andriol tc

Active ingredient 200 mg helios steroid Excipients andriol tc:. Microcrystalline cellulose, lactose, povidone K25, sodium starch glycolate (type A), colloidal silicon dioxide, magnesium stearate, 1 ml of a suspension for oral administration contains active ingredient: 10.35 mg andriol tc hemihydrate, corresponding to 10 mg of andriol tc

Excipients:
carbomer, polysorbate 80, 70 sorbitol, sucrose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium hydroxide, purified water.

Description:
The tablets are oval, biconvex, white. On one side there is a designation of “54” and “193”, “54” numbers and “193” share the risk. On the opposite side of the tablet -. Marked with the symbol of
white or almost white homogeneous suspension, allowed to bundle slurry is resuspended easily by shaking.

 

Pharmacotherapeutic group:

Pharmacological Properties of: Pharmacodynamics: andriol tc is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. andriol tc binds directly with reverse transcriptase and blocks the activity of RNA-dependent and DNA-dependent DNA polymerase, causing the destruction of the catalytic site of the enzyme. The activity of andriol tc does not compete with or nucleoside triphosphates matrix. andriol tc inhibits the reverse transcriptase of HIV-2 DNA polymerase and eukaryotic cells (such as human DNA polymerase α, β, γ or δ).

 

Sensitivity of HIV in vitro. The relationship between the sensitivity of HIV-1 to Viramune ® in vitro and the inhibition of the replication of HIV-1 in humans has not been established. andriol tc Antiviral activity was assessed in vitro on peripheral blood mononuclear cells, macrophages monocytic origin and lymphoblast cell lines. IC50 values for laboratory and clinical HIV-1 isolates ranged from 10 to 100 nmol. In cell culture demonstrated that the activity against HIV-1 andriol tc is used in combination with ZDV, ddl, d4T, 3TC, saquinavir and indinavir, were additive or synergistic.

. Resistance In vitro, the possibility of occurrence of HIV isolates with reduced susceptibility (100 – 250 fold) to andriol tc. Genotypic analysis revealed mutations in HIV RT in 181 and / or 106 the amino acid positions, depending on the strain of virus and cell line used. When using andriol tc in combination with several other NNRTIs time of occurrence of andriol tc resistance in vitro, did not change.

The research phase I / II for 1 to ≥12 weeks were monitored phenotypic and genotypic changes isolates of HIV-1 isolates from patients treated with Viramune ® (n = 24) or Viramune ® in combination with ZDV (n = 14). After monotherapy Viramune ® for 1 week reduced susceptibility to andriol tc in vitro was observed in isolates from 3/3 patients. In some patients, the earliest 2 weeks after initiation of therapy, detected one or more mutations in the RT gene, 103, 106, 108, 181, 188 and 190 amino acid positions. By the eighth week monotherapy Viramune ® in all patients (n = 24) isolates of HIV, which are sensitive to in vitro NVP were isolated was reduced more than 100-fold compared with baseline and identified one or more of the RT mutations associated with resistance to andriol tc. In 80% of patients were identified isolates with a mutation at position 181, regardless of the dose. Combination therapy with Viramune ® + of ZDV did not alter the incidence of viruses resistant to andriol tc, or the degree of andriol tc resistance in vitro. However, in these cases, there was another type of mutation, mostly occurring in 103, 106, 188 and 190 amino acid positions. In patients (6 of 14) with the original isolates that took RT wild-type gene, giving the impression that the combination therapy Viramune ® + of ZDV did not detain the appearance of ZDV-resistant RT mutations. In nical and phenotypic stability of the INCAS study genotype was evaluated in patients treated with Viramune ® as part of a triple and a double combination therapy, and the control group of patients who did not receive Viramune ® . In patients previously untreated with antiretroviral therapy (CD4 cell count them was 200-600 / mm3), were treated with Viramune ® + of ZDV (46 of N =), ZDV + ddl (N = 51) or Viramune ® + of ZDV + ddl ( N = 51); observation was carried out for 52 or more weeks of treatment. Virological examination was performed at baseline, after 6 and 12 months. It uses the method of phenotypic resistance testing required for amplification of the virus presence of at least 1000 copies / mL of HIV RNA. In the 3 studied groups of patients were identified baseline isolates available for research. These patients were treated for at least 24 weeks.Initially noted five cases of phenotypic resistance to andriol tc; IC50 values of three of them in increased 5-6.5 fold and two – over 100 times. After 24 weeks, all isolates that could distinguish patients treated with Viramune ® , were resistant to this drug. After 30-60 weeks, these isolates were present in 86% of patients. Suppression of virus below the limit of detection was achieved in 16 patients (<20 copies / ml – from 14 <400 copies / ml – y 2). By using the assumption that suppression below <20 copies / ml virus indicates sensitivity to the drug Viramune ® , has been found (by the direct or indirect value), sensitivity to the drug was maintained in 45% of patients. All patients treated with Viramune ® + of ZDV and tested for phenotypic resistance, six months were resistant to Viramune ® . Over the entire period of observation established one case of resistance to didanosine. Resistance to zidovudine occurred more frequently after 30-60 weeks, especially in patients receiving double combination therapy.Based on an increase in IC50, it was found that the resistance to ZDV occurs apparently less frequently in patients treated with Viramune ® + ZDV + ddl, in patients other than the treatment groups.

In terms of resistance to Viramune ® it has been shown that all isolates had received at least one mutation associated with resistance. The most common single changes were subjected K103N and Y181C.Thus, the use of highly active drug therapy regimes accompanied slowing the development of resistance to antiretroviral drugs. Genotypes correlated with phenotypic resistance to Viramune ® , have been identified in 12 isolates plasma from patients receiving triple therapy. Mutations associated with resistance to Viramune ® , developing during treatment, are shown in the table below:

 

Mutation Frequency
K101E 2
K103N 8
V106A 2
Y181C 5
G190A 6

These data from INCAS study show that the use of highly active modes of drug therapy is accompanied by slowing down the development of resistance to antiretroviral drugs.

The clinical relevance of phenotypic and genotypic changes associated with andriol tc therapy has not been established.

Resistance in the perinatal transmission of
mutations that cause resistance to andriol tc, were found in 19% of women within 6-8 weeks after a single dose of the drug (research HIVNET 012). Among the mutations associated with resistance to andriol tc, these women most often discover K103N mutation (57%), followed by a mutation in a mixture of K103N and Y181C (19%). In re-examination after 12-24 months after birth mutations associated with resistance to andriol tc, were not detected in 11 women (all of these patients mutations were detected in 6-8 weeks). NVP resistance was detected in 46% of infected newborns (HIVNET 012 study).The most frequently detected Y181C mutation. Among all of those newborns (n = 7), whose mutations were found in the age of 6-8 weeks, when re-examination at the age of 12 months mutations associated with resistance to andriol tc, were identified. The clinical significance of these findings and their impact on the subsequent treatment with an NNRTI is not clear.

Cross-resistance. In the in vitro studies have established the rapid emergence of HIV strains that have cross-resistance to NNRTIs. Data on cross-resistance between the NNRTI andriol tc and representative nucleoside reverse transcriptase inhibitors are very limited. In in vitro studies have demonstrated that ZDV-resistant isolates were obtained from four patients were susceptible to andriol tc, and that are resistant to andriol tc isolates obtained from six patients were susceptible to ZDV and ddl. Cross-resistance between andriol tc and HIV protease inhibitors is unlikely because of differences involved fermentov- “targets”.

Cross-resistance among the currently registered to NNRTIs widespread. Some genotypic studies suggests that in case of failure of an NNRTI in most of these patients revealed virus strains, characterized by cross-resistance to other drugs of this group. Currently available data indicate a consistent application of the unreasonableness of different NNRTIs.

Pharmacokinetics

Adults
andriol tc is good (> 90%) absorbed after oral administration. The absolute bioavailability after administration of a single dose of the drug were as follows: for tablets containing 50 mg, 93 ± 9% (mean ± SD), and for the solution (ingestion) 91 ± 8%. Peak plasma concentrations of andriol tc following a single dose of the drug at a dose of 200 mg was achieved through 4 was 2 hour, and 0.4 ug / ml (7.5 mM). After repeated administration of the drug in doses of 200 to 400 mg / day of andriol tc peak concentrations increased linearly with dose quantities. Basal andriol tc concentrations during steady state pharmacokinetics with 400 mg per day was 4.5 ± 1.9 pg / ml (17 ± 7 mM).

Meal or antacid drugs, the dosage form comprising an alkaline buffer (for example, didanosine), the absorption of andriol tc is not affected.

andriol tc is highly lipophilic and practically not ionized at physiological pH. andriol tc good crosses the placental barrier and is determined in breast milk. Binding of NVP plasma protein is about 60%, and its plasma concentration range from 1 to 10 micrograms / ml. andriol tc concentrations in the cerebrospinal fluid in humans are 45% (± 5%) of concentration in plasma; this ratio is roughly equivalent to the fraction of the drug is not bound to plasma proteins.

andriol tc is extensively biotransformed by metabolism (oxidation reaction) with the participation of cytochrome P450 to several hydroxylated metabolites. The oxidative metabolism of andriol tc is carried out mainly by cytochrome P450 isozymes from the family of CYP3A, may play a complementary role and other isoenzymes. According to the results of pharmacokinetic studies deduced approximately 91.4 ± 10.5% isotopically labeled dose, preferably (81,3 ± 11,1%) in urine, and to a lesser extent (10,1 ± 1,5%), the feces . More than 80% of the radiolabel found in the urine was associated with conjugates of hydroxylated metabolites glucuronides. Thus, the main route of andriol tc biotransformation and excretion in human metabolism is a cytochrome P450, and conjugation to glucuronide metabolites excretion associated with glucuronides in urine. Only a small fraction (<5%) of radioactivity in the urine (which corresponded to <3% of the total dose) was associated with the unmodified compound, ie, renal excretion plays a minor role in the removal of andriol tc.

It is shown that andriol tc is an inducer of cytochrome P450 metabolic enzymes in the liver. If, after receiving a single dose treatment is continued for 2-4 weeks (receiving 200-400 mg / day), the pharmacokinetic performance characterized by auto-induction: the apparent oral clearance of andriol tc increased by about 1.5-2 times. Autoinduction also leads to a corresponding reduction in the final phase of the half-life of plasma andriol tc: approximately 45 hours (single dose) to about 25-30 hours (after repeated administration of the drug in doses of 200-400 mg / day).

Although women andriol tc volume distribution (correction in relation to the body weight) was slightly higher than in men, no significant differences in plasma andriol tc concentrations (after single or multiple dosing) depending on the sex was noted. The pharmacokinetics of andriol tc in HIV-1 infected adult patients apparently does not change depending on the age (range 18-68 years) or race (Negroid, or Hispanic caucasian race). This information is obtained from the evaluation of the combined data of several clinical studies.

Insufficiency of kidney function. The comparison figures pharmacokinetics after a single dose of the drug Viramune ® in patients with a small (50 <creatinine clearance <80 mL / min), moderate (30 <creatinine clearance <50 mL / min) or significant renal dysfunction (creatinine clearance < 30 ml / min), have been reported with kidney disease or end-stage renal failure requiring dialysis and in patients with normal renal function (creatinine clearance> 80 mL / min). Renal failure (small, moderate or large) did not lead to significant changes in the pharmacokinetics of the drug Viramune ® . However, in patients with end stage renal failure requiring dialysis, during the exposure period is 1 week, there was a decrease AUC NVP 43.5%. It was also noted the accumulation of andriol tc hydroxylated metabolites in the plasma. Auxiliary andriol tc therapy with after each dialysis session an additional dose of 200 mg, could compensate for the effects of dialysis on clearance of the drug. On the other hand, patients who have a creatinine clearance of> 20 ml / min, not require matching doses Viramune ® .

Insufficiency of liver function. A comparison of pharmacokinetic parameters after a single dose of the drug Viramune ® in patients with hepatic insufficiency and in patients with normal liver function. In patients with mild to moderate impairment of liver function is not required for individual selection of doses.

However, the results of the study the pharmacokinetics of the patients with moderate ascites indicate the possibility of accumulating andriol tc in the systemic circulation in patients with significant hepatic impairment.

Pregnant women. The study shows that during childbirth in HIV-1-infected women the half-life of the drug Viramune ® (after a single oral dose of 200 mg) is extended (60-70 hours) and the clearance varies considerably (2 1 ± 1,5 liters / h), which depends on the physiological stress during childbirth. andriol tc is rapidly crosses the placental barrier. andriol tc concentrations in blood after administration of umbilical cord mothers dose is 200 mg, greater than 100 ng / ml, and the ratio of the concentrations in the umbilical cord blood and maternal blood was 0,84 ± 0,19 (n = 36; range 0.37 -1.22).

Mothers who breastfeed their babies. It is recommended to avoid the risk of postnatal transmission of HIV to HIV-infected mothers do not resort to breastfeeding infants. Results from two pharmacokinetic studies showed that Viramune ® easily crosses the placenta and can be found in breast milk. The ACTG 250 study, conducted the study of breast milk samples obtained from HIV-1-infected pregnant after a single dose of Viramune inside ® at a dose of 100 mg or 200 mg (mean time to delivery was 5.8 hours). It was found that the average ratio of the concentrations of Viramune ® in breast milk and in the blood serum of mothers was 76% (54-104%). In HIVNET 006 study showed that after a single oral administration of the drug at a dose of 200 mg average ratio of concentrations in breast milk and in maternal plasma was 60.5% (25-122%).

Pharmacokinetics in children

Newborn. In infants (born to HIV-1-infected women, once treated with andriol tc 200 mg during labor) that within 72 hours after delivery received Viramune suspension ® oral dose of 2 mg / kg, the geometric mean value of the half-life period andriol tc was 47 hours. Levels in plasma during the first weeks of life is more than 100 ng / ml.

The pharmacokinetics of andriol tc has been studied in two open-label studies in children with HIV-1 infection in age from 9 months to 14 years who received a single dose of andriol tc suspension (7.5 mg, 30 mg or 120 mg per m2) in the morning, on an empty stomach. The value of AUC and peak concentration increased in proportion to dose andriol tc. After its absorption of andriol tc (expressed logarithmically) plasma concentrations decreased linearly with time. The final phase half-life after a single dose of andriol tc was 30,6 ± 10,2 hours.

In a study using multiple andriol tc (in suspension or tablets at a dose of 240-400 mg / m2 / day), the drug used as monotherapy or in combination with ZDV or ZDV and ddl in 37 HIV-1 infected children aged 2 months to 15 years. These patients received andriol tc in a dose of 120 mg / m2 / day for about 4 weeks, and subsequently – 120 mg / m2, 2 times a day (patients older than 9 years) or at a dose of 200 mg / m2 of 2 times per day ( patients up to 9 years old). The clearance of andriol tc, based on the body weight reached maximum values in children aged 1 to 2 years, and then decreased with increasing age. Clearance andriol tc, based on body weight in children under age 8 was approximately twice as high as in adults. The half-life of andriol tc for the entire group of patients as a whole (after the period of steady state pharmacokinetics) was 25,9 ± 9,6 hours. With increasing duration of use of the drug average terminal half-life of andriol tc phase changed with age as follows: from 2 months to 1 year – 32 hours, from 1 year to 4 years – 21 hours, from 4 to 8 years -18 hours over 8 years – 28 hours.

Indications
Treatment of HIV infection in combination with other antiretroviral drugs used to treat HIV-1 infection. In monotherapy Viramune ® fast and almost always there are resistant strains of the virus. Therefore Viramune ® should always be used in combination with at least two other antiretroviral drugs.

To prevent transmission of HIV-1 from mother to baby, pregnant, who do not receive antiretroviral therapy during childbirth, Viramune ® shows and can be used in the mother as a single agent, in the form of a single dose taken inside during the birth, and the child also as a single dose, administered orally after birth. In order to minimize the risk of transmission of HIV-1 child combination therapy recommended in the mother before giving birth, in those cases where it is possible.

Contraindications
Viramune ® is contraindicated in patients with clinically significant hypersensitivity to the active ingredient or to any component of the drug.

Viramune ® should not be administered to patients with severe liver dysfunction, or in the case of the initial increase in the level of AST or ALT more than 5 times the upper limit of normal, as long as the value of AST / ALT will not decrease (stable) to a level that does not exceed upper limit of normal in 5 times.

Viramune ® should not be re-used in patients who took its cancellation due to severe rash, rash accompanied by general symptoms, hypersensitivity reactions and the development of symptomatic hepatitis, caused by andriol tc.

Viramune ® should not be re-administered to patients who have previously, in the course of therapy with andriol tc was an increase in AST or ALT levels above the upper limit of normal for more than 5 times, or for patients who, after repeated use of andriol tc noted the resumption of liver dysfunction.

Pregnancy and lactation
High-grade well-controlled studies of treatment in HIV-1-infected pregnant women has not yet been carried out. Viramune ® should be used during pregnancy only when the potential benefit outweighs the potential risk to the fetus.

Safety and efficacy of Viramune ® , used to prevent the transmission of HIV-1 from mother to child, set in the case of the drug as part of treatment regimen that included a single oral dose of 200 mg of the mother during labor, and oral administration of a single dose of 2 mg / kg the newborn within 72 hours after birth.

In accordance with the recommendation that HIV-infected mothers should not breast-feed newborns (to avoid the risk of postnatal transmission of HIV), mothers who receive Viramune ® , should stop breastfeeding.

Dosing and Administration
Inside.

Adults: The recommended dose Viramune ® : one tablet of 200 mg daily for the first 14 days (use this initial period necessary since found that this decreases rash frequency) and subsequently one tablet 200 mg, 2 times a day in combination with at least two additional antiretroviral agents. In the case of combination therapy is necessary to follow the rules of dosing and monitoring by the manufacturer.

Children: The recommended dose Viramune ® for ingestion in children aged 2 months to 8 years of age is 4mg / kg once a day for two weeks, and subsequently 7 mg / kg two times a day. For patients aged 8 years and above the recommended dose is 4 mg / kg once a day for two weeks, and subsequently to 4 mg / kg, 2 times a day. The total daily dose for any patient can not exceed 400 mg.

General recommendations. Patients should be informed of the need to take Viramune ® daily, as it is prescribed. In the case of missing of the drug the patient should not double the next dose, it should be as soon as possible to take another dose.
Before you start taking Viramune ® and at appropriate intervals during therapy biochemical studies should be carried out, including liver function tests.

Patients who during the initial 14-day period of daily dosing at 200 mg per day the rash is noted, should not increase the dose up to until rash disappears.

Patients with an interrupted receive Viramune ® for more than 7 days, at the resumption of therapy must again use the recommended application mode, that is, to take the drug at a dose of 200 mg (children 4 mg / kg / day) once daily (initial period) and then one tablet of 200 mg twice a day (children 4 or 7 mg / kg, 2 times a day, depending on age).

. Preventing the transmission of HIV from mother to child
is recommended that the following dosing regimen for pregnant women and their newborn children: Dosage mothers: 200 mg single dose as soon as possible after the onset of labor. Dosing of the newborn: a single administration orally 2 mg / kg within 72 hours of birth. If the mother received Viramune ® in less than two hours before giving birth, the newborn must enter a first dose of Viramune ® (2 mg / kg) immediately after birth, and the second dose (2 mg / kg) – within 24-72 hours after the first.

Side effect

In adults,
skin rash and changes in liver function.

The most frequently reported during all clinical trials adverse events related to therapy were nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain, and myalgia. In very rare cases – anemia and neutropenia. In rare cases, patients treated with Viramune ® as part of treatment regimens, arthralgia was reported as a single adverse event.

Experience of application showed that the most serious side effects include Stevens-Johnson syndrome, toxic epidermal necrolysis, serious hepatitis / hepatic failure and hypersensitivity syndrome characterized by rash, general symptoms (such as fever, arthralgia, myalgia and limfadenopaimya) and signs of internal organ involvement ( such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction). The critical period during which requires careful monitoring, are the first 18 weeks of treatment.

Skin and subcutaneous tissues
The most common clinical signs of toxicity Viramune ® is a rash. Legitimate or life-threatening skin reactions occur in about 2% (see. Table 1). These include Stevens-Johnson syndrome (SS) and, rarely, toxic epidermal necrolysis (TEN), which occur most commonly during the first six weeks of therapy. The total frequency of SSc, according to data obtained from 2861 patients who took andriol tc in clinical trials was 0.3% (9/2861).

The rash occurs in isolation or as part of a hypersensitivity syndrome characterized by common symptoms (such as fever, arthralgia, myalgia and lymphadenopathy) and signs of internal organ involvement (such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction). Reported deaths SSD, TEN and hypersensitivity syndrome.

Table 1. The risk of rash (%) in adult patients who participated in placebo-controlled studies, 1.2 , during 52 weeks of treatment, 3 (regardless of causality)

Viramune ® Placebo
n = 1374
%
n = 1331
%
Rash all grades 4 24.0 14.9
Gradation 3 or 4 4 1.7 0.2

1 Study 1090: Background therapy included 3TC for all patients and combinations of NRTIs and PIs 2 Research 1037, 1038 and 1046: Background therapy included ZDV and ZDV + ddl; some patients as monotherapy used Viramune ® 3 Interest is calculated on the basis of probability estimates obtained using the Kaplan-Meier method 4 System gradations NCI

 

The rash is usually mild or moderately expressed, is characterized by erythematous maculopapular elements, accompanied or not by itching, localized on the trunk, face and extremities. It was reported about allergic reactions (including anaphylaxis, angioedema and urticaria). Rash (any grade) most often develops within the first 6 weeks of treatment.

Hepatobiliary reactions
include changes in laboratory parameters most commonly observed increase in liver function tests, including ALT, AST, GGT, total bilirubin and alkaline phosphatase. Most often it observed asymptomatic increase of GGT. It reported cases of jaundice. In patients treated with andriol tc, reported cases of hepatitis, a significant and life-threatening hepatotoxicity, and fatal fulminant hepatitis. According to clinical studies, the risk of clinical Hepatitis reactions in patients treated with Viramune ® , to one year of treatment is about 2 times higher than the risk of the use of a placebo. As a group, where used Viramune ® , and in the control group, with the greatest risk of undesired reactions Hepatitis associated increase in AST or ALT and / or seropositivity against hepatitis B and / or C. Hepatitis Risk reactions in patients without evidence of hepatitis B and / C in the treatment or Viramune ® was less than 2% over 1 year. The critical period which requires close monitoring, are the first 18 weeks of treatment. The greatest risk of Hepatitis violations observed during the first 6 weeks of therapy. However, this risk is stored and subsequently, so frequent monitoring should be continued throughout the entire treatment period.

Symptomatic hepatitis can be isolated or accompanied by a rash and / or general symptoms.

children

Safety was evaluated in HIV-1-infected children aged from 3 days to 19 years. The majority of these patients received Viramune ® in combination with ZDV and ddl, or ZDV + ddl (two studies). In the open-label trial BI 882 (ACTG 180) patients were followed for a mean of 33.9 months (from 6.8 months to 5.3 years, including long-term monitoring phase of the BI 892 study). The study ACTG 245 (double-blind, placebo-controlled study) patients, whose average age was 7 years (range 10 months to 19 years) treated with combination therapy, including Viramune ®, for at least 48 weeks at a dose of 120 mg / m2 once per day for two weeks, and subsequently 120 mg / m2 of 2 times a day.

The most frequently reported adverse events associated with Viramune ® , were similar to the adverse reactions seen in adults, with the exception of granulocytopenia, which is more common in children.Two patients treated in these studies, Viramune ® , developed SSD or syndrome, the transition between the syndrome Stevens-Johnson and toxic epidermal necrolysis. After the abolition of Viramune ® this complication in both patients was quiet.

Prevention of vertical transmission

Safety Viramune ® , is applied once in a dose of 200 mg (two doses in one study) in HIV-infected pregnant women at the onset of labor and newborns during the first 72 hours of life [single injection of a suspension of 2 mg / kg (6 mg one study)] was evaluated in more than 950 pairs (mother-child) in a randomized, controlled clinical trials. Observation of newborns after application of a single dose lasts from 6 weeks to 18 months. These studies established a similar low incidence of adverse events in the group, which was used Viramune ® , and in the control groups. Serious dermatologic reactions or Hepatitis, which would be regarded as being associated with Viramune ® , was not observed in mothers or neonates.

Thus, in the treatment of drug Viramune ® can expect the following side reactions:

  • rash (including severe and life-threatening skin reactions, including fatal cases SSD / TEN)
  • hypersensitivity syndrome characterized by rash, general symptoms (fever, arthralgias, myalgias, and swollen lymph nodes), as well as one or more of the following manifestations: hepatitis, eosinophilia, granulocytopenia, renal dysfunction (also reported about other signs of internal organ damage)
  • changes in liver function tests (AST, ALT, GGT, total bilirubin, alkaline phosphatase)
  • jaundice
  • hepatitis, including serious and life-threatening hepatotoxicity, and fatal fulminant hepatitis
  • nausea
  • fatiguability
  • fever
  • headache
  • vomiting
  • diarrhea
  • abdominal pain
  • myalgia
  • arthralgia
  • granulocytopenia
  • allergic reactions (anaphylaxis, angioedema, urticaria)
  • anemia.

Overdose
Antidote to address overdose are not available. Reported cases of overdoses Viramune ® (reception from 800 to 6000 mg per day for 15 days). Patients were observed edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, increase in transaminases and weight loss. After discontinuation of the drug all of these events stopped.

Interactions with other drugs
shown that Viramune ® is an inductor-metabolizing enzymes of the cytochrome P450 liver (CYP3A, CYP2B) and may lead to a decrease in plasma concentrations of other simultaneously applied drugs that are extensively metabolized by CYP3A or CYP2B (see. “Pharmacokinetics” section ). Therefore, if a patient who has previously been selected dosing regimen of a drug is metabolized via CYP3A or CYB2B, begins treatment with Viramune ® , you may need to correct dose of this drug.

Nucleoside analogues. In the case of simultaneous use of andriol tc with zidovudine, didanosine, or zalcitabine andriol tc dose adjustment is required. The analysis data on the use of AZT in HIV-1 infected patients (n = 11), andriol tc (400 mg / day) in combination with zidovudine (100-200 mg 3 times a day), it is found that andriol tc resulted in insignificant decrease (28%) of the area under the curve “concentration-time» (AUC) of zidovudine and insignificant decrease (30%) the Cmax of zidovudine, while there was a significant variation in both parameters. Pairwise comparison method data showed that AZT does not appear to have any effect on the pharmacokinetics of andriol tc. In a crossover study found that andriol tc had no effect on the pharmacokinetics (in its steady state phase), didanosine (n = 18) or zalcitabine (n = 6).

Results of 28-day study in HIV-infected patients (n = 22) who used Viramune ® , nelfinavir (750 mg three times a day) and stavudine (30-40 mg twice a day), showed no statistically significant changes in AUC or Cmax of stavudine. In addition, population pharmacokinetic study of 90 patients administered together with lamivudine Viramune ® or placebo was found no change in apparent clearance and volume of distribution of lamivudine, indicating no induction effect Viramune ® for lamivudine clearance.

Non-nucleoside analogues. The results of the clinical study (n = 23) showed that the pharmacokinetics of indicators (in the phase of its steady state) of andriol tc have not changed, while the use of efavirenz. However, the concentration of efavirenz in the presence of andriol tc was significantly decreased. AUC of efavirenz decreased by 28% and Cmin by 32%. With simultaneous use of andriol tc and efavirenz may need to increase the dose of the latter to 800 mg (once a day).

. Protease inhibitors In the following studies Viramune ® was applied at a dose of 200 mg once a day for two weeks and for 14 or more successive days – 200 mg 2 times a day.

Saquinavir. The results of the clinical trial in HIV-infected patients (n = 23), andriol tc and saquinavir (hard gelatin capsule, 600 mg three times a day), have shown that the simultaneous use of these drugs has led to a decrease in the average value AUC saquinavir 38% and it did not affect significantly on the plasma levels of andriol tc. The clinical significance of this interaction is not known, but it is possible that may require increased doses of saquinavir. In another study (n = 20) evaluated the use of saquinavir (Soft gelatin capsule once a day) together with ritonavir (100 mg). All patients concurrently received NVP. This study showed that the combination of saquinavir (soft gelatin capsules) and ritonavir 100 mg had no significant effect on the pharmacokinetics of andriol tc. Effect on the pharmacokinetics of andriol tc, saquinavir (Soft gelatine capsules) ritonavir in the presence of 100 mg regarded as clinically insignificant and weak.

Ritonavir. In the case of joint use of Viramune ® with ritonavir correction mode is not required. Results of clinical studies in HIV-infected patients (n = 25) treated with andriol tc and ritonavir (600 mg twice daily, using a mode of gradual dose escalation), showed no significant changes in concentrations of ritonavir or andriol tc plasma.

. Indinavir A clinical study in HIV-infected patients (n = 19) treated with NVP and indinavir (800 mg every 8 hours), have shown that the simultaneous use of these drugs leads to a decrease in the average values of indinavir AUC 31%; andriol tc concentrations were not significantly changed in the plasma. There are no specific clinical findings on the potential mutual influence of both an andriol tc and indinavir has not been done. In the case of indinavir together with andriol tc in a dose of 200 mg twice a day, should be considered to increase the dose of 1000 mg of Indinavir (every 8 hours). However, there is currently no firm opinion that the short-term or long-term antiviral activity of indinavir 1000 mg (every 8 hours), used in conjunction with andriol tc 200 mg twice a day, will be different from indinavir effect at a dose of 800 mg ( every 8 hours) and andriol tc in a dose of 200 mg twice a day.

Nelfinavir. The results of the 28-day study in HIV-infected patients (n = 23) treated with Viramune ® and nelfinavir (750 mg three times a day), showed no statistically significant changes in the pharmacokinetics of nelfinavir after adding Viramune ® . Concentration Viramune ® , apparently also did not change.
However, in respect of the main metabolite nelfinavir, M8, which has a comparable activity with a basic compound, found a decrease of mean values AUC by 62%, Cmax by 59% and 66% Cmin. Adequate (the safety and efficacy) nelfinavir dosage for use in combination with andriol tc not yet been established.

Lopinavir / ritonavir. andriol tc, used in combination with lopinavir / ritonavir 400/100 mg (3 capsules) 2 times a day, leading to a decrease in the average values of lopinavir AUC by 27% and reduced Cmax and Cmin of 22% and 55%, respectively. For use in combination with andriol tc is recommended to increase the dose of lopinavir / ritonavir to 533/133 mg 2 times a day (4 capsules), reception with food.The results of pharmacokinetic studies in children have shown that concentrations of lopinavir by combining it with andriol tc reduced. When used in combination with andriol tc (in cases where there is clinical suspicion, based on the results of previous treatment or laboratory data) should be considered an increase in the dose of lopinavir / ritonavir (in children aged 6 months to 12 years) to 13 / 3.25 mg / kg in children weighing from 7 to <15 kg to 11 / 2.75 mg / kg for children weighing 15 to 45 kg and the maximum dose component 533/133 mg, in children weighing more than 45 kg; receiving two times a day.
When using any of andriol tc protease inhibitors specific safety concerns arose.

Ketoconazole. Application andriol tc (200 mg twice daily) together with ketoconazole (400 mg once daily) resulted in a significant reduction in median AUC for ketoconazole and 63% decrease in median Cmax of ketoconazole by 40%. In the same study it was found that ketoconazole resulted in an increase of 15-28% in the plasma concentration of NVP and NVP ketoconazole should not be used together.The effects of andriol tc on the pharmacokinetics of itraconazole are not known.

Fluconazole. Concomitant use of fluconazole and andriol tc resulted in increased exposure to andriol tc, approximately 100% (compared to previous studies, where andriol tc was used as a single agent).In the case of simultaneous application of these drugs is accompanied by the risk of increased exposure to andriol tc, caution should be exercised and patients carefully observed. No clinically significant effect of andriol tc on fluconazole were observed.

Anticoagulants. The observed in vitro interaction between andriol tc and the anticoagulant warfarin is complex. The interaction in the case of joint use of these drugs, warfarin plasma concentration may vary so that there is a risk of increase or decrease in clotting time. The net effect of this interaction may change during the first weeks of the simultaneous use of drugs, or after the cancellation of andriol tc. In the case of simultaneous use of warfarin and andriol tc needed frequent monitoring of prothrombin time.

Inducers of CYP isoenzymes

Rifampin. In the open-label study (n = 14) in the study of the effect of Viramune ® on the pharmacokinetics (phase steady state) rifampicin shown no significant changes Cmaxi AUC of rifampicin. In contrast, rifampicin significantly reduces the AUC (-58%), Cmax ( -50%) and Cmin (-68%) andriol tc compared with the original data. Therefore, rifampicin and andriol tc should not be used simultaneously. If necessary, treatment of mycobacterial infections in patients treated with andriol tc, you should consider the use of rifabutin instead of rifampicin.

Rifabutin. Application andriol tc (200 mg twice a day) in conjunction with rifabutin (300 mg 1 time per day, or, in the case of simultaneous application zdovudina or protease inhibitors, 150 mg 1 time per day) resulted in misleading change rifabutin concentrations (increasing the median rifabutin AUC and 12% decrease in median Cminss rifabutin 3%) and a significant increase in median Cmaxss 20%. No significant changes of concentrations of the active metabolite 25-O-desacetyl rifabutin not established. There was considerable inter-individual variability of the results. Some patients showed a significant increase in the concentrations of rifabutin, which may expose them to a higher risk of toxicity. The same study shows that the use of rifabutin resulted in obvious and significant increase in systemic clearance of andriol tc (by 9% compared to the control). However, none of these changes in the median value was not considered clinically significant.
It is not recommended to use simultaneously Viramune ® tinctures St. John (tincture Hypericum perforatum) or St. individual ingredients tinctures John, as follows from the data on the interaction St. John’s wort tincture with other antiretroviral agents. It is assumed that the combined use of non-nucleoside reverse transcriptase inhibitors (NNRTIs), including Viramune ® , St. tincture John and reduces the concentration of NNRTIs, leading to sub-optimal levels of Viramune ® , may cause loss of virologic effect and resistance to Viramune ® or to the entire class of NNRTIs.

Inhibitors of the isoenzyme CYP. The results of studying the interaction of andriol tc and clarithromycin (n = 18) showed that there is significant reduction in AUC (30%), Cmax (-21%) and O ™ (-46%) of clarithromycin, but a significant increase in both AUC ( 58%) and Cmax (62%) of its active metabolite, 14-OH clarithromycin. There was a significant increase in Cmin (28%) and andriol tc nonsignificant increase its AUC (26%) and Cmax (24%). These data suggest that while the use of these drugs are any changes of dosing is required. However, when treating a patient with an infection caused by Mycobacterium complex avium-intracellulare, should be considered the appointment of an alternative drug as the active metabolite of clarithromycin in this case is not effective.
In the subpopulation analysis conducted in patients treated with Viramune ® in clinical studies, it was shown that basal andriol tc plasma concentrations (during the steady-state pharmacokinetics) were elevated in patients who received cimetidine (+ 7%, n = 13).

. Oral contraceptives andriol tc (200 mg twice daily) was used in conjunction with birth control pills (Ortho-Novum is ® 1/35), containing ethinyl estradiol (Eel; 0,035 mg) and noretidron (NaN; 1.0 mg), taken once inside . In comparison with plasma concentrations set to andriol tc, median AUC 17alpha-ethinylestradiol 28 days andriol tc significantly decreased (by 29%). It was also observed a significant decrease in the average values of the circulation time and half-life of ethinyl estradiol. It installs a significant reduction (18%) of the median AUC NaN (with no change of average values circulation time or half-life). The extent of these changes may indicate a need to adjust the dose of oral contraceptive use if it is not the purpose of contraception, and for other reasons (e.g., to treat endometriosis), if used together with andriol tc. However, the use of oral contraceptives containing estrogen / progesterone, there is also risk of ineffective contraception. In the appointment of andriol tc to women having the ability to conceive, it is recommended to use other methods of contraception (eg barrier). In the case of patients receiving andriol tc, oral contraceptives for other medical indications, need control of their therapeutic effect.

Other information
Studies in vitro using human liver microsomes revealed that the formation of hydroxylated metabolites in the presence of andriol tc dapsone, rifabutin, rifampin, and trimethoprim / sulfamethoxazole is not changed. Ketoconazole and erythromycin significantly inhibited the formation of andriol tc hydroxylated metabolites. Clinical studies in this respect is not yet carried out.
It will be appreciated that in the case of simultaneous application of Viramune ® other compounds that are substrates for CYP3A or CYP2B6, may reduce their concentrations in plasma.

Taking into account the known data on the metabolism of methadone, it is possible that andriol tc may decrease plasma concentrations of methadone by increasing its hepatic metabolism. It reported on the development of drug withdrawal in patients receiving both Viramune ® and methadone. Patients receiving methadone to replace the drugs, when they started andriol tc should be monitored carefully for early detection of withdrawal and the corresponding correction of the dose of methadone.

Cautions
critical importance are the first 18 weeks of therapy with andriol tc. During this period, patients require careful monitoring to detect possible serious and life-threatening skin reactions (including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis) or serious hepatitis / hepatic failure. The greatest risk of Hepatitis and dermatological reactions exists in the first 6 weeks of therapy. The risk of adverse effects from the liver increased in women and in patients with higher CD4 cell counts. You must strictly adhere to the recommended regimen, especially during the initial 14-day period.

The reactions of the skin
in patients receiving Viramune ® , observed serious and life-threatening dermatological reactions, including fatalities. There were cases of Stevens-Johnson syndrome (DSS), toxic epidermal necrolysis (TEN), and hypersensitivity syndrome characterized by rash, general reactions and visceral. Careful monitoring of patients during the first 18 weeks of treatment. Careful supervision is required in the case of an isolated rash. Viramune ® should be canceled in any patient in case of severe rash or rash accompanied by general symptoms (fever, blistering, changes in the mouth, conjunctivitis, facial edema, pain in the joints or muscles, malaise), and Stevens-Johnson syndrome or toxic epidermal necrolysis. Viramune ® should be discontinued in any patient in case of hypersensitivity reactions, characterized by rash and general symptoms, as well as visceral changes, including hepatitis, eosinophilia, granulocytopenia, and renal dysfunction, or other signs of internal organ involvement (see. “Section Side effect”).

Patients should report that the main manifestation of toxicity of Viramune ® is a rash. It must be used the initial period of treatment since found that it reduces the frequency of rash (see. “Dosage and application” section). In most cases, the rash associated with taking Viramune ® , occurs in the first six weeks of therapy. Therefore, it is during this period, patients should be carefully monitored in dermatological reactions. Patients should be advised that in the event of any rash during the treatment period, the initial dose should not be increased as long as rash disappears.

It is shown that the simultaneous use of prednisone (40 mg / day for the first 14 days of Viramune ® ) did not reduce the incidence of rash, but rather may become more frequent dermatological response over the first 6 weeks of therapy.

Among the risk factors for severe skin reactions include violation of the recommendations on the use of the drug at a dose of 200 mg per day for an initial period of therapy. The risk of more serious outcomes of dermatological reactions increases in the case of delay in seeking medical advice after the onset of symptoms. The risk of rash in women apparently larger than in men, as in the case of Viramune ® , therapy and not containing Viramune ® .

Patients who develop severe rash or rash accompanied by general symptoms (fever, blistering, changes in the mouth, conjunctivitis, facial edema, pain in the joints or muscles, malaise), should stop taking the drug and consult a doctor. Repeated use of Viramune ® in these patients is not allowed. If the patient has a rash and is suspected connection with taking Viramune ® , should be a study of liver function.In patients with moderate or severe impairment (AST or ALT levels above the upper limit of normal for more than 5 times), Viramune ® should byb canceled.
In case of hypersensitivity reactions characterized by rash, accompanied by general symptoms (fever, arthralgia, myalgia and lymphadenopathy) combined with signs of internal organ involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction, andriol tc should be repealed; re-use of andriol tc is not allowed.

The reactions of the liver
in patients treated with andriol tc, there are serious or life-threatening hepatotoxicity, including fatal fulminant hepatitis. The critical importance are the first 18 weeks of treatment, during which careful monitoring. The highest risk of reaction on the part of the liver observed in the first 6 weeks of therapy. Increased risk of adverse reactions observed in Hepatitis women and patients with higher CD4 cell counts. This risk persists in the future, so frequent monitoring should continue throughout the entire treatment. Patients should be informed that from the reaction of the liver is the main view of the toxicity of Viramune ® and the appearance of signs indicating the development of hepatitis, should be cause for immediate consultation with a physician.

On a serious hepatotoxicity, including hepatic failure requiring liver transplantation was reported when using multiple doses of Viramune ® for the purpose of post-exposure prophylaxis of individuals who were not infected with HIV, which is not among the approved indications for the use of this drug.

A higher risk of adverse reactions from the liver at the time of any antiretroviral therapy, including during application modes that include Viramune ® , indicated for the initial increase in the levels of AST or ALT more than 2.5 times compared to the upper limit of normal and / or in the presence of hepatitis B and / or C. risk of hepatitis reactions associated with a rash, women appear to three times higher than in men (4.6% vs. 1.5%). Risk of Hepatitis reactions associated with a rash in the treatment of Viramune ® , can also be higher in patients with a higher number of CD4 cells. According to a retrospective analysis, a number of women with more than 250 CD4 cells cells / mm3, the risk of Hepatitis reactions associated with rash was 9 times higher than in women with the number of CD4 cells than 250 cells / mm3 (8.4% vs. from 0.9%). The increased risk was observed in men with CD4 cell counts> 400 cells / mm3 compared to men with CD4 cell counts <400 cells / mm3 (4.5% versus 0.7%).

Monitoring liver state

When using Viramune ® was informed of changes in liver function, sometimes occurring in the first week of therapy. Asymptomatic increase in liver enzymes is described frequently and is not an absolute contraindication to the use of Viramune ® . Asymptomatic increase of gamma-glutamyl transferase is not a contraindication to continue therapy.

It recommended strict control of the liver function at short intervals, depending on the clinical condition of patients, particularly during the first 18 weeks of treatment. Clinical and laboratory monitoring should continue throughout the entire treatment period Viramune ® . Physicians and patients should be wary of such prodromal signs or symptoms of hepatitis, as anorexia, nausea, jaundice, bilirubinemia, aholichny stools, hepatomegaly or liver tenderness. Patients should be informed of the need to seek medical advice in such cases.

In the case of an increase in AST or ALT more than 2.5 times as compared to the upper limit of normal before or during treatment, liver function tests should be checked more frequently during regular clinic visits. Viramune ® should not be administered to patients who have baseline AST or ALT more than 5 times the upper limit of normal (as long as it does not fall steadily to levels less than 5 times the ULN).

If AST or ALT levels increase to more than 5 times the ULN during treatment, Viramune ® should be immediately repealed. If the level of AST and ALT levels returned to baseline values and if the patient does not experience any clinical signs or symptoms of hepatitis, common symptoms or other phenomena that indicate dysfunction of internal organs, the use of Viramune ® may be resumed (if there is a clinical need). This decision should be taken in each case, based on clinical considerations. Reappointment Viramune ® should be administered under conditions of increased clinical and laboratory vigilance, at an initial dose of 200 mg / day (14 days), with its subsequent increase to 400 mg / day. If liver function abnormalities are renewed, andriol tc should be permanently canceled.

If there is a hepatitis accompanied by such clinical symptoms as anorexia, nausea, vomiting, jaundice, and laboratory abnormalities (moderate or significant changes in liver function, excluding GGT), andriol tc must be permanently revoked. Viramune ® should not be reappointed to those patients who have required its abolition as a result of the development of symptomatic hepatitis, caused by andriol tc.

More warnings
in the case of Viramune ® in combination with other antiretroviral agents and reported on the development of these adverse reactions, as pancreatitis, peripheral neuropathy and thrombocytopenia. These phenomena are often associated with other antiretroviral agents. Their appearance can be expected when using Viramune ® in combination with other drugs; Probability of these reactions with the use of andriol tc is small.

In patients receiving Viramune ® or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore, such patients should remain under close clinical supervision of physicians experienced in the treatment of diseases associated with HIV infection. Data on the ability of Viramune ® to reduce the risk of horizontal transmission of HIV-1 to others are not available.

Despite the fact that the ability to Viramune ® to prevent the transmission of HIV-1 from mother to child is set (in women not receiving other antiretroviral drugs), to minimize the possibility of transmission of HIV-1 child, we recommend more intensive treatment of the mother before giving birth to the use of antiretroviral drug combinations ( when it’s possible).

Viramune ® is extensively metabolized by the liver and andriol tc metabolites derived mainly kidneys. The results of pharmacokinetic studies point to the need to observe caution when assigning Viramune ®in patients with moderate hepatic dysfunction. Viramune ® should not be administered to patients with significant hepatic impairment. A pharmacokinetic study conducted in patients with impaired renal function who were on dialysis, showed that adjuvant therapy Viramune ® with the addition of a dose of 200 mg after each dialysis session can help compensate for the effects of dialysis on clearance of Viramune ® . Thus, patients with a creatinine clearance of 20 ml / min change dosing Viramune ® is required.

In women taking Viramune ® , should not be used as the primary method of contraception, oral contraceptives and other hormonal methods, because andriol tc can reduce the concentration of these drugs in the plasma. Furthermore, in the case of treatment during Viramune ® oral contraceptive purposes in hormonal regulation, requires monitoring of therapeutic effect of the hormonal treatment.

Existing data from pharmacokinetic studies indicate the unreasonableness of the simultaneous use of rifampicin and andriol tc. If necessary, concomitant treatment of tuberculosis in patients receiving therapy regimen containing andriol tc, may be considered the use of rifabutin. Rifabutin and andriol tc can be used together without dosage changes.

Effects on ability to drive vehicles and management mechanisms
Special studies on the ability to drive vehicles and management mechanisms are not carried out.

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