Etravirine antagonist is not any of the studied antiretrovirals. He has an additive antiviral activity in anadrol steroid combination with protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir; with nucleoside or nucleotide reverse transcriptase inhibitors: zalcitabine, didanosine, stavudine, abacavir and tenofovir; a non-nucleoside reverse transcriptase inhibitors efavirenz, delavirdine and nevirapine in combination with the fusion inhibitor enfuvirtide, the integrase inhibitor raltegravir and the CCR5 antagonist maraviroc receptors. Etravirine provides a synergistic or additive antiviral effect in combination with nucleoside reverse transcriptase inhibitors emtricitabine, lamivudine and zidovudine.
limited cross-resistance between etravirine and efavirenz was identified in vitro in 3 out of 65 mutant strains of HIV-1 that carry a mutation that causes resistance to the NNRTIs. Other strains of the provisions of amino acids associated with reduced susceptibility to etravirine and efavirenz were different. Etravirine retains anadrol steroid clinical isolates resistant to delavirdine, efavirenz and / or nevirapine. It is not recommended to treat delavirdine, efavirenz and / or nevirapine patients whose regimen containing etravirine, was ineffective with virological point of view.
after oral administration with food maximum concentration etravirine plasma achieved within 4 hours.
In healthy people absorption etravirine not dependent on simultaneous ingestion of ranitidine or omeprazole, which increase gastric pH.
Concentration etravirine does not depend on the type of food intake (normal caloric – 561 kcal or fatty foods – 1160 kcal). Drug concentration was lower when applied to food (17%), or on an empty stomach (51%) compared with its administration after meals. Thus, to maintain optimum etravirine plasma concentrations must take the medication after a meal.
Distribution In vitro about 99.9% etravirine binds to plasma proteins, mainly albumin (99.6%) and α 1 -kislym glycoprotein (97,66-99,02%). Etravirine distribution in other fluids (such as CSF) in humans have not studied.
Experiments in vitro with human liver microsomes showed that etravirine primarily undergoes oxidative metabolism by the action of CYP3A isozymes in liver and to a lesser extent, by the action of a family of isozymes CYP2C, and after this occurs glucuronidation.
After oral administration of the labeled dose of 14 C-etravirine 93.7% and 1.2% of the dose were detected in the feces and urine, respectively. The share unchanged etravirine in anadrol steroid faeces accounted for 81,2-86,4% of the dose. In the urine as unchanged etravirine was not found. The final elimination half etravirine was approximately 30-40 hours.
Special patient populations Children and adolescents are currently under study pharmacokinetics of etravirine in patients in this age group.
Pharmacokinetics etravirine not dependent on age studied (18 to 77 years).
Men and women
between men and women, there were no significant differences in the pharmacokinetics of etravirine.
Patients with hepatic impairment
Etravirine is metabolised by the liver and is eliminated predominantly intestine. The pharmacokinetics of etravirine have not changed in patients with mild to moderate hepatic impairment. There is no need to change the dose of the drug Intelence ® in these patients. In patients with severely impaired hepatic function (class C Child-Pugh), the pharmacokinetics of Intelence ® have not studied.
Patients infected with hepatitis B and / or hepatitis C virus
clearance etravirine in patients infected with HIV-1 and hepatitis B and / or hepatitis C virus is reduced. Based on the safety profile of etravirine, the dose does not need to lower these patients.
Patients with impaired renal function
In patients with renal impairment the pharmacokinetics of etravirine have not studied. The urine is eliminated less than 1.2% of the dose etravirine. Etravirine in unchanged form in the urine is detected, therefore, the effect of renal impairment on etravirine elimination is minimal. Since etravirine has a very high ability to bind to plasma proteins, it is unlikely to be removed from the body in any significant quantities by hemodialysis or peritoneal dialysis.
Treating infections caused by the human immunodeficiency virus – HIV-1 in adult patients who received anadrol steroid antiretroviral drugs, including patients with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), in a combination therapy.
- Hypersensitivity to etravirine or any component of the formulation.
- Children’s age (18 years).
- Pregnancy and lactation.
- Galactose intolerance, lactase or glucose-galactose malabsorption.
Dosing and Administration
Intelence ® should always be used in combination with other antiretroviral agents.
Adults : the interior of 200 mg (2 tablets), 2 times a day after meals. The maximum daily dose – 400 mg. The tablets should be swallowed whole with water. Patients who have difficulty swallowing pills Intelence ® , can grind them and mix in a glass of water. In this case, the patient should immediately drink the contents of anadrol steroid the cup. In order to receive a full dose of the glass should be rinsed several times with water and drink the contents completely.
Elderly patients : There is limited information on the treatment of Intelence ® patients in this age group. No dose adjustment is required.
Patients with impaired hepatic function : In patients with mild or moderate hepatic impairment (Class A or B on the scale of Child-Pugh) dose adjustment is required. In patients with severe hepatic impairment (class C Child-Pugh), the pharmacokinetics of the drug Intelence ® have not studied.
Patients with impaired renal function : In patients with impaired dose adjustment renal function is not required.
If the patient has forgotten to take the next dose of the drug Intelence ® and thought about it no later than 6 hours after the usual time of taking the drug, it should be as soon as possible to accept it after a meal, and then take the next dose at the usual time for her. If more than 6 hours after the normal time of drug administration, the patient should not take missed dose and simply resume the normal reception scheme preparation.
Pregnancy and lactation
Adequate and well-controlled studies etravirine in pregnant women were not conducted. Animal studies revealed no direct or indirect negative impact on etravirine during pregnancy, prenatal development, childbirth and postnatal development.
It is not known whether etravirine is able to penetrate into the breast milk of nursing women. Due to the possibility of HIV transmission from mother to baby during breastfeeding and occurrence of themselves in nursing women the potential side effects of etravirine, HIV-infected women should avoid breastfeeding if they take Intelence ® .
There is currently no data on the effect of etravirine on fertility in humans.
Adverse effects reported in clinical studies Side effects classified by organ system and frequency. By incidence of adverse events are classified as very frequent (≥1 / 10 cases), frequent (≥1 / 100, <1/10 cases) and infrequent (≥1 / 1000 and <1/100 cases).
Since the cardiovascular system:
often – myocardial infarction, high blood pressure,
rarely – atrial fibrillation, angina, haemorrhagic stroke.
On the part of the blood and lymphatic system :
often – thrombocytopenia, anemia.
From the nervous system:
often – peripheral neuropathy, headache, anxiety, insomnia,
rarely – seizures, syncope, amnesia, tremor, somnolence, paresthesia, hypoesthesia, confusion, disorientation, nightmares, sleep disturbances (including hypersomnia ), nervousness, abnormal dreams, impaired concentration.
From the sensory organs:
rarely – blurred vision, vertigo.
From the respiratory system :
rarely – bronchospasm, dyspnea on exertion.
From the gastrointestinal tract :
often – gastroesophageal reflux disease, diarrhea, vomiting, nausea, abdominal pain, flatulence, gastritis,
rarely – pancreatitis, bloody vomiting, stomatitis, constipation, dry mouth, the urge to vomit, bloating.
From the urinary system:
often – renal failure.
Skin and soft tissue:
often – a rash, night sweats, lipohypertrophy,
infrequently – facial swelling, rash, pruritus, dry skin, lipodystrophy, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome.
Disorders of metabolism and nutrition:
often – diabetes, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, dyslipidemia;
rarely – anorexia.
Violations of a general nature:
often – fatigue;
rare – lethargy.
Infrequent – immune reconstitution syndrome, hypersensitivity to the drug.
On the part of the hepatobiliary system:
rare – hepatitis, fatty degeneration of anadrol steroid the liver, cytolytic hepatitis, hepatomegaly.
Reproductive system and breast:
From the laboratory parameters:
. Enhancing activity of pancreatic amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevated serum creatinine concentration, total cholesterol, LDL, triglycerides, glucose, and decreased the number of neutrophils, leukocytes
most frequently observed adverse events were skin rash, diarrhea, nausea, and hypertriglyceridemia.
The most frequent reason for discontinuation was rash. Rash was mostly mild or moderate, generally makuleznoy, maculo-papular erythematous and usually occurred in the second week of treatment and rarely appears after the 4th week. Most often, the rash does not require special treatment and usually disappear within 1-2 weeks on the background of continuing treatment. The incidence of rash on background therapy with Intelence ® were more common in women.
Moderately severe side effects (no more than 0.5% of patients) were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke. Rare (<0.1%) observed Stevens-Johnson syndrome (less than 0.1%), and very rarely – toxic epidermal necrolysis (less than 0.01%).
Additional information on special patient populations
In patients co-infected with hepatitis B and / or hepatitis C virus was observed increased activity of AST and ALT.
Side effects recorded in the post-marketing period:
observed hypersensitivity reactions, including DRESS-syndrome characterized by rash, fever, eosinophilia and systemic symptoms (including, but not limited to, severe rash or rash accompanied by fever, general malaise , fatigue, pain in muscles and joints, bullous lesions, lesions of the mucous membranes of the mouth, conjunctivitis, hepatitis, eosinophilia)
From the musculoskeletal tissue:
Data on overdose Intelence ® in humans is limited. Probably the most common symptoms of overdose are the most commonly observed side effects caused by the use of Intelence ® , such as rash, diarrhea, nausea, headache.
Specific antidote etravirine does not exist. Treatment of overdose consists in carrying out general maintenance of symptomatic therapy, including monitoring of vital signs and observation of the clinical status of the patient. If necessary, etravirine can be removed from the stomach using an artificial or emesis by gastric lavage. To this end, useful for the introduction of the activated carbon. Etravirine has a high ability to bind plasma proteins, therefore, dialysis and, most likely, will not lead to significant removal of the active substance from the body.
Interaction with other drugs
Drugs that affect the concentration of etravirine plasma
Etravirine is metabolized isoenzymes CYP3A4, CYP2C9 and of CYP2C19, and its metabolites undergo glucuronidation under the influence of the enzyme uridindifosfatglyukuronoziltransferazy. Drugs that induce isozymes CYP3A4, CYP2C9 or CYP2C19, can accelerate the clearance of etravirine, thereby reducing its concentration in plasma.
Simultaneous use of the drug Intelence ® and drugs that inhibit isozymes CYP3A4, CYP2C9 or CYP2C19, can slow clearance etravirine and increase its concentration in plasma.
Medicinal products which affect the metabolism of etravirine
Etravirine is a weak inducer of CYP3A4 isoenzyme. Simultaneous application Intelence ® and drugs that are metabolized mainly isoenzyme CYP3A4, may reduce the concentrations of such drugs in the plasma and thus reduce or shorten their therapeutic effects.
In addition, etravirine is a weak inhibitor of CYP2C9 and isozymes CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein, but not its substrate. And etravirine simultaneous use of drugs that are metabolized mainly isozymes CYP2C19 or CYP2C9 or transported by P-glycoprotein may increase the concentration of drugs in plasma and hence enhance or prolong their therapeutic effects or side.
Drug interactions etravirine with other antiretroviral agents Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (eg, efavirenz, nevirapine, delavirdine, rilpivirine) is not recommended to use Intelence ® concurrently with other non-nucleoside reverse transcriptase inhibitors. clenbuterol kob