VYRAMUN (Suspension)

Active material: Nevirapine
When ATH: J05AG01
CCF: Viricide, active against HIV
ICD-10 codes (testimony): B24
When CSF: 09.01.04.01.02
Manufacturer: BOEHRINGER INGELHEIM INTERNATIONAL GmbH (Germany)

Pharmaceutical form, composition and packaging

Oral suspension white or nearly white, uniform; allowed separation, which is easily resuspended by shaking.

Excipients: karʙomer, polysorbate 80, sorbitol 70%, sucrose, metilparagidroksiʙenzoat, propilparagidroksibenzoat, Sodium hydroxide, Purified water.

240 ml – plastic bottles (1) complete with a measured plastic syringe and extra cover – packs cardboard.

Pharmacological action

Viricide. Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) HIV-1. Nevirapine 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 nevirapine does not compete with or nucleoside triphosphates matrix. Nevirapine inhibits the reverse transcriptase of HIV-2 and DNA polymerase of eukaryotic cells (such as DNA polymerase α, b, или c d).

The relationship between the sensitivity of HIV-1 to Viramune^® in vitro and inhibition of HIV-1 replication in humans has not been established.

Antiviral activity of nevirapine in vitro was evaluated on peripheral blood mononuclear cells, macrophages and monocytic origin lymphoblastic cell lines. Znaçenïya case₅₀ (inhibitory concentration) laboratory and clinical isolates of HIV-1 ranged from 10 to 100 nmol. In cell culture show, The activity against HIV-1 NVP, used in combination with zidovudine, didanozinom, lamivudine, stavudine, saquinavir and indinavir, had an additive or synergistic.

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

Studies Phase I / II for from 1 to ≥12 weeks were monitored phenotypic and genotypic changes in HIV-1 isolates, isolated from patients, receiving Viramune^® (n=24) or Viramune^® in combination with AZT (n=14).

After Viramune monotherapy^® during 1 week reduced susceptibility to nevirapine in vitro was observed in isolates, isolated from 3/3 patients. Some patients (the earliest – through 2 weeks after start of therapy) I detected one or more mutations in RT, in 103, 106, 108, 181, 188 and 190 amino acid positions. By the eighth week monotherapy Viramune^® in all patients (n=24) HIV isolates were identified, whose sensitivity to nevirapine in vitro was reduced by more than 100 times compared with the original and detected by one or more mutations of the gene RT, associated with resistance to nevirapine. In 80% patients were isolated isolates with mutations in positions 181, irrespective of dose.

Combination therapy Viramune^® + Zidovudine has not changed the frequency of virus, resistant to nevirapine, or the degree of nevirapine resistance in vitro. However, in these cases, there is a different type of mutation, mainly arising 103, 106, 188 and 190 amino acid positions. Patients (in 6 from 14) with baseline isolates, RT had the wild-type gene, Combination therapy Viramune^® + zidovudine delayed the emergence of zidovudine is not resistant mutations RT.

The study INCAS genotypic and phenotypic resistance was evaluated in patients, receiving Viramune^® composed of double and triple combination therapy, and in the control group, not receiving Viramune^®. Patients, who have not received antiretroviral therapy (the number of CD4 cells in their 200-600 / mm³), were treated with Viramune^® + zidovudine (n=46), zidovudine + didanosine (n=51) or Viramune^® + zidovudine + didanosine (n=51); observation was carried out for 52 weeks of treatment or more. Virological examination was performed at baseline, through 6 and 12 months. Methods used to estimate phenotypic resistance required for amplification of the virus presence, least, 1000 copies / mL of HIV RNA. IN 3 studied groups of patients were identified baseline isolates, available for research. These patients were treated for, at least, 24 weeks. Initially it noted five cases of phenotypic resistance to nevirapine; The IC₅₀ three of them grew in 5-6.5 time, and two – more than 100 time. Through 24 week all isolates, who succeeded in isolating patients, receiving Viramune^®, They were resistant to this drug. Through 30-60 Weeks like isolates were from 86% patients. Viral suppression below the limit of detection was achieved in 16 patients (less 20 copies / ml – in 14, less 400 copies / ml – in 2). When using the assumption, that suppression below 20 copies / mL indicates the sensitivity of the virus to the drug Viramune^®, It was found (by direct or indirect estimation), sensitivity to the drug persisted in 45% patients. All patients, receiving Viramune^® + zidovudine and testirovavshiesya presence of resistances fenotipicheskoy, through 6 months were resistant to Viramune^®. Over the entire period of observation has a single case of resistance to didanosine. Resistance to AZT occurs more frequently through 30-60 weeks, especially in patients, receiving double combination therapy. Based on an increase in IC₅₀, It was found, that there is resistance to zidovudine, apparently, rarely patients, receiving Viramune^® + zidovudine + didanosine, than those of other treatment groups. In terms of resistance to Viramune^® It was shown, that all isolates were obtained, least, one mutation, associated with resistance. The most common single changes were subjected K103N and Y181C. Thus, the use of highly active modes of drug therapy is accompanied by slowing down the development of resistance to antiretroviral drugs. Genotipы, correlated with phenotypic resistance to Viramune^®, identified in 12 izolyatov, isolated from plasma of patients, receiving triple therapy. Mutations, associated with resistance to Viramune^®, developing during treatment, are shown in Table:

This data, obtained in the study INCAS, 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 significance of phenotypic and genotypic changes, associated with nevirapine therapy, is not installed.

Mutations, conditional resistant to nevirapine, They have been found in 19% for women 6-8 weeks after a single dose of the drug (Study HIVNET 012). Among the mutations, associated with resistance to nevirapine, these women most frequently detected K103N mutation (57%), Further mutation K103N and Y181C mixture (19%). During re-examination by 12-24 months after delivery mutations, associated with resistance to nevirapine, It was not detected in 11 Women (all of these patients mutations were detected through 6-8 weeks). Resistance to nevirapine was found in 46% infected infants (Study HIVNET 012). The most frequently detected mutation Y181C. Among all those newborns (n=7), whose mutations were found in the age 6-8 weeks, the re-examination at the age of 12 months mutations, associated with resistance to nevirapine, It has been identified. The clinical significance of these findings and their impact on the subsequent treatment with NNRTIs are not clear.

In in vitro studies found rapid emergence of HIV strains, are cross-resistant to NNRTIs. Data on cross-resistance between the NNRTI nevirapine and representative nucleoside reverse transcriptase inhibitors are very limited. In in vitro studies show, that zidovudine-resistant isolates, obtained from four patients, They were susceptible to nevirapine, and that isolates resistant to nevirapine, obtained from six patients, They were susceptible to zidovudine and didanosine. Cross-resistance between nevirapine and HIV protease inhibitors is unlikely because of differences involved fermentov-“targets”.

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

Pharmacokinetics

Adult

Absorption

After oral administration of nevirapine is rapidly absorbed (more 90%). After receiving a single dose of the drug 200 mg C_max Nevirapine plasma levels achieved through 4 h and was 2 ± 0.4 pg / ml (7.5 mmol). In exchange application of the drug in a dose range 200-400 mg / day there was a linear increase in C_max nevirapine in plasma.

Eating, antacids and other medications, containing an alkaline buffering component (eg, didanosine), It has no effect on the absorption of nevirapine.

Distribution

At concentrations in plasma 1-10 ug / ml plasma protein binding is 60%.

C_ss^min achieved while taking the drug at a dose of 400 mg / day was 4.5 ± 1.9 pg / ml (17± 7mkmol); This ratio approximately corresponds to the fraction of the drug, is not bound to plasma proteins.

Nevirapine is a lipophilic substance and substantially not ionized at physiological pH. In humans, the concentration of nevirapine in the cerebrospinal fluid is 45%(±5%) of plasma concentration.

Studies show, during childbirth in HIV-infected women T_1/2 nevirapine after a single oral dose 200 mg to udlynyaetsya 60-70 no, and clearance varies considerably (2.1± 1.5 l /), that depends on the physiological stress during childbirth. Nevirapine is rapidly crosses the placental barrier. Nevirapine concentrations in cord blood after administration of the drug at a dose of mother 200 mg exceeded 100 ng / ml, and the ratio of concentrations in umbilical cord blood and maternal blood was 0.84 ± 0.19 (n=36; range 0.37-1.22).

The results of the two pharmacokinetic studies showed, that nevirapine readily crosses the placental barrier and can be detected in breast milk. The study ACTG 250 conducted the study samples of breast milk, obtained from HIV-1-infected pregnant after a single dose of Viramune inside^® dose 100 mg or 200 mg (the average time before the birth was 5.8 no). Established, the average ratio of the concentrations of nevirapine in breast milk and in maternal serum was 76% (54-104%). The study HIVNET 006 shows, after a single oral dose of the drug 200 mg average ratio of concentrations in breast milk and maternal plasma was 60.5% (25-122%).

Metabolism and excretion

Nevirapine is actively biotransformed in the liver, with the participation of cytochrome P450 isoenzymes (oxidation) with the formation of several hydroxylated metabolites. The oxidation process is carried out mainly nevirapine isoenzyme CYP3A, although other isozymes may play an additional role in the metabolism of the drug.

The main route of nevirapine biotransformation and elimination in humans is in the metabolism involving the cytochrome P450, conjugation to glucuronide metabolites and excretion, related glucuronides, urine. Only a small proportion of (<5%) radioactivity in urine (corresponded <3% of the total dose) It was associated with the unmodified compound, ie, renal excretion plays a minor role in the removal of nevirapine.

It has been shown, that nevirapine is able to induce cytochrome P450 isoenzymes. Pharmacokinetic inductance is characterized by approximately 1.5-2-fold increase in the apparent clearance of nevirapine while taking the drug inside of 200 mg 2 times / day for 2-4 week compared with dosing of the drug at this dose once. Self-inductance also result in a corresponding reduction of the final T_1/2 c 45 h while taking the drug once before 25-30 h at course taking the drug at a dose of 200-400 mg / day.

Pharmacokinetics in special clinical situations

The pharmacokinetic parameters of Viramune^® HIV-1-infected patients, apparently, not vary depending on the age (range 18-68 years) or ethnicity (Negroid, caucasian).

V_d slightly higher in women, than men, but when taking the drug Rewritable no significant gender-related differences in concentrations of nevirapine were found.

A comparison of pharmacokinetic parameters after a single dose of the drug Viramune^® in patients with renal insufficiency, mild (CC 50-80 ml / min), moderate (CC 30-50 ml / min) and severe (CC less than 30 ml / min), notes in renal disease or end-stage renal failure, requiring dialysis, and in patients with normal renal function (QC more 80 ml / min). In renal failure of varying severity were observed 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 in the AUC of nevirapine 43.5%. It was also accumulation of nevirapine hydroxylated metabolites in plasma. Adjuvant therapy with the use of nevirapine following each dialysis additional dose, component 200 mg, would compensate for the effects of dialysis on clearance of the drug. On the other hand, Patients, CC which is more 20 ml / min, do not require the selection of doses of Viramune^®.

In patients with mild to moderate impairment of liver function does not require individual selection of doses. However, the results of a study of the pharmacokinetics in patients with moderate / severe ascites indicate the possibility of accumulation of nevirapine in the systemic circulation in patients with significant hepatic impairment.

Children

Newborns (born to HIV-1-infected women, single dose nevirapine 200 mg during labor), which for 72 h after birth received Viramune^® in the form of suspensions for oral dose 2 mg / kg, Average T_1/2 nevirapine was 47 no. Concentrations in plasma during the first week of life were more 100 ng / ml. The pharmacokinetics of nevirapine has been studied in two open-label studies in children aged from 9 Months before 14 s against HIV-1 infection, who received a single dose of nevirapine suspension (7.5 mg, 30 mg or 120 mg / m²) morning, fasting. Величина AUC и C_max increased in proportion to dose nevirapine. After absorption of nevirapine plasma concentrations (expressed logarithmically) decreased linearly with time. The final phase T_1/2 after a single dose of nevirapine was 30.6 ± 10.2 hours.

In a study with repeated use of nevirapine (in the form of suspensions or tablets at a dose 240-400 mg / m²/d) the drug was used as monotherapy or in combination with zidovudine or AZT + didanosine in 37 HIV-1-infected children aged 2 Months before 15 years. These patients received a dose of nevirapine 120 mg / m²/day for about 4 weeks, and subsequently – dose 120 mg / m² 2 times / day (Patients older 9 years) or in a dose of 200 mg / m² 2 times / day (Patients up 9 years). The clearance of nevirapine based on the weight of the body reaches a maximum value at children between the ages of 1 Year to 2 years, and then decreases with increasing age. The clearance of nevirapine in terms of body weight in children under 8 years has been approximately 2 times, than in adults. T_1/2 nevirapine for the whole group of patients in general (after reaching the equilibrium state pharmacokinetics) was 25.9 ± 9.6 hours. With increasing duration of use of the drug the mean terminal phase T_1/2 NVP varies with age as follows:: from 2 Months before 1 year – 32 no, from 1 Year to 4 years – 21 no, from 4 to 8 years – 18 no, senior 8 years – 28 no.

Testimony

- The treatment of HIV infection in combination with other antiretroviral agents, is used to treat HIV-1 infection (monotherapy drug Viramune^® quickly and almost always arise-resistant strains of the virus, therefore Viramune^® It should always be used in combination, at least, with two other antiretroviral drugs);

- To prevent the transmission of HIV-1 from mother to child, in pregnant women, who do not receive antiretroviral therapy during childbirth. Vyramun^® It is shown and can be used in the mother as monotherapy in a single dose, Ingest during childbirth, and the child, also as a single dose, entered into after birth. For, to minimize the risk of transmission of HIV-1 child, recommended that a combination therapy of the mother before birth, where, whenever possible.

Dosage regimen

Adults in the initial period of the drug is prescribed in a dose 200 mg 1 times / day daily for the first 14 days (found, that at such a dosage regimen decreases the incidence of rash), then increase the dose to 200 mg 2 times / day every day (in combination with at least two additional antiretrovirals). In the case of combination therapy must follow the rules of dispensing and monitoring, the manufacturer.

Children aged 2 Months before 8 years the drug is prescribed in a dose 4 mg / kg body weight 1 time / day during the first 14 days, then 7 mg / kg body weight 2 times / day. The recommended dose for children 8 and older is 4 mg / kg 1 time / day during the first 14 days, then 4 mg / kg 2 times / day.

The maximum daily dose for patients of all ages 400 mg.

To prevention of HIV transmission from mother to child recommend a single dose of Viramune^® pregnant women during childbirth (as soon as possible after the onset of labor) dose 200 mg followed by a single oral administration to newborn during 72 hours after birth in a dose of 2 mg / kg body weight. If the mother took Viramune^® less than 2 hours before delivery, the newborn must enter the first dose (2 mg / kg) immediately after birth, and the second dose (2 mg / kg) – during 24-72 hours after the first.

Patients should be informed of the need to take Viramune^® daily so, as it is prescribed. In the case of the admission of the drug the patient should not double the next dose, should as soon as possible to take the next dose. Before you start taking Viramune^® and at appropriate intervals during therapy should be performed biochemical studies, incl. liver function tests.

Patients, in which during the initial 14-day period of daily administration of the drug at a dose 200 mg / day is celebrated rash, We should not increase the dose until, until the rash disappears.

Patients, interrupt a receive Viramune^® for more than 7 days, when resuming therapy must again use the recommended dosing regimen: taking the drug at a dose of 200 mg (in children – 4 mg / kg / day) 1 time / day (the initial period), and then 200 mg 2 times / day (in children – 4 mg / kg or 7 mg / kg 2 times / day, depending on the age).

Side effect

In Adult

Most often in the course of clinical studies AEs, associated with therapy Viramune^®, were nausea, fatiguability, fever, headache, vomiting, diarrhea, abdominal pain, and myalgia; rarely – anemia and neutropenia.

IN Rare cases patients, receiving Viramune^® consisting regimens, reported arthralgia, as the only adverse event.

Experience has shown the use of, the most serious side effects is Stevens-Johnson, toxic epidermal necrolysis, serious hepatitis / hepatic failure and hypersensitivity syndrome, characterized by rash, common symptoms (fever, artralgii, myalgia and lymphadenopathy) and symptoms of internal organ involvement (hepatitis, eozinofilija, granulocytopenia, and renal dysfunction). The critical period, during which requires close monitoring, They are the first 18 weeks of treatment.

Dermatological reactions

The most common clinical signs of toxicity Viramune^® a rash.

Serious or life-threatening skin reactions occur in about 2%. These include Stevens-Johnson syndrome and, less often, toxic epidermal necrolysis, which occur most frequently during the first 6 weeks of therapy. The overall incidence of Stevens-Johnson syndrome, according to, obtained from 2861 patients, taking nevirapine in clinical trials, made 0.3% (9/2861).

The rash occurs in isolation or as part of a hypersensitivity syndrome, characterized by common symptoms (fever, artralgii, myalgia and lymphadenopathy) and signs of internal organ involvement (hepatitis, eozinofilija, granulocytopenia, and renal dysfunction). Reported deaths Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity syndrome.

The rash is usually mild to moderate expressed, It characterized by papular erythematous maculo-elements, accompanied or not by itching, localized on the trunk, face and extremities. Allergic reactions have been reported (including anaphylaxis, angioedema and urticaria). Rash (any severity) often develops in the first 6 weeks of treatment.

Adverse reactions of the liver

Among the changes in laboratory parameters most frequently observed increase in liver function tests, including ALT, ACT, GGT, total bilirubin and alkaline phosphatase. Most often observed asymptomatic increase of GGT. Reported cases of jaundice. Patients, poluchavshih nevirapine, reported cases of hepatitis, significant and life-threatening hepatotoxicity, and fatal fulminant hepatitis. According to clinical studies, the risk of clinical reactions of the liver in patients, taking Viramune^®, to 1 year of treatment is about 2 times higher than the risk with placebo. As a group, where I used Viramune^®, and in the control group, with the highest risk of reactions in the liver associated increase in ACT or ALT and / or seropositivity against hepatitis B and / or C. The risk of side reactions with the liver in patients without evidence of hepatitis B and / or C in the treatment Viramune^® during 1 It totaled less 2%.

The critical period, which requires close monitoring, They are the first 18 weeks of treatment. The greatest risk of hepatic reactions from the notes in the first 6 weeks of therapy. However, this risk is stored and subsequently, therefore, frequent monitoring should continue throughout the treatment period.

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

In children

Safety was assessed in HIV-1 infected children from 3 days before 19 years. The majority of these patients received Viramune^® in combination with AZT or ddI, or zidovudine + didanosine (2 research). In the open-label study BI 882 (ACTG 180) patients were followed for an average of 33.9 Months (from 6.8 Months before 5.3 years, including long-term monitoring phase of the study BI 892). The study ACTG 245 (double-blind, placebo-controlled study) Patients, average age of 7 years (from 10 Months before 19 years), combination therapy, incl. Vyramun^® during, least, 48 week dose 120 mg / m² 1 time / day for two weeks, and subsequently 120 mg / m² 2 times / day. The most frequently reported adverse events, associated with Viramune^®, were similar to the adverse reactions, seen in adults, except granulocytopenia, which is more common in children. Two patients, treated in these studies, Viramune^®, developed Stevens-Johnson syndrome or syndrome, the transition between the Stevens-Johnson syndrome and toxic epidermal necrolysis. After the cancellation of Viramune^®and this complication in patients undergoing both.

Security Viramune^®, to apply a single dose 200 mg (Two doses of one study) HIV-infected pregnant women in early labor, and newborns during the first 72 hours of life (introducing the slurry in a single dose 2 mg / kg (6 mg in one study)), estimated at more than 950 couple (mother-child) randomized, controlled clinical trials. Newborn care after application of a single dose of the continued 6 weeks before 18 Months. These studies established similar low incidence of adverse events in the group, where I used Viramune^®, and in the control groups. Severe dermatologic reactions or reactions of the liver, that would be regarded as being associated with Viramune^®, not observed in mothers, audio neonates. Thus, in the treatment of drug Viramune^® You can expect the following adverse reactions:

-syp (incl. serious and life-threatening skin reactions, including fatal cases of Stevens-Johnson syndrome and toxic epidermal necrolysis);

-sindrom hypersensitivity, characterized by rash, common symptoms (fever, artralgii, myalgia and lymphadenopathy), as well as one or more of the following symptoms (hepatitis, eozinofilija, granulocytopenia, renal dysfunction, also informed about other signs of internal organs);

• Changes in liver function tests (ACT, GOLD, GGT, total bilirubin, shtelochnaya phosphatase);

-zheltuha, hepatitis (incl. serious and life-threatening hepatotoxicity, and fatal fulminant hepatitis);

-toshnota, vomiting, diarrhea, abdominal pain;

-headache, fatiguability;

-lihoradka, mialgii, artralgii;

-granulotsitopeniya, anemia;

-allergicheskie reaction (anaphylaxis, angioedema, hives).

Contraindications

- A clinically significant increase in sensitivity to nevirapine or any other component of the drug.

The drug is not prescribed for severe liver dysfunction, or in the case of the original increase the ACT or ALT more than 5 times the ULN, until, while the value of AST / ALT levels will not drop (stably) up to the level, which does not exceed the ULN in 5 time. Viramune should not be administered to patients again, who earlier in the course of therapy with nevirapine was an increase in the level of ACT or ALT, greater than ULN over 5 time, or patients, which after repeated use of nevirapine noted the resumption of liver dysfunction.

The drug should not be given repeatedly to patients, who took it as a result of the abolition of severe rash (incl. accompanied by common symptoms), hypersensitivity reactions and the development of symptomatic hepatitis, caused by nevirapine.

Pregnancy and lactation

Full-controlled trials of Viramune^® HIV-1-infected pregnant women has not yet been conducted. Vyramun^® It should be used during pregnancy only if, 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, It is set in the case of the drug in the composition regimen, which included a single oral dose 200 mg of the mother during childbirth, and oral administration of a single dose of 2 mg / kg body weight for the newborn 72 hours after birth.

In accordance with the recommendation, that HIV-infected mothers should not breastfeed newborns (to avoid the risk of postnatal transmission of HIV), mother, receiving therapy Viramune^®, You should stop breast-feeding.

Cautions

It should be taken into account, the first 18 weeks of treatment with Viramune^® It is an important period, requires careful monitoring of patients for timely detection of possible severe and life-threatening skin reactions (incl. Stevens-Johnson syndrome, toxic epidermal necrolysis), expressed hepatitis or hepatic insufficiency. The greatest risk of hepatotoxic and dermatological reactions exist in the first 6 weeks of therapy. The risk of adverse effects from the liver is increased in women and patients with higher CD4 cell count. During the initial 14-day period, special attention should be paid to the careful observance of dosage regimen.

Patients, receiving Viramune^®, marked a serious and life-threatening dermatological reactions, incl. Fatal. There were cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity syndrome, which was characterized by a rash, general reactions and visceral. Careful monitoring of patients during the first 18 weeks of treatment. Monitoring is required in the case of an isolated rash. Vyramun^® It must be revoked in any patient in the case of severe rash or rash, accompanied by common symptoms (fever, blistering, changes in the mouth, conjunctivitis, swelling of the face, pain in the joints or muscles, general malaise), at Stevens-Johnson syndrome or toxic epidermal necrolysis. Vyramun^® It should be abolished in any patient in the event of hypersensitivity reactions, characterized by rash and general symptoms, as well as changes in internal organs (incl. hepatitis, eozinofilii, granulocytopenia, and renal dysfunction) or other signs of internal organ involvement.

Patients should report, that the main manifestation of toxicity of Viramune^® a rash. In appointing the drug dosing regimen should be used, recommended for the initial treatment period, tk. found, it reduces the incidence of rash. In most cases, rash, associated with taking Viramune^®, It occurs in the first 6 weeks of therapy. Therefore, it is during this period should be carefully monitored in patients dermatological reactions. Patients should be informed about, that in the case of any rash during the initial treatment period the dose should not be increased until, until the rash disappears.

Displaying, Concurrent use of prednisone (40 mg / day, during the first 14 days of Viramune^®) It does not reduce the incidence of rash, and, opposite, dermatologic reactions may become more frequent during the first 6 weeks of therapy.

Among the risk factors for developing serious cutaneous reactions include violation of the recommendations on the use of the drug at a dose of 200 mg / 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, longer than men, in the case of Viramune^®, and therapy, not containing Viramune^®.

Patient, which occurs severe rash or rash, accompanied by common symptoms (fever, blistering, changes in the mouth, conjunctivitis, swelling of the face, pain in the joints or muscles, general malaise), should stop taking the drug and consult your doctor. Repeated use of Viramune^® these patients are not allowed.

If the patient has a rash and is suspected to communicate with the reception Viramune^®, It should be investigated liver function. In patients with moderate or severe impaired (ACT or ALT greater than ULN over 5 time), Vyramun^® should be abolished.

In case of hypersensitivity reactions, characterized by rash, which is accompanied by general symptoms (fever, artralgii, myalgia and lymphadenopathy) combined with signs of internal organ involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction, nevirapine should be abolished; re-use of nevirapine is not allowed.

Patients, treated with nevirapine, It marked a serious or life-threatening hepatotoxicity, including fatal fulminant hepatitis. The critical importance are the first 18 weeks of treatment, during which requires careful monitoring. The highest risk of reactions from 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 count. This risk is stored and subsequently, therefore, frequent monitoring should continue throughout treatment. Patients should be informed about, that the reaction of the liver toxicity is the main type of Viramune^® and the appearance of symptoms, pointing to the development of hepatitis, It should be cause for immediate consultation with a doctor.

On a serious hepatotoxicity, including the development of liver failure, requiring liver transplantation, It reported using multiple doses of Viramune^® for the purpose of post-exposure prophylaxis of persons, that were not infected with HIV, that is not among the approved indications for use of the drug. A higher risk of adverse reactions from the liver at the time of any antiretroviral therapy, incl. and during the application of the regime, including Viramune^®, marked increase in the initial levels of ACT or ALT more than 2.5 times compared to the ULN and / or in the presence of hepatitis B and / or C. The risk of hepatotoxic reactions, associated with a rash, female, apparently, in 3 times higher, than men (4.6% compared to 1.5%). The risk of hepatotoxic reactions, rash associated with the treatment of Viramune^®, It may also be higher in patients with higher CD4 cell count. According to a retrospective analysis of women with a CD4 cell count 250 cells / mm³, the risk of hepatotoxic reactions, associated with a rash, I was in 9 times higher, than women with CD4 cell count less 250 cells / mm³ (8.4% compared to 0.9%). The increased risk was observed in men with CD4 cells more 400 cells / mm³ compared with men with a CD4 cell count of less than 400 cells / mm³ (4.5% compared to 0.7%).

When using Viramune^® reported changes in liver function tests, sometimes arise in the first weeks of therapy. Asymptomatic liver enzyme elevations often described and is not an absolute contraindication to the use of Viramune^®. Asymptomatic elevations of GGT is not a contraindication to continue therapy. It is recommended that strict control of liver function tests at short intervals, depending on the clinical condition of the patient, especially during the first 18 weeks of treatment. Clinical and laboratory monitoring should continue throughout the period of treatment Viramune^®. Physicians and patients should be wary of prodromal symptoms of hepatitis such as anorexia, nausea, jaundice, bilirubinemia, aholichny chair, hepatomegaly or liver tenderness. Patients should be informed of the need to seek medical advice in such cases.

In the case of increasing or ALT ACT more than 2.5 times compared to the ULN before or during treatment, liver function tests should be monitored more frequently during regular clinic visits. Vyramun^® should not be administered to patients, in which the reference level or ALT ACT more than 5 times the ULN (until, it is stably reduced to a level not less than 5 times the ULN).

If ACT and ALT exceed by more than 5 times ULN during treatment, Vyramun^® It should be immediately abolished. If ACT 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, indicating dysfunction of internal organs, the use of Viramune^® It can be resumed (if there is a clinical need). This decision should be taken in each individual case, the clinical situation. Reappointment Viramune^® It should be carried out under conditions of high clinical suspicion and laboratory, at an initial dose 200 mg / day (during 14 days), with its subsequent increase to 400 mg / day. If abnormal liver function renewed, nevirapine should be permanently canceled.

If there hepatitis, are accompanied by clinical symptoms, anorexia, nausea, vomiting, jaundice, and laboratory disorders (moderate or significant changes in liver function tests, excluding GGT), nevirapine should be permanently revoked. Vyramun^® should not be administered to those patients again, who took it as a result of the cancellation of clinical hepatitis, caused by nevirapine.

In the case of Viramune^® in combination with other antiretroviral agents and reported on the development of adverse reactions, as pancreatitis, perifericheskaya 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 nevirapine is low.

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 doctors, with experience in the treatment of diseases, associated with HIV infection. Data on the ability of Viramune^® reduce the risk of horizontal transmission of HIV-1 to others not available.

Despite, the ability of Viramune^® to prevent transmission of HIV-1 from mother to child is set (female, not receiving other antiretrovirals), to minimize the possibility of transmission of HIV-1 child, It recommends more intensive treatment of the mother before birth using combinations of antiretroviral drugs (where possible).

Vyramun^® It is extensively metabolized in the liver, and nevirapine metabolites derived mainly kidneys. The results of pharmacokinetic studies indicate the need for caution in the appointment of Viramune^® in patients with moderate hepatic dysfunction. Vyramun^® It should not be administered to patients with significant hepatic impairment.

Pharmacokinetic studies, conducted in patients with impaired renal function, were on hemodialysis, shown, that adjuvant therapy Viramune^® adding dose, component 200 mg, after each dialysis session can help compensate for the effects of dialysis on clearance of Viramune^®. Thus, in patients with CC more 20 ml / min change dosing Viramune^® not required.

Women, receiving Viramune^®, should not be used as the main method of contraception, oral contraceptives and other hormonal methods, t.k.nevirapin can reduce the concentration of these drugs in plasma.

Besides, when used during therapy Viramune^® oral contraceptives in order to hormonal regulation, necessary to monitor the therapeutic effect of hormonal treatment.

Existing data pharmacokinetic studies indicate inappropriateness simultaneous use of rifampicin and nevirapine. If necessary, concomitant treatment of TB patients, receiving therapy with nevirapine, It may consider using rifabutin. Rifabutin and nevirapine can be used together without dosage changes.

Effects on ability to drive vehicles and management mechanisms

Special studies on the effect of the drug on the ability to drive the car and machinery has not been.

Overdose

Symptoms: There are reported cases of overdose when using Viramune^® daily dose 800-6000 mg and the duration of treatment up 15 days. Patients were observed swelling, uzlovataya эritema, fatiguability, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, dizziness, vomiting, increase in transaminases and weight loss. After discontinuation marked regression of all symptoms.

Treatment: removal of the drug. Antidote unknown.

Drug Interactions

Displaying, that Viramune^® способен индуцировать изоферменты CYP3A и CYP2B, perhaps as a result of a decrease in plasma concentrations of drugs, It is applied in combination therapy, which is extensively metabolized with them. Therefore, while the appointment with Viramune^® preparations, метаболизирующихся CYP3A и CYP2B, may require correction of the dose.

Nucleoside analogues

Not applicable clinically significant interactions between Viramune^® and nucleoside analogues (zidovudine, didanosine, zalьcitabin), so you do not want to change the dosing regimen with concomitant administration of Viramune^® with these drugs. The analysis data on the use of AZT in HIV-1 infected patients (n=11), poluchavshih nevirapine (400 mg / day) in combination with AZT (100-200 mg 3 times / day), found, that nevirapine resulted in a reduction of unreliability (on 28%) AUC of zidovudine and insignificant decrease (on 30%) FROM_max Zidovudine, At the same time, there was considerable variability in both parameters. The method of paired comparison data showed, Zidovudine does not appear to have any effect on the pharmacokinetics of nevirapine. In a crossover study found, that nevirapine had no effect on the pharmacokinetics (at equilibrium) didanozina (n=18) or zalcitabine (n=6). The results of the 28-day study in HIV-infected patients (n=22), which was used Viramune^®, Nelfinavir (750 mg 3 times / day) and stavudine (30-40 mg 2 times / day), showed no statistically significant changes in AUC or C_max Stavudine. Besides, in a population pharmacokinetic study 90 patients, which lamivudine was administered together with Viramune^® or placebo, it was found no change in apparent clearance and volume of distribution of lamivudine, indicating no induction effect Viramune^® on the clearance of lamivudine.

Non-nucleoside analogues

Results of a clinical study (n=23) shown, that the pharmacokinetics (at equilibrium) Nevirapine has not changed, while the use of efavirenz. However, the concentration of efavirenz in the presence of nevirapine was significantly reduced. AUC of efavirenz decreased by 28%, and C_min – on 32%. With simultaneous use of nevirapine and efavirenz may need to increase the dose to the last 800 mg (1 time / day).

Protease inhibitors

In the following studies, Viramune^® was applied at a dose 200 mg 1 time / day for two weeks, and in a dose 200 mg 2 times / day – during 14 or more consecutive days.

Results of clinical studies in HIV-infected patients (n=23), poluchavshih nevirapine and saquinavir (600 mg 3 times / day), shown, that the simultaneous use of these drugs has led to reduction in the mean AUC values ​​for saquinavir 38% and it does not significantly affect the levels of nevirapine in plasma. The clinical significance of this interaction is unknown, but not excluded, that may require increased doses of saquinavir. In another study (n=20) evaluated the use of saquinavir co-administered with ritonavir (100 mg). All patients received both nevirapine. This study showed, The combination of ritonavir and saquinavir dose 100 mg had no significant effect on the pharmacokinetics of nevirapine. The influence on the pharmacokinetics of nevirapine in the presence of saquinavir ritonavir dose 100 mg regarded as weak and clinically insignificant.

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), prinimavshih nevirapine and ritonavir (600 mg 2 times / day with gradual dose escalation mode), showed no significant changes in the concentration of ritonavir or nevirapine plasma.

In clinical trials,, during which HIV-infected patients received Viramune^® and indinavir (800 mg every 8 no), It shows a decrease in indinavir AUC on average 31%; Nevirapine concentrations in plasma were not significantly changed. There are no specific clinical findings on the potential mutual influence both nevirapine and indinavir is applied has not been made. In the case of indinavir together with nevirapine in a dose of 200 mg 2 times / day should be considered to increase the dose of indinavir 1000 mg (every 8 no). However, there is currently no firm opinion about, Short-term or long-term antiviral activity of indinavir at a dose of 1000 mg (every 8 no), used with a dose of nevirapine 200 mg 2 times / day, It will differ from the effect of a dose of Indinavir 800 mg (every 8 no) and a dose of nevirapine 200 mg 2 times / day.

The results of the 28-day study in HIV-infected patients (n=23), taking Viramune^® and nelfinavir (750 mg 3 times / day), showed no statistically significant changes in the pharmacokinetics of nelfinavir after adding Viramune^®. The concentration of Viramune^®, apparently, not changed. However, in respect of the main metabolite of nelfinavir (M8), that has comparable activity with a basic compound, It found a decrease in the mean values ​​for AUC 62%, FROM_max on 59% and C_min on 66%. Adequate (with respect to safety and efficacy) nelfinavir dose for use in combination with nevirapine has not been established.

Nevirapine, used in combination with lopinavir / ritonavir 400/100 mg 2 times / day, It leads to a decrease of mean values ​​for AUC of lopinavir 27% and a decrease in C_max and C_min on 22% and 55%, respectively. For use in combination with nevirapine is recommended increasing the dose of lopinavir / ritonavir to 533/133 mg 2 times / day (reception during meal). The results of pharmacokinetic studies in children have shown, lopinavir concentrations when combined with the use of nevirapine reduced. When used in combination with nevirapine (where, when there is clinical suspicion, Based on the results of previous treatment or laboratory data) It should be considered an increase in the dose of lopinavir / ritonavir (in children between the ages of 6 months before 12 years) to 13/3.25 mg / kg for children weighing from 7 to 15 kg, to 11/2.75 mg / kg for children weighing from 15 to 45 kg to a maximum dose, component 533/133 mg, in children weighing more than 45 kg; reception 2 times / day. When using any of nevirapine protease inhibitors specific safety concerns did not arise.

Antifungals

The use of nevirapine (200 mg 2 times / day) together with ketoconazole (400 mg 1 time / day) It led to a significant decrease in median AUC for ketoconazole 63% and lower median C_max of ketoconazole 40%. In the same study it was found, that ketoconazole resulted in an increase of 15-28% Nevirapine concentrations in plasma. Ketoconazole and nevirapine should not be used together.

The impact of nevirapine on the pharmacokinetics of itraconazole is not known.

Concomitant use of fluconazole and nevirapine resulted in increased exposure to nevirapine around 100% (compared with previous studies, where nevirapine was used as monotherapy). In the case of simultaneous use of these drugs, accompanied by an increased risk of exposure to nevirapine, you must be careful and closely monitor patients. Clinically significant effect of nevirapine on fluconazole were observed.

Antykoahulyantы

The observed in vitro interaction between nevirapine and warfarin is complex. The interaction in the case of joint use of these drugs in the plasma concentration of warfarin may vary so, that there is a risk as the increase, and reduce the 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 nevirapine. In the case of simultaneous use of warfarin and nevirapine requires frequent monitoring of prothrombin time.

Индукторы изоферментов CYP

In the open-label study (n=14) the study of the effect of Viramune^® of farmakokinetiku (at equilibrium) rifampin demonstrated no significant changes in C_max и AUC рифампицина. Opposite, Rifampicin significantly reduces the AUC (on 58%), FROM_max (on 50%) and C_min (on 68%) nevirapine compared with the original data. Therefore, rifampicin and nevirapine should not be used at the same time. If necessary, the treatment of mycobacterial infections in patients, prinimayushtih nevirapine, should consider using rifabutin instead of rifampicin.

When concomitant administration of Viramune^® dose 200 mg 2 times / day and a dose of rifabutin 300 mg 4 times / day (or 150 mg 4 times / day with AZT or protease inhibitors) noted nonsignificant change in the concentrations of rifabutin (увеличение медианы AUC рифабутина на 12% and a decrease in the median C_min of rifabutin 3%) and a significant increase in median C_max on 20%. There were no significant changes in concentrations of the active metabolite, 25-O-desacetyl rifabutin, not installed. There was a large inter-individual variability of the results. Some patients showed a significant increase in the concentrations of rifabutin, which may expose them to greater risk of toxicity. The same study shows, that the use of rifabutin resulted in a significant increase explicit and systemic clearance of nevirapine (on 9% compared with the control). Nonetheless, None of these changes are median values ​​were not considered clinically significant.

When concomitant administration of Viramune^® and preparations, containing St. John's wort, may reduce the concentration below the therapeutic levels of nevirapine, that can lead to loss of efficiency and virological virus to develop resistance Viramune^®. Therefore it is not recommended to assign the same time this combination.

Inhibitors of CYP isoenzymes

The results of the study of the interaction of nevirapine and clarithromycin (n=18) shown, that there is a significant decrease in AUC (on 30%), C_max (on 21%) and C_min (on 46%) clarithromycin, but also a significant increase in AUC (on 58%) and C_max (on 62%) ego aktivnogo metabolite, 14-OH clarithromycin. There was a significant increase in C_min (on 28%) nevirapine and nonsignificant increase in its AUC (on 26%) and C_max (on 24%). These data suggest, that while the application of these drugs are any changes they do not require batching. However, when treating a patient with an infection, вызываемой комплексом Mycobacterium avium-intracellulare, It should be considered the appointment of an alternative drug, tk. active metabolite of clarithromycin is ineffective in this case.

In the subpopulation analysis, conducted in patients, receiving Viramune^® in clinical studies,, shows, that basal plasma concentrations of nevirapine (at equilibrium) It was increased in patients, prinimavshih cimetidine.

Oral contraceptives

Nevirapine (200 mg 2 times / day) It was used in conjunction with birth control pills, containing ethinyl estradiol and noretidron. In comparison with plasma concentrations of, set to nevirapine, median AUC 17α-эtinilэstradiola cherez 28 days nevirapine decreased significantly (on 29%). It was also a significant decrease in the average values ​​of the circulation time, and T_1/2 ethinyl estradiol. It was found a significant decrease (on 18%) Media AUC norétïdrona (in the absence of changes in average circulation time values ​​or T_1/2). The extent of these changes may indicate a need to adjust the dose oral contraceptive if used not for contraception, and other indications (eg, for the treatment of endometriosis), if it is used in conjunction with nevirapine. However, the use of oral contraceptives, containing estrogen / progesterone, as there is a risk ineffective contraception. Therefore, we recommend the use of other contraceptive methods (eg, bariyernykh). In the case of patients, poluchayushtih nevirapine, oral contraceptives for other medical reasons, requires monitoring of therapeutic effect.

Other interactions

In in vitro studies with liver microsomes man shows, that the formation of nevirapine hydroxylated metabolites is not broken in the presence of dapsone, rifaʙutina, rifampicin, and trimethoprim / sulfamethoxazole. Ketoconazole and erythromycin result in a significant reduction in the formation of nevirapine hydroxylated metabolites. Clinical studies have been conducted.

It should be noted, that the concentration of some other substances, являющихся субстратами CYP3A и CYP2B, when appointing them with Viramune^®, It may be reduced.

Due to the nature of metabolism of methadone, Nevirapine may reduce its concentration in the blood plasma by enhancing hepatic metabolism of methadone. Patients, treated with the combination of methadone and Viramune^®, there were cases of drug withdrawal (when using such a combination should monitor the patient's condition and to adjust the dose of methadone).

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored at a temperature no higher than 30 ° C. Shelf life – 3 year. The drug should be used for 2 months from the date of opening the bottle.