as well as selection of NNRTI-resistant HIV-1 strains, occurred with both high and low viral inoculum. The development of resistance to etravirine usually required multiple reverse transcriptase mutations, the most common of which were: L100I, E138K, E138G, V179I, Y181C, and M230I.

The mutations that most frequently occurred in patients with virological treatment failure with regimens containing Etravirine were V179F, V179I, Y181C, and Y181I.

Limited cross-resistance between etravirine and efavirenz was identified in vitro in 3 out of 65 mutant HIV-1 strains carrying a mutation that causes NNRTI resistance. In other strains, the amino acid positions associated with reduced susceptibility to etravirine and efavirenz were different. Etravirine retains an EC₅₀ <10 nM against 83% of 6171 clinical isolates resistant to delavirdine, efavirenz, and/or nevirapine. It is not recommended to treat with delavirdine, efavirenz, and/or nevirapine in patients for whom a regimen containing Etravirine has been virologically ineffective.

Pharmacokinetics

After oral administration with food, the C_max of etravirine in plasma is reached within 4 hours.

The plasma concentrations of etravirine are similar when taken after a standard meal and after a high-fat meal. Compared to the concentration of etravirine when taken after a standard meal, the concentrations of this drug decreased when taken before a standard meal (by 17%), or on an empty stomach (by 51%).

In healthy individuals, the absorption of etravirine is not affected by the simultaneous oral administration of ranitidine or omeprazole, which increase the pH of gastric contents.

In vitro, approximately 99.9% of etravirine is bound to plasma proteins, primarily to albumin (99.6%) and to α₁-acid glycoprotein (97.66-99.02%). The distribution of etravirine into other fluids (e.g., cerebrospinal fluid) has not been studied in humans.

In vitro experiments with human liver microsomes have shown that Etravirine is primarily metabolized oxidatively by hepatic isoenzymes of the CYP3A family and, to a lesser extent, by isoenzymes of the CYP2C family, followed by glucuronidation.

After oral administration of a dose of radiolabeled ¹⁴C- etravirine, 93.7% and 1.2% of the administered dose were detected in feces and urine, respectively. Unchanged etravirine in feces accounted for 81.2-86.4% of the administered dose. Unchanged Etravirine was not detected in urine. The terminal T_1/2 of etravirine is about 30-40 hours.

The clearance of etravirine is reduced in patients co-infected with HIV-1 and hepatitis B virus and/or hepatitis C virus (based on the safety profile of etravirine, its dose should not be reduced).

Less than 1.2% of the administered dose of etravirine is excreted in the urine. Unchanged Etravirine was not detected in urine, therefore, the effect of renal impairment on the elimination of etravirine is minimal. Since Etravirine has a very high plasma protein binding capacity, it is unlikely to be removed from the body in any significant amount by hemodialysis or peritoneal dialysis.

Indications

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

ICD codes

Dosage Regimen

Administer Etravirine only as part of a combination antiretroviral regimen.

Take 200 mg (two 100 mg tablets) twice daily.

Swallow tablets whole; do not crush or chew.

Take following a meal to ensure adequate absorption.

The maximum daily dose is 400 mg.

If a dose is missed, take it as soon as possible and then resume the normal schedule.

Do not double the next dose to make up for a missed one.

Base the therapeutic regimen on the patient’s treatment history and, when available, genotypic or phenotypic resistance testing.

Do not use Etravirine in combination with only nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) following virological failure on an NNRTI-based regimen.

For patients with difficulty swallowing, the tablets may be dispersed in a glass of water.

Add the tablets to approximately 30 mL (1 oz) of water and stir until dispersed completely.

Drink the dispersion immediately.

Rinse the glass with water and drink the rinse to ensure the entire dose is taken.

The dispersion can also be administered via a nasogastric tube; flush the tube with water after administration.

No dose adjustment is required for patients with renal impairment or mild to moderate hepatic impairment.

The safety and efficacy in patients with severe hepatic impairment have not been established; use with caution.

Monitor patients with hepatitis B or C co-infection closely during therapy.

Discontinuation due to skin rash is the most frequently reported adverse reaction leading to treatment cessation.

Adverse Reactions

From the cardiovascular system common – increased blood pressure; uncommon – myocardial infarction, atrial fibrillation, angina pectoris, hemorrhagic stroke.

From the hematopoietic system common – thrombocytopenia, anemia.

From the central and peripheral nervous system common – peripheral neuropathy, headache, anxiety, insomnia; uncommon – seizures, collapse, amnesia, tremor, drowsiness, paresthesia, hypesthesia, hypersomnia, confusion, disorientation, nightmares, sleep disorders, nervousness, unusual dreams.

From the senses uncommon – blurred vision, vertigo.

From the respiratory system uncommon – bronchospasm, exertional dyspnea.

From the digestive system common – gastroesophageal reflux, diarrhea, vomiting, nausea, abdominal pain, flatulence, gastritis; uncommon – pancreatitis, hematemesis, stomatitis, constipation, dry mouth, retching, hepatitis, fatty liver degeneration, cytolytic hepatitis, hepatomegaly.

From the urinary system common – renal failure.

From metabolism: common – diabetes mellitus, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, dyslipidemia; uncommon – anorexia; ≤ 5% – moderately severe acquired lipodystrophy.

Dermatological reactions common – skin rash (the most common reason for drug discontinuation); uncommon – facial edema, lipohypertrophy, night sweats, hyperhidrosis, pruritus, dry skin, lipodystrophy.

From the immune system uncommon – immune reconstitution syndrome, hypersensitivity to the drug.

Allergic reactions not more than 0.5% – moderately severe angioedema, erythema multiforme; rare (<0.1%) – Stevens-Johnson syndrome.

From laboratory parameters increased levels of amylase, lipase, total cholesterol, LDL, glucose, ALT, AST and decreased neutrophil count.

Other common – fatigue; uncommon – lethargy, gynecomastia. In patients co-infected with hepatitis B virus and/or hepatitis C virus, increased AST and ALT activity was observed.

Contraindications

Children and adolescents under 18 years of age, pregnancy, lactation (breastfeeding), hypersensitivity to etravirine.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies on the safety of etravirine use during pregnancy have not been conducted.

It is unknown whether Etravirine is excreted in human breast milk. If it is necessary to use etravirine during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

During treatment with etravirine, standard clinical monitoring is recommended in patients with chronic hepatitis.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

Patients should be informed that current antiretroviral drugs do not cure HIV infection and do not prevent the transmission of HIV to others through blood or sexual contact. During treatment, patients should continue to take appropriate safety precautions.

Treatment should be carried out by a physician with sufficient experience in the therapy of HIV infection.

When using etravirine, one should be guided by the therapeutic history and, where possible, the results of HIV-1 susceptibility testing to antiretroviral drugs. For the treatment of patients who have experienced virological failure with NNRTI and nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI) therapy, Etravirine is not recommended to be prescribed in combination with NtRTI alone.

In patients with chronic hepatitis, standard clinical monitoring is recommended.

In HIV-infected patients, combined antiretroviral therapy is associated with redistribution of body fat (lipodystrophy). This redistribution includes loss of peripheral and facial subcutaneous fat, an increase in intra-abdominal and visceral fat, breast hypertrophy, and fat accumulation in the dorso-cervical area (buffalo hump formation). The long-term consequences of this phenomenon are currently unknown, and its mechanisms are not sufficiently understood. There is a hypothesis about the association between visceral lipomatosis and protease inhibitors, and between lipoatrophy and nucleoside reverse transcriptase inhibitors. An increased risk is associated with such patient characteristics as older age, 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 redistribution.

In HIV-infected patients with severe immunodeficiency, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur during the initiation of combined antiretroviral therapy, which may manifest as a worsening of the clinical condition and an increase in existing symptoms. Such reactions are usually observed in the first weeks or months after starting combined antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

Drug Interactions

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

Concomitant use of etravirine and drugs that inhibit CYP3A4, CYP2C9, or CYP2C19 may slow the clearance of etravirine and increase its plasma concentration.

Etravirine is a weak inducer of the CYP3A4 isoenzyme. Concomitant use of etravirine and drugs that are primarily metabolized by CYP3A4 may lead to a decrease in the plasma concentrations of such drugs and, consequently, weaken or shorten their therapeutic effects.

In addition, Etravirine is a weak inhibitor of CYP2C9 and CYP2C19 isoenzymes. Concomitant use of etravirine and drugs that are primarily metabolized by CYP2C9 or CYP2C19 may increase the plasma concentration of such drugs and, consequently, enhance or prolong their therapeutic or side effects.

It is not recommended to use atazanavir concomitantly with etravirine without the simultaneous administration of low-dose ritonavir (atazanavir concentration decreases by 47%, etravirine concentration increases by 58%).

With etravirine and full-dose ritonavir (600 mg twice daily), a clinically significant decrease in the plasma concentration of etravirine is possible. This may lead to loss of the therapeutic effect of etravirine. Therefore, it is not recommended to use Etravirine and full-dose ritonavir concomitantly.

When used concomitantly with etravirine, an increase in nelfinavir plasma concentrations is possible.

When etravirine and fosamprenavir are used concomitantly, an increase in amprenavir plasma concentrations is possible. It is not recommended to use Etravirine with other protease inhibitors without the simultaneous administration of low-dose ritonavir (including saquinavir).

It is not recommended to use the tipranavir/ritonavir combination and Etravirine concomitantly, because the concentration of tipranavir increases by 24%, the concentration of etravirine decreases by 82%.

When using etravirine in combination with fosamprenavir/ritonavir, dose adjustment of these drugs may be required.

When used concomitantly with etravirine, a decrease in the plasma concentration of the following antiarrhythmic drugs is possible (amiodarone, bepridil, disopyramide, flecainide, intravenous lidocaine, mexiletine, propafenone, quinidine).

A change in warfarin plasma concentration is possible when used concomitantly with etravirine. Monitoring of INR is recommended when warfarin and etravirine are co-administered.

Carbamazepine, phenobarbital, phenytoin are inducers of CYP450 isoenzymes. Etravirine should not be prescribed concomitantly with these drugs, as this may cause a significant decrease in the plasma concentration of etravirine, which, in turn, may lead to loss of the therapeutic effect of etravirine.

Antifungal drugs fluconazole, itraconazole, ketoconazole, posaconazole are strong inhibitors of CYP3A4 isoenzymes and may cause an increase in etravirine plasma concentrations. On the other hand, Etravirine can reduce the plasma concentrations of itraconazole and ketoconazole, as they are also substrates of CYP3A4. Voriconazole is a substrate of CYP2C19 and an inhibitor of CYP3A4 and CYP2C. The use of voriconazole concomitantly with etravirine may lead to an increase in the plasma concentrations of both drugs.

Azithromycin is excreted by the kidneys, so it is unlikely to interact with etravirine.

Etravirine reduced the plasma concentration of clarithromycin by 53%; however, the concentration of the active metabolite, 14-hydroxy-clarithromycin, increased by 46%. Since 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), the overall activity of clarithromycin and its metabolite against MAC may change. Therefore, for the treatment of MAC infections, it is advisable to use drugs alternative to clarithromycin, for example, azithromycin.

Antituberculosis drugs rifampicin, rifapentine are strong inducers of CYP450 isoenzymes. Etravirine should not be used in combination with rifampicin and rifapentine, as this may cause a significant decrease in etravirine plasma concentrations and, consequently, loss of its therapeutic effect.

When etravirine is used concomitantly with diazepam, an increase in the plasma concentration of the latter is possible.

Dexamethasone induces the CYP3A4 isoenzyme and can reduce etravirine plasma concentrations. The consequence of this may be the loss of the therapeutic effect of etravirine. Dexamethasone (except for topical use) should be prescribed with caution or alternative drugs should be used, especially during long-term therapy.

The combination of estrogen- and/or progesterone-based contraceptives and etravirine can be used without dose adjustment.

St. John’s wort (Hypericum perforatum) is a strong inducer of CYP450 isoenzymes. Etravirine should not be used concomitantly with preparations containing St. John’s wort, as this may lead to a significant decrease in etravirine plasma concentrations and loss of its therapeutic effect.

When etravirine and atorvastatin (40 mg once daily) are taken concomitantly, the dose of the latter must be adjusted to achieve the required clinical effect (atorvastatin concentration decreases by 37%, 2-hydroxyatorvastatin concentration increases by 27%).

Lovastatin, rosuvastatin, and simvastatin are substrates of CYP3A4, so the concomitant use of these drugs with etravirine may cause a decrease in their plasma concentrations.

Fluvastatin, rosuvastatin, and, to a lesser extent, pitavastatin are metabolized by the CYP2C9 isoenzyme and their concomitant use with etravirine may lead to an increase in the plasma concentrations of statins. Their dose adjustment may be required.

Etravirine may alter the plasma concentrations of systemic immunosuppressants (cyclosporine, sirolimus, tacrolimus), so caution is necessary with these combinations.

Against the background of concomitant use of methadone and etravirine and thereafter, there was no need for methadone dose adjustment.

When PDE5 inhibitors (sildenafil, vardenafil, tadalafil 50 mg) and etravirine are used concomitantly, dose adjustment of the PDE5 inhibitor may be required to achieve the desired clinical effect (concentrations of sildenafil and N-desmethyl-sildenafil decreased by 57% and 41%, respectively).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F).

Keep in original packaging, protected from light.

Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.