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

Lactose monohydrate 64.0 mg, microcrystalline cellulose 64.0 mg, pregelatinized starch 15.0 mg, sodium carboxymethyl starch 14.0 mg, sodium lauryl sulfate 5.0 mg, silicon dioxide colloid 3.0 mg, talc 2.0 mg, magnesium stearate 3.0 mg.

Description:

Tablets capsular form from white to almost white with engraving "NVR" on one side and risk on the other side.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.G.01 Nevirapine

Pharmacodynamics:Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Nevirapine directly binds to reverse transcriptase and blocks the activity of RNA-dependent and DNA-dependent DNA polymerase,causing the destruction of the active center of this enzyme. Nevirapine Do not compete with matrix triphosphates or nucleoside triphosphates. Nevirapine does not have a significant inhibitory effect on HIV-2 reverse transcriptase and DNA polymerase of eukaryotic cells (such as human DNA polymerases α, β, γ or δ).

Nevirapine should not be used as a monotherapy for the treatment of HIV infection or added as a single drug to existing therapy due to rapid development of virus resistance, which is characteristic of other non-nucleoside reverse transcriptase inhibitors.

Also, when choosing antiretroviral drugs for use in combination with nevirapine, the possibility of developing cross-resistance should be considered.

In the case of withdrawal of the antiretroviral therapy regimen containing nevirapine, it is necessary to keep in mind the long half-life of this drug. If antiretroviral drugs with shorter half-lives are reduced at the same time, then due to low concentrations of nevirapine that persists for a week or more, resistance to HIV can develop.

Pharmacokinetics:

Suction:

Nevirapine is well absorbed (more than 90%) in healthy volunteers and in adult patients with HIV-1 infection. Absolute bioavailability after a single admission of 50 mg of nevirapine is 93 ± 9% for tablets and 91 ± 8% for the suspension. The maximum concentration of nevirapine in plasma (Cmax = 2 ± 0.4 μg / ml (7.5 μM)) - achieved within 4 hours after a single dose of 200 mg once a single tablet. After taking multiple doses of Cmnevirapine increased linearly in the dose range from 200 to 400 mg / day. In the equilibrium state Cmah is 5.74 μg / ml (5.00-7.44), Cmin - 3.73 μg / ml (3.20-5.08) with AUC 109.0 h * μg / ml (96.0-143.5), which corresponds to an equilibrium concentration of 4.5 ± 1.9 μg / ml in patients receiving 200 mg of nevirapine twice daily.

Distribution:

Nevirapine has a high lipophilicity and is practically not ionized at physiological pH. After intravenous administration to healthy volunteers, the volume of nevirapine distribution was 1.21 ± 0.09 l / kg, indicating a broad distribution of nevirapine in the human body. Nevirapine well penetrates the placenta and is determined in breast milk. About 60% of nevirapine binds to plasma proteins at a plasma concentration of 1-10 μg / ml.Concentrations of nevirapine in human cerebrospinal fluid are 45% (± 5%) of plasma concentration; this ratio roughly corresponds to a fraction not associated with plasma proteins.

Metabolism and excretion:

In studies like in vivo, and in vitro it was shown that nevirapine is subjected to intensive biotransformation with the participation of cytochrome P450 isoenzymes (oxidative metabolism) to several hydroxylated metabolites.

It is assumed that the oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 isoenzymes from the family CYP3A, other isoenzymes may play an additional role. In a study of mass balance / elimination (in the equilibrium state with the administration of 200 mg twice daily with the subsequent administration of 50 mg of 14C-nevirapine), approximately 91.4 ± 10.5% of the isotope-labeled dose was determined in urine (81.3 ± 11.1 %), indicating the prevalent value of renal excretion in comparison with excretion through the intestine (10,1 ± 1,5%). More than 80% of 14C-nevirapine, determined in urine, consisted of conjugates of glucuronide and hydroxylated metabolites. Thus, metabolism by cytochrome P450, conjugation with glucuronide and excretion in urine are the primary pathway of biotransformation and removal of nevirapine in humans.Only a small fraction (<5%) of 14C-nevirapine in urine (corresponding to <3% of the dose) was excreted unchanged. It was shown that nevirapine is the inducer of cytochrome P450 isoenzymes. The pharmacokinetics of the autoinduction of nevirapine when administered orally as a single dose followed by a two to four week dose of 200-400 mg / day is characterized by an increase in its clearance of about 1.5-2 times. Autoinduction also results in a corresponding reduction in the terminal phase of nevirapine half-life in plasma from 45 hours (single dose) to about 25-30 hours after repeated administration of the drug at doses of 200-400 mg / day.

Renal insufficiency:

Renal failure (mild creatinine clearance 50 to 80 mL / min, mean creatinine clearance 30-50 mL / min or severe severity-creatinine clearance less than 30 mL / min) did not significantly alter the pharmacokinetics of nevirapine. However, in patients with terminal stage of renal failure requiring hemodialysis, AUC nevirapine decreased by 43.5% after a week of admission. There was also an accumulation of nevirapine hydroxymetabolites in plasma.

Auxiliary therapy with nevirapine with the use of an additional dose of 200 mg after each dialysis session could compensate for the effect of dialysis on the clearance of the drug.

Liver failure:

Nevirapine is contraindicated in patients with severe hepatic impairment (class (Child-Pugh classification).) Based on data from pharmacokinetic studies, caution should be used to prescribe nevirapine patients with hepatic insufficiency of moderate severity (class B but Child-Pugh classification).

Sex, age:

In women, nevirapine clearance was 13.8% less than the men, but the difference is not clinically significant. Body mass and body mass index (BMI) do not affect the clearance of nevirapine.

It is believed that the pharmacokinetics of nevirapine in HIV-1 infected adult patients does not change with age (in the range of 19-68 years). Special studies of the use of nevirapine in patients older than 65 years have not been conducted.

Patients of childhood:

The nevirapine's clearance increased with age, which corresponded to an increase in body surface area. The dose of nevirapine is 150 mg / m² two times a day (after an initial two-week introductory period of 150 mg / m² daily) provided average geometric values of the minimum concentration of nevirapine within 4-6 μg / ml (as planned based on the data of adult patients). Calculation of the surface area of the body is carried out according to the Mosteller formula (section "Method of application and dose").

Indications:Treatment of HIV-1 infection in combination antiretroviral therapy. To prevent the transmission of HIV-1 from mother to child in women who do not receive antiretroviral therapy during childbirth, nevirapine is shown and can be used in the mother, as a single dose, taken orally during labor.

Contraindications:

Hypersensitivity to the active ingredient or any other component of the drug.

Nevirapine should not be re-assigned to patients who had previously been treated with nevirapine for treatment because of severe rash, hypersensitivity reactions, or the development of clinically expressed hepatitis caused by taking the drug.

Severe liver function disorders (Child-Pugh class C) or cases of initial increase in activity of aspartate aminotransferase (ACT) or alanine aminotransferase (ALT), more than 5 times the upper limit of the norm, until the ACT / ALT activity decreases steadily to less than 5 times the upper limit of the norm.

Nevirapine should not be re-assigned to patients who have previously experienced an increase in activity ACT or ALT to a level more than 5 times higher than the upper limit of the norm, or to patients who, after repeated use nevirapine was marked with a renewed liver function disorder.

During the administration of nevirapine should not be used herbal preparations containing St. John's wort extract perforated (Hypericum perforatum), due to the risk of reducing plasma nevirapine and reducing its clinical effect. Nevirapine It is not recommended for use with efavirenz, rifampicin, ketoconazole, delavirdine, etravirine, rilpivirin, elvitegravir (together with cobicystate), boceprevirov, and also with fosamprenavir, saquinavir, atazanavir (when not used together with low-dose ritonavir).

Patients with rare hereditary disorders (lactose intolerance, lactase deficiency, glucose-galactose malabsorption).

Children under 16 years of age, weight less than 50 kg or body surface area less than 1.25 square meters (for this dosage form).

Carefully:

Hepatic insufficiency of mild and moderate severity.

Simultaneous therapy with telaprevir, rifabutin, warfarin, methadone, lopinavir / ritonavir, clarithromycin, fluconazole, intraconazole, ethinyl estradiol, indinavir.

Pregnancy and lactation:

In women receiving nevirapine, oral contraceptives and other hormonal methods should not be used as the only contraceptive method, since nevirapine can reduce their concentration in the plasma. For this reason, the use of barrier methods of contraception is recommended. In addition, in the case of hormonal therapy in the postmenopausal period during treatment with nevirapine, control of the therapeutic effect of hormone therapy is necessary.

The safety and efficacy of nevirapine, used to prevent the transmission of HIV-1 from mother to child, was established with the use of one 200 mg tablet once with the mother during labor.

Data obtained from pregnant women during I, II, IIIth trimesters (according to the data US Antiretroviral Pregnancy Registry), indicate a lack of fetal development or toxicity in relation to the embryo / fetus.

Special and well-controlled studies of treatment in HIV-1 infected pregnant women have not yet been conducted.

Nevirapine should be used during pregnancy only in cases where the potential benefit exceeds the potential risk to the fetus.

Application in pregnancy:

In studies it was shown that at the time of delivery in HIV-infected women, the half-life of nevirapine after single ingestion at a dose of 200 mg is prolonged (up to 60-70 hours), and the clearance significantly varies (2.1 ± 1.5 l / h), depending on the degree of physiological stress during childbirth.

Nevirapine quickly penetrates the placental barrier. The concentration of nevirapine in the blood of the umbilical cord after the mother's intake of a dose of 200 mg was more than 100 ng / ml, and the ratio of blood concentrations in the umbilical cord and in the mother's blood was 0.84 ± 0.19.

Breastfeeding period:

HIV-infected mothers should not breast-feed newborns to avoid the risk of postnatal HIV transmission.

Nevirapine freely penetrates the placenta and is found in breast milk, so women who take nevirapine, should stop breastfeeding.

Fertility:

In studies on reproductive toxicology in animals, a decrease in fertility in rats was observed.

Dosing and Administration:

Inside.

Nevirapine should be prescribed by a doctor with experience in the treatment of HIV infection. The drug should be taken only in combination with at least two additional antiretroviral drugs.

Tablets should be taken with water, do not break and do not chew. Nevirapine can be taken regardless of food intake.

The total daily dose in any patient should not exceed 400 mg.

Treatment of HIV infection:

Patients from 16 years old with a body weight of more than 50 kg or with a body surface area (PPT according to the Mosteller formula) of more than 1.25 m².

The recommended dose of nevirapine is 200 mg per day for the first 14 days of treatment (it is shown that the use of such an introductory period reduces the incidence of the rash), followed by taking 200 mg tablets twice a day in combination with at least two additional antiretroviral agents .If the patient missed taking the next dose of the drug, and after the pass was passed no more than 8 hours, you should take the missed dose as soon as possible. If from the moment passing the next dose was more than 8 hours, the patient should take only the next dose at the usual time. If skin rash develops in this period, immediately consult a doctor for advice and do not increase the dose. Children under 16 years of age with a body weight of less than 50 kg or a body surface area of less than 1.25 m²(according to the Mosteller formula).

It is recommended to use a suspension for oral administration.

Mosteller's formula: PPT(m²) =

General recommendations:

Patients who developed an eruption during the initial 14-day follow-up period of 200 mg / day should not increase the dose of nevirapine until the rash disappears. The appearance of a rash when taking nevirapine always requires close monitoring.

The dosage regimen of 200 mg per day should not be continued for more than 28 days, by this time it is necessary to select an alternative therapy in due time, in connection with the risk of development of resistance against the background of the use of insufficient doses of the drug.

Patients who discontinued taking the drug Nevirapine for more than 7 days, should begin therapy again from a two-week introductory period of 200 mg once a day.

Prevention of mother-to-child transmission of HIV-1.

To prevent the vertical transmission of HIV-1 infection during labor, a pregnant woman should receive a single tablet of 200 mg once as soon as possible after the onset of labor.

Special patient groups:

Elderly patients:

Special studies of drug use Nevirapine patients over 65 years old were not carried out.

Impaired renal function:

Patients with renal dysfunction requiring hemodialysis (CC ≤ 20 ml / min), an additional intake of 200 mg of the drug after each procedure of hemodialysis is recommended. Patients with a higher clearance clearance dosage is not required.

Impaired liver function:

Application of the drug Nevirapine contraindicated in patients with severe impairment of liver function (Child-Pugh class C). In patients with mild to moderate hepatic insufficiency, dose adjustment ns is required, but such patients need careful monitoring for registration purposes undesirable drug reactions.

Side effects:

The most common adverse events associated with nevirapine therapy were rash, allergic reactions, changes in liver function indicators, nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain and myalgia. The most serious side effects are Stevens-Johnson syndrome, toxic epidermal necrolysis, severe hepatitis / hepatic insufficiency, and hypersensitivity syndrome characterized by a rash, general symptoms (such as fever, arthralgia, myalgia and lymphadenopathy) and signs of internal damage (such as hepatitis, eosinophilia , granulocytopenia and renal dysfunction). The critical period during which careful monitoring is required is the first 18 weeks of treatment.

The following are undesirable events likely associated with nevirapine therapy, according to the generally accepted frequency classification: very often (≥ 1/10), often (≥ 1/100, <1/10) infrequently (≥ 1/1000, <1 / 100), rarely (≥ 1/10000, <1/1000), very rarely (<1/10000).

Violations from the blood and lymphatic system: often - granulocytopenia; infrequently, anemia.

Immune system disorders: often - hypersensitivity (including angioedema, hives); infrequently, anaphylactic reactions; rarely allergic reactions, accompanied by eosinophilia and systemic symptoms.

Impaired nervous system: often a headache.

Disorders from the gastrointestinal tract: often - nausea, vomiting, diarrhea, abdominal pain.

Disorders from the liver and bile ducts: often - hepatitis, including serious or life-threatening hepatotoxicity; infrequently - jaundice; rarely fulminant hepatitis (including fatal).

Disturbances from the skin and subcutaneous tissues: very often - a rash; infrequently, Stevens-Johnson syndrome, toxic epidermal necrolysis (possible fatal outcome), angioedema, hives.

Disturbances from the musculoskeletal and connective tissue: infrequently - myalgia, arthralgia; rarely - rhabdomyolysis (in patients who had a reaction from the skin and liver when taking nevirapine)

General disorders and disorders at the site of administration: often fatigue, fever.

Laboratory and instrumental data: often - increasing levels functional liver tests (alanine aminotransferase, transaminase, aspartate aminotransferase, gamma-glutamate transferase, hepatic enzymes, hypertransaminase); infrequently - hypophosphatemia; increase in blood pressure.

Description of individual adverse reactions

According to the clinical study 1100.1090. from which the majority of undesirable reactions were received (0 = 28), in patients receiving placebo, granulocytopenia developed more often (3.3%) than in patients receiving nevirapine (2,5 %).

Anaphylactic reactions were observed in the post-marketing period, but ns were recorded in randomized controlled clinical trials. The frequency of their development was determined by statistical counting, based on the total number of patients participating in randomized controlled clinical trials (n=2718).

An increase in blood pressure and a decrease in the level of phosphorus in the blood was observed during clinical trials with the concomitant use of tenofovir or emtricitabine.

Metabolic indicators:

Weight gain, blood lipids and blood glucose levels have been reported during antiretroviral therapy.

In the case of drug use Nevirapine In combination with other antiretroviral drugs, the development of unwanted reactions, such as pancreatitis, peripheral neuropathy and thrombocytopenia, has also been reported. These phenomena are often associated with other antiretroviral drugs. Their occurrence can be expected with the use of the drug Nevirapine in combination with other drugs; the likelihood of these reactions being related to the use of the drug Nevirapine is not large.

In HIV-infected patients with severe immunodeficiency at the time of the appointment of combined antiretroviral therapy (CAPG), inflammatory responses to symptom-free or residual opportunistic microorganisms may occur. Also reported was the development of autoimmune diseases (such as Graves' disease) that appeared against the background of immune reactivation; but the described time before their onset is very variable, and these phenomena can appear many months after the initiation of therapy.

Skin and subcutaneous fat:

The most frequent clinical sign of the toxicity of nevirapine is a rash. The rash is usually mild or moderately expressed, characterized by maculopapular erythematous elements,accompanied or not accompanied by itching, is localized on the trunk, face and limbs. Allergic reactions have been reported (including anaphylaxis, angioedema and urticaria). The rash occurs either singly or in the context of a rash with eosinophilia and systemic manifestations characterized by common symptoms (such as fever, arthralgia, myalgia, and lymphadenopathy) and signs of internal organ damage (such as hepatitis, eosinophilia, granulocytopenia and kidney dysfunction).

In patients receiving Nevirapine such severe and life-threatening reactions as Stevens-Johnson syndrome and toxic epidermal necrolysis can develop. There have also been reports of deaths from Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic manifestations. The greatest risk of developing severe dermatological reactions exists in the first 6 weeks of nevirapine therapy, some of which require hospitalization. One patient who required surgical intervention was reported.

Disorders from the liver and bile ducts:

The most frequent adverse reactions were violations of biochemical parameters of liver function, including increased concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyltransferase (GGT), total bilirubin and alkaline phosphatase. The most common asymptomatic increase in the concentration of gamma-glutamyl transferase (GGT). Individual cases of jaundice development and cases of development of severe and life-threatening hepatotoxicity, including fulminant hepatitis with lethal outcome, have been reported. The best predictor of severe complications from the liver is an increase in the concentration of biochemical indicators of liver function. Strict monitoring of liver function parameters at short intervals is recommended, depending on the clinical state of the patients, especially during the first 18 weeks of treatment.

Pediatric use:

Safety data nevirapine in children were obtained in clinical trials with the participation of 361 patients, most of whom received nevirapine in combination with zidovudine (ZDV) or didanosine (ddl), or ZDV+ddl. The most frequently reported adverse events associated with nevirapine were similar to those observed in adults, except for granulocytopenia, which was more common in children. In an open clinical trial (ACTG 180), the incidence of granulocytopenia, estimated as associated with the study drug, was 13.5%. In a double-blind, placebo-controlled clinical trial ACTG245 the incidence of granulocytopenia was 1.6%. Individual cases of development of Stevens-Johnson syndrome or a syndrome transitional between Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Overdose:

Symptoms: edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, lung infiltrates, rash, dizziness, vomiting, increased transaminase activity and weight loss.

Treatment: cancellation of the drug. There is a specific antidote.

Interaction:

Nevirapine is an inducer of cytochrome P450 isoenzymes of the liver (CYP3A, CYP2B6) and can lead to a decrease in plasma concentrations of other concomitantly used drugs that are heavily metabolized by isoenzymes CYP3A or CYP2B. Therefore, if a patient who previously had a dosing regimen for a drug metabolized by isoenzyme CYP3A or CYB2B, treatment with nevirapine begins, it may be necessary to adjust the dose of this drug. Maximum induction is observed within 2-4 weeks after the initiation of therapy.

With concomitant administration of plasma concentrations of nevirapine, medications that are also metabolized by 1450 can be reduced.

The intake of food, antacids or medicines containing an alkaline buffer does not affect the absorption of nevirapine.

The interaction data are presented as a geometric mean with a 90% confidence interval, regardless of the time of obtaining this data. NA = not determined, ↑ = elevated, ↓ = reduced, ↔ = no impact

Medicinal products	Interaction	Recommendations for designation
Anti-infectious
Antiretroviral
NRTI (nucleoside reverse transcriptase inhibitors)
Didanosine 100-150 mg 2 r / day	Didanosine AUC ↔ 1.08 (0.92-1.27) Cmin of Didanosine is not definable (NO) The amount of didanosine ↔ 0.98 (0.79-1.21)	nevirapine and didanosine can be administered simultaneously without dose adjustment.
Emtricitabine	Emtricitabine is not an inhibitor of the CYP 450 enzyme in humans	nevirapine and emtricitabine can be administered simultaneously without dose adjustment.
Abacavir	Abacavir does not inhibit cytochrome P450 isoforms in human liver microsomes.	nevirapine and abacavir can be administered simultaneously without dose adjustment.
Lamivudine 150 mg 2 p / day	There is no change in the apparent clearance and volume of lamivudine distribution.	nevirapine and lamivudine can be administered simultaneously without dose adjustment.
Stavudine: 30/40 mg 2 p / day	Stavudine AUC 0.96 (0,89-1,03) Stavudine Cmin NO Stavudine Cmax ↔ 0.94 (0.86-1.03) Nevirapine: in comparison with the retrospective control data, the levels remain unchanged.	nevirapine and stavudine can be administered simultaneously without dose adjustment.
Tenofovir 300 mg daily	With concomitant administration with nevirapine, tenofovir levels in plasma remain unchanged.	tenofovir and nevirapine can be administered simultaneously without dose adjustment.
Zidovudine 100-200 mg 3 r / day	Zidovudine AUC ↓ 0.72 (0.60-0.96) Zidovudine Cmin NO Zidovudine FROMmah ↓ 0.70 (0.49-1.04) Nevirapine: zidovudine does not affect its pharmacokinetics	zidovudine and nevirapine can be administered simultaneously without dose adjustment. Against the background of zidovudine, granulocytopenia often develops, therefore, such patients should be carefully monitored for hematological parameters.
NNRTIs (non-nucleoside reverse transcriptase inhibitors)
Efavirenz 600 mg daily	Efavirenz AUC ↓ 0,72 (0,66-0,86) Efavirenz Cmin ↓ 0,68 (0,65-0,81) Efavirenz Cmah ↓ 0.88 (0,77-1,01)	Simultaneous administration of efavirenz and nevirapine is not recommended due to increased toxic effects and a lack of improved efficacy compared with the appointment of only NIHFROM.
Delavirdine	The interaction was not studied.	Simultaneous administration of nevirapine and NNRTI is not recommended.
Etravirine	The simultaneous administration of etravirine and nevirapine can cause a significant decrease in plasma concentrations of etravirine and the loss of its therapeutic effect.	Simultaneous administration of nevirapine and NNRTI is not recommended.
Rilpivirine	The interaction was not studied.	Simultaneous administration of nevirapine and NNRTI is not recommended.
IP (Protease Inhibitors)
Atazanavir / ritonavir 300/100 mg daily 400/100 mg daily	Atazanavir / r 300 / 100mg: Atazanavir / r AUC ↓ 0,58 (0,48-0,71) Atazanavir / r Cmin ↓ 0,28 (0,20-0,40) Atazanavir / p CmOh ↓ 0,72 (0,60-0,86) Atazanavir / p 400 / 100mg: Atazanavir / p AUC ↓ 0.81 (0,65-1,02) Atazanavir / p Cmin ↓ 0.41 (0.27-0.60) Atazanavir / p Cmah ↔ 1.02 (0.85-1.24) (in comparison with 300/100 mg without nevirapine) Nevirapine AUC ↑ 1,25 (1,17-1,34) Nevirapine Cmin ↑ 1.32 (1,22-1,43) Nevirapine Cmah ↑ 1.17 (1,09-1,25)	Simultaneous administration of atazanavira/ ritonavir and nevirapine is not recommended
Darunavir / ritonavir 400/100 mg 2 r / day	Darunavir AUC ↑ 1,24 (0,97-1,57) Darunavir Cmin ↔ 1.02 (0,79-1,32) Darunavir Cmah ↑ 1.40 (1,14-1,73) Nevirapine AUC ↑ 1,27 (1,12-1,44) Nevirapine Cmin ↑ 1.47 (1,20-1,82) Nevirapine Cmah ↑ 1.18 (1,02-1,37)	Darunavir and nevirapine can be administered simultaneously without dose adjustment.
Fosamprenavir 1,400 mg 2 r / day	Amprenavir AUC ↓ 0.67 (0,55-0,80) Amprenavir Cmin ↓ 0.65 (0,49-0,85) Amprenavir Cmah ↓ 0.75 (0,63-0,89) Nevirapine AUC ↑ 1.29 (1,19-1,40) Nevirapine Cmin ↑ 1.34 (1,21-1,49) Nevirapine Cmax ↑ 1,25 (1,14-1,37)	The simultaneous administration of fosamprenavir and nevirapine is not recommended if fosamprenavir is prescribed without ritonavir.
Fosamprenavir / ritonavir 700/100 mg 2 r / day	Amprenavir AUC ↔ 0.89 (0.77-1.03) Amprenavir Cmin ↓ 0.81 (0,69-0,96) Amprenavir Cmah ↔ 0.97 (0.85-1.10) Nevirapine AUC ↑ 1.14 (1,05-1,24) Nevirapine Cmin ↑ 1.22 (1,10-1,35) Nevirapine Cmah ↑ 1.13 (1,03-1,24)	Fosamprenavir / ritonavir and nevirapine can be administered simultaneously without dose adjustment
Lopinavir / ritonavir (capsules) 400/100 mg 2 r / day	Adults: Lopinavir AUC ↓ 0.73 (0,53-0,98) Lopinavir Cmin ↓ 0.54 (0,28-0,74) Lopinavir Cmah ↓ 0.81 (0,62-0,95)	With simultaneous administration with nevirapine, an increase in dose is recommendedlopinavir / ritonavir to 533/133 mg (4 capsules) or 500/125 mg (5 tablets of 100/25 mg each) twice daily with meals. With a simultaneous appointment with lopinavir, dose adjustment for nevirapine is not required.
Lopinavir / ritonavir (solution for oral administration) 300/75 mg / m² 2 p / day	Children: Lopinavir AUC ↓ 0.78 (0,56-1,09) Lopinavir Cmin ↓ 0.45 (0,25-0,82) Lopinavir Cmah ↓ 0.86 (0,64-1,16)	When used simultaneously with nevirapine in children, the question of increasing the dose of lopinavir / ritonavir to 300/75 mg / m² twice a day, especially if there is a suspected decrease in susceptibility to lopinavir / ritonavir.
Ritonavir 600 mg 2 p / day	Ritonavir AUC ↔ 0.92 (0,79-1,07) Ritonavir Cmin ↔ 0.93 (0,76-1,14) Ritonavir Cmah ↔ 0.93 (0,78-1,07) Nevirapine: simultaneous administration of ritonavir does not lead to any clinically significant changes in nevirapine plasma levels.	ritonavir and nevirapine can be administered simultaneously without dose adjustment.
Saquinavir / ritonavir	The limited information available on the use of soft gel capsules of saquinavir supplemented with ritonavir does not indicate any clinically significant interaction of saquinavir enhanced with ritonavir and nevirapine	Saquinavir / ritonavir and nevirapine can be administered simultaneously without dose adjustment.
Tipranavir / ritonavir 500/200 mg twice daily	No special drug-drug studies have been conducted. The limited data obtained in the Phase II study in patients infected with HIV showed a clinically insignificant 20% decrease in Cmin of tipranavir.	Tipranavir and nevirapine can be administered simultaneously without dose adjustment.
Inhibitors of fusion / penetration
Enfuvirtide	Due to the peculiarities of the metabolic pathway, no clinically significant pharmacokinetic interactions between enfuvirtide and nevirapine are expected.	Enfuvirtide and nevirapine can be administered simultaneously without dose adjustment.
Maraviroc 300 mg daily	Maraviroc AUC ↔ 1,01 (0,6 -1,55) Maraviroc Cmin BUT Maraviroc Cmah ↔ 1.54 (0.94-2.52) in comparison with the previously known control data. Concentrations of nevirapine were not measured, no impact is expected.	Maraviroc and nevirapine can be administered simultaneously without dose adjustment.
Integrase inhibitors
Elvitegravir / cobicystate	The interaction was not studied. Kobitsystat, a cytochrome P450 inhibitor, inhibits hepatic enzymes, as well as other metabolic pathways. Therefore, with concomitant administration, a change in plasma levels is likelycobicystate and nevirapine.	The simultaneous administration of nevirapine and the combination of elvitegravir and cobicystate is not recommended.
Raltegravir 400 mg 2 r / day	There are no clinical data available. In connection with the peculiarities of the pathway of metabolism of raltegravir, no interactions are expected.	Raltegravir and nevirapine can be administered simultaneously without dose adjustment.
Antibiotics
Clarithromycin 500 mg 2 p / day	Clarithromycin AUC ↓ 0.69 (0,62-0,76) Clarithromycin Cmin ↓ 0.44 (0,30-0,64) Clarithromycin Cmax ↓ 0.77 (0,69-0,86) Metabolite of clarithromycin 14-OH AUC ↑ 1.42 (1,16- 1,73) Metabolite of clarithromycin 14-OH Cmin ↔ 0 (0,68-1,49) Metabolite of clarithromycin 14-OM Cmax ↑ 1.47 (1,21- 1,80) Nevirapine AUC ↑ 1.26 Nevirapine Cmin ↑ 1.28 Nevirapine Сmах ↑ 1,24 Compared with the available historical control data.	The concentrations of clarithromycin decreased significantly, the concentrations of metabolite 14-OH significantly increased. Since the action of the active metabolite of clarithromycin on the Mycobacterium avium intracellular complex was reduced, the overall activity against pathogens may vary. Consideration should be given to the use of alternative drugs, such as azithromycin. It is recommended to carry out careful monitoring of changes in the liver.
Rifabutin 150 or 300 mg daily	Rifabutin AUC ↑ 1.17 (0,98-1,40) Rifabutin Cmin ↔ 1.07 (0,84-1,37) Rifabutin Сmах ↑ 1,28 (1,09-1,51) Metabolite 25-0-deacetyltrifabutin AUC ↑ 1,24 (0,84-1,84) Metabolite 25-0-deacetyltrifabutin Cmin ↑ 1.22 (0,86-1,74) Metabolite 25-0-deacetyltrifabutin Cmax ↑ 1.29 (0,98-1,68) A clinically insignificant increase in the apparent clearance of nevirapine (by 9%) was reported compared to the previously known data.	There was no significant effect on the pharmacokinetic parameters of rifabutin and nevirapine. Rifabutin and nevirapine can be administered simultaneously without dose adjustment. However, due to the high interindividual variability, in some patients there may be an increase in the action of rifabutin, which may lead to an increased risk, the development of toxic effects of rifabutin. Therefore, with the simultaneous appointment should be cautious.
Rifampicin 600 mg daily	Rifampicin AUC ↔1.11 (0.96-1.28) Rifampicin Cmin NO Rifampicin Cmah ↔ 1.06 (0.91-1.22) Nevirapine AUC ↓ 0.42 Nevirapine Cmin ↓ 0.32 Nevirapine Cmah ↓ 0.50 compared to the previously known control data.	Simultaneous administration of rifampicin and nevirapine is not recommended. To treat patients with tuberculosis infection, rifabutin should be considered instead of rifampicin.
Antifungal drugs
Fluconazole 200 mg daily	Fluconazole AUC ↔ 0,94 (0,88-1,01) Fluconazole Cmin ↔ 0,93 (0,86-1,01) Fluconazole Cmah ↔ 0.92 (0.85-0.99) Nevirapine: Effects: ↑ 100% compared to previously known data, when only one was assigned nevirapine.	Risk of increased effects of nevirapine. Patients should be closely monitored.
Itraconazole 200 mg daily	Itraconazole AUC ↓ 0.39 Itraconazole Cmin ↓ 0.13 Itraconazole Cmah ↓ 0.62 Nevirapine: there was no significant difference in the parameters of the pharmacokinetics of nevirapine.	With the simultaneous administration of these two drugs, the possibility of increasing the dose of itraconazole should be considered.
Ketoconazole 400 mg daily	Ketoconazole AUC ↓ 0.28 (0.20-0.40) Ketoconazole Cmin NO Ketoconazole Cmah ↓ 0.56 (0,42-0,73) Nevirapine: plasma levels: ↑ 1.15-1.28 compared to previously known control data.	Simultaneous administration of ketoconazole and nevirapine is not recommended.
Antiviral drugs for the treatment of chronic hepatitis B and C
Adefovir	The results of in vitro studies showed a weak antagonism of nevirapine and adefovir. This has not been confirmed by clinical studies, and no decrease in efficacy is expected. Adefovir does not affect the normal isoforms of the SRM enzyme, which, as is known, are involved in the metabolism of drugs in humans, and is excreted by the kidneys. Clinically significant drug interaction is not expected.	Adefovir and nevirapine I can t be administered simultaneously without dose adjustment.
Boceprevir	Bocepreviir is partially metabolized by the enzyme CYP3A4 / 5. Simultaneous administration with drugs that activate or inhibit CYP3A4 / 5 may increase or decrease the effect. Residual plasma concentrations of bocepreviir decreased with NNRTI administered with a similar metabolic rate, as in nevirapine. The clinical outcome of such a decrease in the residual concentration of bocetrephir was not directly studied.	Simultaneous administration of bocapreviir and nevirapine is not recommended.
Entecavir	Entecavir is not a substrate, inducer or inhibitor of cytochrome P450 (CYP450). Due to the peculiarities of the pathway of entecavir metabolism, no clinically significant drug interactions are expected.	Entecavir and nevirapine can be administered simultaneously without dose adjustment.
Interferons (pegylated interferons alpha 2a and alpha 2b)	Interferons do not exert any known effects on CYP 3A4 or 2B6. No clinically relevant drug interactions are expected.	Interferons and nevirapine can be administered simultaneously without dose adjustment.
Ribavirin	Ribavirin does not inhibit cytochrome P450. In toxicity studies ribavirin did not induce the induction of hepatic enzymes. No clinically relevant drug interactions are expected.	Ribavirin and nevirapine may be appointed simultaneously without dose adjustment.
Telaprevir	Telaprevir is metabolized in the liver by the enzyme CYP3A and is a substrate of the P-glycoprotein. In this metabolism, other enzymes can also participate. Simultaneous administration of telaprevir and drugs that induce CYP3A and / or P-glycoprotein can reduce plasma concentrations of telaprevir. No studies of the interaction between telaprevir and nevirapine have been carried out, however, studies of the interaction of NNRTIs with analogous nevirapine by metabolism have shown a decrease in the level of both drugs.	When concomitant administration of telaprevir and nevirapine should be cautious and bear in mind the possibility of correcting the dose of telaprevir.
Telbivudine	Telbivudine is not a substrate, inducer or inhibitor of cytochrome P450 (CYP450). In connection with the peculiarities of the metabolism pathway of telbivudine, no clinically significant drug interactionsexpected.	Telbivudine and nevirapine can be administered simultaneously without dose adjustment.
Antacids
Cimetidine	Cimetidine: no significant effect on the pharmacokinetics of cimetidine was observed. Nevirapine Cmin ↑ 1.07	Cimetidine and nevirapine can be administered simultaneously without dose adjustment.
Anticoagulants
Warfarin	The interaction between anticoagulant warfarin and nevirapine is complex; while there is a likelihood of both increasing and reducing the coagulation time when they are simultaneously applied.	Careful monitoring of clotting levels is required.
Contraceptive means
Depo-medroxyprogesterone acetate (DMPA) 150 mg every 3 months	DMPA AUC ↔ DMPA Cmin ↔ DMPA Cmah ↔ Nevirapine AUC ↑ 1.20 Nevirapine CmOh ↑ 1,20	With simultaneous appointment nevirapine does not affect the suppression of ovulation, caused by DMPA. DMPA and nevirapine can be administered simultaneously without dose adjustment.
Ethinylestradiol (EE) 0.035 mg	EE AUC ↓ 0.80 (0,67 - 0,97) EE Cmin NO EE Cmah ↔ 0,94 (0,79 1,12)	Oral hormonal contraceptives should not be used as the only contraceptive method in women taking nevirapine. The safety and efficacy of acceptable doses of hormonal contraceptives (oral or other forms of administration), in addition to DMPA, were not established.
Norethindrone (NET) 1.0 mg per day	NET AUC ↓ 0.81 (0,70 - 0,93) NET Cmin ND NET Stach ↓ 0.84 (0,73 - 0,97)
Analgesics / opioids
Methadone. individual dosing	Methadone AUC ↓ 0,40 (0,31 - 0,51) Methadone Cmin BUT Methadone Cmah ↓ 0,58 (0,50 - 0,67)	Patients taking methadone before treatment with nevirapine should be monitored to detect withdrawal symptoms, and the dose of methadone should be adjusted accordingly.
Herbal preparations
St. John's wort	With the simultaneous use of herbal medicine St. John's wort (Hypericum perforatum) serum levels of nevirapine may be reduced.	You can not simultaneously prescribe the herbal preparations of St. John's Wort and nevirapine. If the patient is already taking these drugs, you should check the concentration of nevirapine and, if possible, the level of viral load, and stop using drugs containing the herb extract of St. John's Wort. After their cancellation the concentration of nevirapine may increase. You may need to change the dose of Nevirapine. After discontinuation of admission preparations containing the herb extract of St. John's wort, the inducing effect can persist for at least 2 weeks.

Special instructions:

The first 18 weeks of therapy with the drug Nevirapine are critical and require careful monitoring of patients to identify possible severe and life-threatening skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), and severe hepatic / renal insufficiency. The greatest risk of developing reactions from the liver and skin occurs in the first 6 weeks of therapy. It should also be remembered that the drug Nevirapine does not prevent the transmission of HIV-1.

Clinical biochemical tests, including functional liver tests, should be performed prior to initiating therapy with the drug Nevirapine and at regular intervals during therapy - every two weeks for the first 2 months of therapy, for the third month of therapy and then regularly. Control of liver samples should be performed if the patient has symptoms or signs of hepatitis and / or hypersensitivity. If the level ACT or ALT exceeds the upper limit of the norm by more than 2.5 times before or during treatment, liver tests should be monitored more often with regular visits. Nevirapine can not be administered to patients with elevated ACT or ALT more than 5 times from the upper limit of the norm to stabilize the initial values ACT or ALT at a level below the fivefold excess of the upper limit of the norm.

Liver diseases: Nevirapine It should not be used in patients with severe impairment of liver function (Child-Pugh class C).

All patients, especially those with mild to moderate hepatic insufficiency, must be carefully monitored for early detection toxic reactions. The risk of any reactions from pensions remains after the first 18 weeks of therapy, so monitoring should continue at frequent intervals. Patients with chronic hepatitis B or C who receive combination antiretroviral therapy are at increased risk for severe and life-threatening adverse events from the hepatobiliary system. In case of simultaneous use of antiviral drugs for the treatment of viral hepatitis B or C, the instructions for the use of these drugs should be followed.In patients with an initially present impaired hepatic function, including an active form of chronic hepatitis, there is an increase in the incidence of liver function abnormalities in combination antiretroviral therapy. Such patients need to be monitored in accordance with standard clinical practice. It is necessary to consider the possibility of suspending or stopping treatment in the event of manifestations of worsening liver disease in such patients.

Belonging to the female sex and / or increasing the number of 0-4 cells (> 250 / mm3 in adult women and> 400 / mm3 in adult men) at the beginning of drug therapy Nevirapine are associated with a higher risk of adverse reactions from the liver, if HIV RNA is detected in the patient's plasma. those. concentration ≥50 copies / ml at the beginning of drug therapy Nevirapine.

Due to the possible development of severe and life-threatening hepatotoxic reactions, drug therapy Nevirapine should not be started in adult women with number of cells Cd4 more than 250 in 1 ml3 or adult men with a number of cells Cd4 more than 400 in 1 mm3, in which plasma HIV-1 RNA is determined in the plasma, if the benefit is not exceeds the risk.Rhabdomyolysis: in rare cases in patients with reactions from the side skin and liver associated with the use of nevirapine, rhabdomyolysis was observed.

Osteonecrosis: cases of osteonecrosis have been reported, especially in patients with defined risk factors, progression of HIV infection, or long-term receiving combined antiretroviral therapy (CART). Frequency of development is unknown. Patients should be advised to seek medical the appearance of aches and pains in the joints or difficulties in moving.

Reactions from the skin: drug Nevirapine should be withdrawn from any patient in the the development of a severe rash or rash accompanied by common symptoms (fever, blistering, changes in the oral mucosa, conjunctivitis, facial edema, joint and muscle pain, general malaise), with the syndrome Stevens-Johnson or toxic epidermal necrolysis. The drug Nevirapine should be withdrawn and should not be prescribed again in any patient in the case of development of hypersensitivity reactions characterized by a rash and general symptoms of internal organ damage such as hepatitis, eosinophilia,granulocytopenia and renal dysfunction, as well as in case of other changes in internal organs. Patients should be informed that the main manifestation of drug toxicity Nevirapine is a rash. An introductory initial treatment period should be used, since it is determined that this reduces the incidence of the rash. In most cases, the rash associated with taking the drug occurs in the first six weeks of therapy, so it is during this period that patients should be closely monitored for dermatological reactions. Patients should be informed that if any rash develops during the initial treatment start-up period, the dose should not be increased to two times a day until the rash disappears. The dosage regimen using 200 mg of the drug once a day should not last more than 28 days, at which point a different regimen should be developed. In rare cases, in patients with skin and liver reactions associated with the use of nevirapine, rhabdomyolysis was observed.

It was shown that simultaneous application of prednisone (40 mg / day,during the first 14 days of taking nevirapine) does not reduce the incidence of rash, but, on the contrary, may increase the frequency of dermatological reactions during the first 6 weeks of therapy.

Among the risk factors for the development of serious skin reactions is a violation of the recommendation on the use of the drug at a dose of 200 mg per day during the introductory initial treatment period. The risk of developing more serious outcomes of dermatological reactions increases in the event of delay in seeking medical advice after the onset of symptoms. The risk of developing rash in women is higher than that of men, as in the case of nevirapine, and in the case of therapy that does not contain nevirapine.

Granulocytopenia: patients receiving nevirapine in combination with zidovudine, especially in pediatrics, patients receiving high doses of zidovudine and patients with low bone marrow reserve, in particular, HIV-infected have an increased risk of developing granulocytopenia. Such patients should periodically monitor blood levels.

Reactions from the liver: it is necessary to inform the patient that liver reactions are the main type of drug toxicity Nevirapine. Patients with signs or symptoms of hepatitis should stop taking the drug and immediately go to a medical facility for a checkup that should include an assessment of liver function. Using multiple doses of the drug Nevirapine with the purpose of post-exposure prophylaxis of persons who were not infected with HIV, serious manifestations of hepatotoxicity were reported, incl. on the development of liver failure, requiringliver transplantation.

Postexposure prophylaxis of people who have not been infected with HIV is not considered an approved indication for the use of the drug and is therefore strongly discouraged.

A high risk of adverse reactions from the liver during any antiretroviral therapy (including during therapy including nevirapine) is noted with the initial increase in enzyme activity ACT or ALT more than 2.5 times compared with the upper limit of the norm, and / or in the presence of hepatitis B and / or C.

Monitoring the liver: the asymptomatic increase in the activity of liver enzymes and gamma-glutamyltransferase (GGT) is often described and is not an unconditional contraindication for the use of the drug Nevirapine.

Strict monitoring of liver function parameters at short intervals is recommended, depending on the clinical state of the patients, especially during the first 18 weeks of treatment. Clinical and laboratory monitoring should continue throughout the treatment period. Doctors and patients should be wary of such prodromal signs or symptoms of hepatitis such as anorexia, nausea, jaundice, bilirubinemia, fecal staining, hepatomegaly or liver soreness. Patients should be informed of the need to seek medical advice in such cases.

In the case of increased activity of enzymes ACT or ALT more than 2.5 times higher than the upper limit of the norm before or during treatment, liver function indicators should be monitored more often during regular examinations. Nevirapine ns should be administered to patients with initial activity ACT or ALT more than 5 times the upper limit of the norm (until it steadily decreases to a level less than 5 times the upper limit of the norm).

If the activity of enzymes ACT or ALT increases more than 5 times compared with the upper limit of the norm during treatment, the drug Nevirapine must be immediately canceled. If the activity of enzymes ACT and ALT returns to baseline values and if the patient does not have any clinical signs or symptoms of hepatitis or general symptoms or other phenomena indicative of a violation of the function of internal organs, the use of the drug Nevirapine can be renewed (if there is a clinical need). The decision on this should be taken in each individual case, based on clinical necessity. Re-appointment preparation Nevirapine should be carried out under conditions of increased clinical and laboratory alertness, at an initial dose of 200 mg / day (for 14 days), followed by an increase to 400 mg / day. If violations of the liver function are resumed, the drug Nevirapine must be finally canceled.

In the case of hepatitis, accompanied by clinical manifestations such as anorexia, nausea, vomiting, jaundice, and changes in laboratory indicators (moderate or significant changes in liver function, without taking into account the activity of gamma-glutamyltransferase), nevirapine must be canceled finally. Nevirapine should not be given again to those patients who required his withdrawal because of the development of clinically expressed hepatitis caused by nevirapine.

Weight and metabolic parameters: against the background of ongoing antiretroviral therapy, there may be an increase in body weight and an increase in the concentration of glucose and lipids in the blood. These changes may be partly related to the disease itself and the way of life. In some cases, it proved the influence of the therapy on the increased concentration of lipids, but there is no conclusive evidence on the effect of therapy on weight gain. Monitoring of glucose and lipid concentrations in the blood should be carried out, guided by information on recommendations for treatment of HIV infection. Disorders of lipid metabolism should be adjusted in case of clinical necessity.

Immunodeficiency Syndrome: In HIV-infected patients with severe immunodeficiency at the time the combination antiretroviral therapy (hag) may occur inflammatory reaction do not cause symptoms or residual opportunistic pathogens that can lead to development of serious medical conditions or disease symptoms worsen.Typically, such reactions were observed during the first few weeks or months after the onset of CART. Typical examples are cytomegalovirus retinitis, generalized and / or local mycobacterial infections and pneumonia caused by Pneumocystis jirovecii. Any inflammatory symptoms should be identified, and if necessary, treatment should be started. Also reported was the development of autoimmune diseases (such as Graves' disease) that appeared against the background of immune reactivation; However, the described time before their onset is very variable and these phenomena can appear many months after the initiation of therapy.

Nevirapine is not recommended for use with efavirenz, rifampicin, ketoconazole, delavirdine, etravirine, rilpivirin, elvitegravir (together with cobicystate), boceprevirov, as well as fosamprenavir, saquinavir, atazanavir (when not used together with low-dose ritonavir).

Nevirapine should not be used as a single drug (monotherapy) for the treatment of HIV-1 infection due to the possibility of developing resistance.

It should be remembered that the drug Nevirapine does not prevent the transmission of HIV-1 to healthy people through blood and unprotected sex.

Effect on the ability to drive transp. cf. and fur:

Special studies on the ability to drive vehicles and management mechanisms have not been conducted. However, patients should be advised that during treatment, adverse reactions such as fatigue and headache are possible, which should be avoided when driving motor vehicles or controlling the mechanisms.

Form release / dosage:Tablets, 200 mg.

Packaging:

For 60 tablets in a container of high density polyethylene, sealed with a polymer screw cap, equipped with a mechanism for protection from children. A self-adhesive label is attached to the container. One container, together with the instruction for use, is placed in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature above 25 ° C.

Keep out of the reach of children!

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004262

Date of registration:28.04.2017

Expiration Date:28.04.2022

The owner of the registration certificate:Emkure Pharmaceuticals Co., Ltd.Emkure Pharmaceuticals Co., Ltd. India

Manufacturer: & nbsp

EMCURE PHARMACEUTICALS Ltd India

Representation: & nbspEMKYUR PHARMACEUTICALS LIMITEDEMKYUR PHARMACEUTICALS LIMITEDRussia

Information update date: & nbsp14.06.2017

Illustrated instructions

Instructions

Nevirapine (Nevirapine)