Nevirpin - instructions for use, doses, side effects, contraindications

Core: Copovidone 2.8 mg / 5.6 mg, crospovidone 14.0 mg / 28.0 mg, silicon colloidal dioxide (Aerosil brand A-300) 1.8 mg / 3.6 mg, magnesium stearate 1.0 mg / 2.0 mg, stearic acid 2.0 mg / 4.0 mg, sorbitol 90.0 mg / 180.0 mg, talc 2.4 mg / 4.8 mg, microcrystalline cellulose 80.0 mg / 160.0 mg.

Film Sheath: Finished water-soluble film shell - 6.0 mg, 12.0 mg. (Sheath composition: hydroxypropylmethylcellulose (hypromellose) 25.0%, copolyvidone 22.5%, polyethylene glycol 6000 (Macrogol 6000) 9.5%, glyceryl caprylcaprate 3.0%, polydextrose 15.0%, titanium dioxide - 25.0%).

Description:

For a dosage of 100 mg: round biconvex tablets, covered with a film coating of white color.

For a dosage of 200 mg: capsular biconvex tablets, with a risk on the one hand, covered with a film shell of white color.

On the cross-section the nucleus is white or white with a yellowish tint of color.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.G.01 Nevirapine

Pharmacodynamics:

Antiviral drug, non-competitive non-nucleoside reverse transcriptase inhibitor HIV-1. Combining with reverse transcriptase, blocks the activity of RNA and DNA-dependent DNA polymerase, causing destruction of the catalytic site of the enzyme. Does not inhibit the reverse transcriptase of HIV-2 and human alpha, beta, gamma or delta-DNA polymerases. In combination with other antiretroviral drugs, reduces the viral load and increases the amount CD4 + cells. With monotherapy, the stability of viruses quickly and practically always develops. In vitro there is cross-resistance with other non-nucleoside reverse transcriptase inhibitors.

Pharmacokinetics:

Nevirapine is well (> 90%) absorbed after ingestion.Absolute bioavailability of nevirapine tablets after a single dose of 50 mg was 93 ± 9% (mean ± SD). The maximum concentration (C_max) of nevirapine in plasma after a single dose of 200 mg was achieved after 4 hours and was 2 ± 0.4 μg / ml (7.5 μmol). After repeated administration of the drug at doses of 200 to 400 mg per day C_max nevirapine increases linearly with dose. The basal level of nevirapine concentrations during the steady state of pharmacokinetics at a dose of 400 mg per day was 4.5 ± 1.9 μg / ml (17 ± 7 μmol). The ingestion of food, antacids or drugs, the dosage form of which contains an alkaline buffer (eg, didanosine), does not affect the absorption of nevirapine.

Nevirapine has a high lipophilicity and is practically not ionized at physiological pH. Nevirapine well penetrates the placental barrier and is determined in breast milk. The binding of nevirapine to plasma proteins is about 60%, its plasma concentration varies from 1 to 10 μg / ml. Concentrations of nevirapine in cerebrospinal fluid in humans are 45% (± 5%) of plasma concentrations; this ratio approximately corresponds to the fraction of the drug not associated with plasma proteins.

Nevirapine is extensively metabolized with the participation of cytochrome P450 to several hydroxylated metabolites. Oxidative metabolism of nevirapine is carried out, mainly, with the help of cytochrome P450 isoenzymes from the subfamily CYP3A, Additional isozymes may play an additional role. According to the results of the pharmacokinetic study, approximately 91.4 ± 10.5% of the isotope-labeled dose of the drug was excreted, mainly (81.3 ± 11.1%) through the kidneys and, to a lesser extent (10.1 ± 1.5%), through the intestine . More than 80% of the radioactive label found in urine was associated with conjugates of hydroxylated metabolites with glucuronides.

Thus, the main pathway of biotransformation and excretion of nevirapine in humans consists in metabolism involving cytochrome P450, conjugation with glucuronides and excretion of metabolites associated with glucuronides through the kidneys. Only a small fraction (<5%) of radioactivity in urine (corresponding <3% of the total dose) was associated with the unchanged compound, that is, renal excretion plays a small role in the induction of nevirapine.

Shown, that nevirapine is the inducer of the enzymes of the cytochrome P450 system in the liver.As a result of autoinduction of metabolism, the terminal half-life (T_1/2) Nevirapine plasma: about 45 hours (single dose) to about 25-30 hours (for multiple dose of the drug in doses of 200-400 mg per day).

Clearance in women is 13.8% lower than in men.

In adults aged 19-68 years and in different races, there are no significant differences in pharmacokinetic parameters.

Special patient groups

Impaired renal function

A comparison of figures pharmacokinetics after a single dose of nevirapine in patients with small (50 <creatinine clearance <80 mL / min), moderate (30 <creatinine clearance <50 mL / min) or significant renal dysfunction (creatinine clearance <30 mL / min) notes for kidney or end-stage renal failure requiring dialysis and in patients with normal renal function (creatinine clearance of> 80 ml / min). Renal insufficiency (small, moderate or significant) did not lead to significant changes in the pharmacokinetics of nevirapine. However, in patients with end-stage renal disease requiring dialysis, a reduction of 1 week was observed AUC nevirapine by 43.5%.There was also an accumulation of hydroxylated nevirapine metabolites 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. On the other hand, patients who have a creatinine clearance of> 20 ml / min do not require a dose of nevirapine.

Impaired liver function

Comparison of pharmacokinetics after single administration of nevirapine in patients with hepatic insufficiency and in patients with normal function of the liver. In patients with mild or moderate liver failure, no individual dose adjustment is required.

However, the results of studying the pharmacokinetics in one patient with moderate expressed ascites indicate the possibility of nevirapine accumulation in systemic circulation in patients with significant impairment of liver function.

Pregnant women

Determined that nevirapine quickly penetrates the placental barrier. The concentration of nevirapine in the blood of the umbilical cord after receiving a dose of 200 mg of drugs by the mothers exceeded 100 ng / ml, and the ratio of blood concentrations in the umbilical cord and in the mother's blood was 0.84 ± 0.19 (n = 36, range 0.37 -1.22).

Mothers breastfeeding

Nevirapine is excreted in breast milk. After a single intake of the drug at a dose of 200 mg, the average ratio of concentrations in breast milk and plasma of mothers was 60.5% (25-122%).

Indications:

Treatment of HIV infection in combination with other antiretroviral drugs used to treat HIV-1 infection. With monotherapy with nevirapine, resistant strains of the virus quickly and practically always occur. therefore nevirapine should always be used in combination with at least two other antiretroviral drugs.

To prevent mother-to-child transmission of HIV-1, in pregnant women who do not receive antiretroviral therapy during childbirth, nevirapine is shown and can be used in the mother as a monotherapy, as a single dose, taken orally during labor. In order to minimize the risk of HIV-1 transmission to a child, it is recommended that a combination therapy be provided in the mother before delivery, where this is possible.

Contraindications:

Clinically significant increased susceptibility to nevirapine or any other component of the drug.

Deficiency of sugar / isomaltase, intolerance to fructose, glucose-galactose malabsorption.

Simultaneous use of nevirapine with efavirenz, delavirdine, etravirine, rilpivirin, atazanavir / ritonavir, fosamprenavir, boceprovir, rifampicin, ketoconazole, preparations based on St. John's wort.

The drug is not prescribed for patients with severe liver function disorders (Child-Pugh class C) or in the case of an initial increase in the level of aspartate aminotransferase (ACT) or alanine aminotransferase (ALT), more than 5 times the upper limit of the norm, until the AST / ALT values decrease (steadily) to a level that does not exceed the upper limit of the norm by a factor of 5.

Nevirapine should not be reused in patients who needed to be withdrawn because of severe rash, rash accompanied by common symptoms, hypersensitivity reactions or the development of clinically expressed hepatitis caused by nevirapine.

Nevirapine should not be re-assigned to patients who had previously had increased levels of nevirapine during therapy ACT or ALT exceeding the upper limit of the norm by more than 5 times, or to patients who, after repeated application of nevirapine, had a renewed liver function disorder.

Children under 18 years (for this dosage form).

Carefully:Pregnancy, violations of liver function of moderate severity (class B according to the Child-Pugh classification), simultaneous use with telaprevir, fluconazole.

Pregnancy and lactation:

Comprehensive controlled studies of treatment in HIV-1-infected pregnant women have not been carried out to date. Nevirapine should be used during pregnancy only in cases where the potential benefit to the mother outweighs the potential risk to the fetus.

The safety and efficacy of nevirapine, used to prevent mother-to-child transmission of HIV-1, was established when the drug was used as part of a treatment regimen that included a single oral dose of 200 mg to the mother during labor and an oral dose of 2 mg / kg to a newborn within 72 hours after birth.

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

Dosing and Administration:

The drug is taken internally.

Adults in the initial period, the drug is administered at a dose of 200 mg once a day daily for the first 14 days (it is found that with this dosage regimen the frequency of development of the rash decreases), then the dose is increased to 200 mg twice a day daily (in combination with at least two additional antiretroviral drugs). In the case of combined therapy, it is necessary to follow the dosing and monitoring rules recommended by the manufacturers. Patients should be informed about the need to take nevirapine daily, as it is prescribed to them. If the patient misses the medication, the patient should not double the next dose, the next dose should be taken as soon as possible.

Before starting nevirapine and at appropriate intervals during therapy, biochemical studies should be conducted, including liver function tests.

Patients who have a rash during the 14-day initial period of daily dosing at a dose of 200 mg per day should not increase the dose until the rash disappears.

Patients who stopped taking Nevirapine for more than 7 days should resume using the recommended regimen, that is, take the drug at a dose of 200 mg once a day for 14 days, and then 200 mg twice a day.

Prevention of mother-to-child transmission of HIV.

The following dosing regimen for pregnant women is recommended: a single dose of 200 mg as soon as possible after the onset of labor.

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. Postmarketing experience has shown that the most serious side effects are Stevens-Johnson syndrome, toxic epidermal necrolysis, severe hepatitis / hepatic insufficiency, and hypersensitivity syndrome characterized by a rash, common symptoms (such as fever, arthralgia, myalgia and lymphadenopathy) and signs of internal organ 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, in accordance with 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).

From the laboratory indicators: often - changes in liver function indicators (increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyltranspeptidase (GGT), increased total bilirubin, alkaline phosphatase); infrequently - hypophosphatemia.

From the blood of the hematopoietic organs: often - granulocytopenia; infrequently, anemia; From the nervous system: often - headache;

From the skin of subcutaneous fat: very often - a rash; infrequently - Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, hives;

From the musculoskeletal system: infrequently - myalgia, arthralgia;

From the gastrointestinal tract: often - nausea, vomiting, diarrhea, abdominal pain;

From the liver and biliary tract: often - hepatitis, including serious and life-threatening hepatotoxicity; infrequently - jaundice; rarely - fulminant hepatitis (including fatal);

From the side of the cardiovascular system: infrequently - increased blood pressure;

From the immune system: often - allergic reactions (including angioedema, hives); rarely - a drug rash, accompanied by eosinophilia and general symptoms, anaphylaxis.

Other: often - fatigue, fever.

Patients who received combined antiretroviral therapy experienced a redistribution of fat, including obesity of the central type, an increase in fatty tissue in the dorso-cervical region ("buffalo buffalo"), a decrease in the volume of peripheral adipose tissue, a decrease in subcutaneous fat in the face, mammary hypertrophy.

Against the background of combined antiretroviral therapy, metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, hyperlactatemia were observed.

Cases of pancreatitis, peripheral neuropathy, and thrombocytopenia have been reported with the use of nevirapine in combination with other antiretroviral drugs.Postmarketing experience: there are reports of cases of severe hepatitis, liver failure and kidney failure.

Overdose:

Symptoms. There have been reports of cases of an overdose of nevirapine (taking 800 to 6000 mg per day for up to 15 days). Patients had swelling, erythema nodosum, fatigue, fever, headache, insomnia, nausea, lung infiltrates, rash, dizziness, vomiting, increased transaminase levels and weight loss. After the drug was discontinued, all of these events stopped.

Treatment: Cancellation of the drug. Antidote for overdose elimination is not available.

Interaction:

Nevirapine is an inducer of the enzymes of the liver cytochrome P450 system (CYP3A4, CYP2B6). With the simultaneous use of nevirapine with other drugs that are metabolized with the participation of isoenzymes CYP3A4, CYP2B6, there may be a decrease in the concentrations of these drugs in the blood plasma. Therefore, in the appointment of nevirapine to a patient who had previously been treated with a dosing regimen of a drug metabolized with isozymes CYP3A4 or CYB2B6, it may be necessary to adjust the dose of this drug.

Nucleoside and nucleotide reverse transcriptase inhibitors

Didanosine: nevirapine does not affect the pharmacokinetic parameters (area under the pharmacokinetic curve "concentration-time" (AUC) and C_max) didanosine. In the case of simultaneous application of nevirapine with didanosine, dose adjustment is not required.

Lamivudine: with simultaneous application, no apparent changes in the apparent clearance and volume of lamivudine distribution, indicating the lack of inductive action of nevirapine on the clearance of lamivudine. Lamivudine can be used simultaneously with nevirapine without dose adjustment.

Stavudine: with simultaneous application with nevirapine of statistically significant changes in AUC or C_max Stavudine has not been identified. Stavudine also does not have a significant effect on the pharmacokinetics of nevirapine. In the case of simultaneous use of nevirapine with stavudine dose adjustment is not required.

Zidovudine: the use of nevirapine in combination with zidovudine revealed an unreliable decrease in AUC and C_max zidovudine. Zidovudine did not have any effect on the pharmacokinetics of nevirapine. In the case of simultaneous use of nevirapine with zidovudine, correction of doses is not required.

Zalcitabine: it has been established that, with simultaneous application nevirapine does not affect the pharmacokinetics of zalcitabine. When applying this combination, dose adjustments are not required.

Tenofovir: with simultaneous use with nevirapine, no significant changes in the concentrations of tenofovir were detected. Tenofovir also does not have a significant effect on the pharmacokinetics of nevirapine. In the case of simultaneous use of nevirapine with tenofovir, dose adjustment is not required.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz: AUC, C_max and C_min Efavirenz in the presence of nevirapine significantly decreased. Simultaneous use of nevirapine and efavirenz is not recommended due to the possible increase in toxicity, as well as the lack of evidence of additive effect in the appointment of this combination.

Delavirdine: interaction with nevirapine has not been studied. The use of this combination is not recommended.

Etravirine: simultaneous administration with nevirapine can lead to a significant decrease in the concentration of etravirin in the blood plasma and reduce the therapeutic effect of etravirine. The simultaneous use of etravirine with nevirapine is not recommended. Rilpivirin: rilpivirine it is metabolized with the participation of cytochrome P450 (CYP3A) isoenzymes, so when used with nevirapine, a decrease in the concentrations of rilpivirin in the blood plasma is possible. Simultaneous use with nevirapine is not recommended.

Protease Inhibitors

Atazanavir / ritonavir: simultaneous use of nevirapine with a combination of atazanavir / ritonavir (400/100 mg or 300/100 mg per day) leads to a decrease in AUC, C_max and C_min atazanavir, while AUC, Cmax and Cmin of nevirapine are increased. The simultaneous use of nevirapine with the combination atazanavir / ritonavir is not recommended.

Darunavir / ritonavir: simultaneous use of nevirapine with a combination of darunavir / ritonavir (400/100 mg 2 times a day) leads to an increase in AUC and C_mi_ndarunavir, while the concentration of nevirapine in the blood increases. With simultaneous use of nevirapine with a combination of darunavir / ritonavir correction of the dosing regimen is not required.

Fosamprenavir: simultaneous use of nevirapine with fosamprenavir (1400 mg twice a day) leads to a decrease in AUC, C_max and C_min amprenavir. The simultaneous use of nevirapine with fosamprenavir, not reinforced with ritonavir, is not recommended.

Fosamprenavir / ritonavir: with the simultaneous use of nevirapine with a combination of fosamprenavir / ritonavir in a usual dose (700/100 mg twice a day) nevirapine does not have a significant effect on the pharmacokinetics of amprenavir. With simultaneous use of nevirapine with a combination of fosamprenavir / ritonavir dosage regimen is not required.

Tipranavir / ritonavir: with the simultaneous use of nevirapine with a combination of tipranavir / ritonavir (500/200 mg twice a day) there was a clinically insignificant decrease C_mi_n tipranavir. With simultaneous use of nevirapine with a combination of tipranavir / ritonavir dosage regimen is not required.

Saquinavir / ritonavir: with simultaneous application, the combination of saquinavir (soft gelatin capsules) and ritonavir at a dose of 100 mg did not have a significant effect on the pharmacokinetics of nevirapine. The effect of nevirapine on the pharmacokinetics of saquinavir (soft gelatin capsules) in the presence of ritonavir at a dose of 100 mg is regarded as weak and clinically insignificant. With simultaneous use of nevirapine with a combination of saquinavir / ritonavir, the dosage regimen is not required.

Ritonavir: simultaneous administration of nevirapine and ritonavir (600 mg twice a day) did not lead to significant changes in plasma nevirapine concentrations. Nevirapine does not have a significant effect on the pharmacokinetics of ritonavir. With simultaneous application, correction of the dosing regimen is not required.

Indinavir: simultaneous administration of nevirapine and indinavir (800 mg every 8 hours) resulted in a decrease in the average values of AIN indinavir by 31%; the concentration of nevirapine in plasma did not change significantly. When indinavir is used together with nevirapine, an increase in the dose of indinavir to 1000 mg should be considered (every 8 hours).

Nelfinavir: with simultaneous application of nevirapine and nelfinavir (750 mg 3 times a day) no statistically significant changes in the pharmacokinetics of nelfinavir have been detected. Nelfinavir has no significant effect on plasma nevirapine concentrations. However, with respect to the main metabolite of nelfinavir, M8, which has comparable activity to the basic compound, a decrease in the mean values of AUC, C_max and C_m_in . With simultaneous use of nevirapine with nelfinavir, correction of the dosing regimen is not required.

Lopinavir / ritonavir: simultaneous use of nevirapine with lopinavir / ritonavir in a dose of 400/100 mg 2 times a day led to a decrease in the average values AUC and reduce Сmах and C_mi_n lopinavir. With simultaneous administration with nevirapine, an increase in the dose of lopinavir / ritonavir is recommended to 533/133 mg (4 capsules) or 500/125 mg (5 tablets with a dosage of 100/25 mg) twice daily with meals.

Correction of the dose of nevirapine is not required.

Inhibitors of fusion

Enfuvirtide: taking into account the peculiarities of metabolism, clinically significant pharmacokinetic interactions between enfuvirtide and nevirapine are not expected. Enfuvirtide is not displaced by nevirapine from the sites of its binding to plasma proteins. With simultaneous use of nevirapine and enfuvirtide correction of the dosing regimen is not required.

Maraviroc: with a simultaneous appointment with nevirapine AiSmaravirokane changes, there is an increase in C_max maraviroc. The effect of maraviroc on plasma nevirapine concentrations has not been studied, no clinically significant effect is expected. When administering maraviroc in a usual dose (300 mg twice a day) simultaneously with nevirapine without including a protease inhibitor or other powerful inhibitor of CYP3A in the regimen, correction of the dosing regimen is not required.

The dose of maraviroc should be reduced to 150 mg x 2 times a day when combined with nevirapine and a protease inhibitor (except for tprinavir / ritonavir.

Inhibitor integrals

Raltegravir: taking into account the peculiarities of metabolism (raltegravir is not a substrate of cytochrome P450 isoenzymes, does not inhibit or induce CYP3A), clinically significant pharmacokinetic interactions between raltegravir and nevirapine are not expected. With simultaneous use of nevirapine and raltegravir, correction of the dosing regimen is not required.

Other antiviral drugs

Boceprevir: boceprevir is partially metabolized by CYP3A4, so the simultaneous use of bocetrephir with drugs that are inducers or inhibitors of CYP3A4 may lead to an increase or decrease in the exposure of bocetrephir. There was a decrease in plasma concentrations of boceprevir with simultaneous administration with NNRTIs having the same metabolic pathways as nevirapine. The clinical significance of reducing the concentrations of bocetrephir was not assessed. The simultaneous use of nevirapine and boceprevir is not recommended.

Adefovir: in vitro There was a weak antagonism between nevirapine and adefovir. In clinical trials, this interaction is not confirmed, a decrease in efficacy is not expected. Adefovir does not affect the cytochrome P450 isoenzymes involved in the metabolism of drugs, and is excreted by the kidneys. It is not expected clinically significant interaction with the simultaneous administration of nevirapine and adefovir. Correction of the dosing regimen is not required.

Entecavir: taking into account the peculiarities of metabolism (entecavir is not a substrate, inducer or inhibitor of cytochrome P450 isoenzymes), clinically significant pharmacokinetic interactions between entecavir and nevirapine are not expected. With simultaneous use of nevirapine and entecavir, correction of the dosing regimen is not required.

Ribavirin: ribavirin is not an inducer or inhibitor of cytochrome P450 isoenzymes, clinically significant pharmacokinetic interactions between ribavirin and nevirapine are not expected. Correction of the dosing regimen is not required.

Telaprevir: telaprevir is mainly metabolized in the liver by the CYP3A isoenzyme, and is also a substrate of the P-glycoprotein.Drugs that are inducers of CYP3A or P-glycoprotein, can reduce the concentration of telaprevir in the blood plasma. The interaction of telaprevir and nevirapine was not studied. But with the simultaneous use of telaprevir with other NNRTIs, which have the same metabolic pathways as nevirapine (e.g. efavirenz), there is a decrease in the concentration of telaprevir in plasma. With simultaneous use of nevirapine with telaprevir, care should be taken, correction of doses of telaprevir is possible.

Telbivudine: taking into account the peculiarities of metabolism (telbivudine is not a substrate, inducer or inhibitor of cytochrome P450 isoenzymes), clinically significant pharmacokinetic interactions between telbivudine and nevirapine are not expected. With simultaneous use of nevirapine and telbivudine correction of the dosing regimen is not required.

Antifungal means

Ketoconazole: the use of nevirapine together with ketoconazole (400 mg once daily) resulted in a significant decrease in the median AUC and a decrease in the median C_maxketoconazole. Ketoconazole increases plasma nevirapine concentrations. Ketoconazole and nevirapine do not apply at the same time.

Fluconazole. The simultaneous use of fluconazole and nevirapine resulted in an increase in the effect of nevirapine by approximately 100%. There was no clinically significant effect of nevirapine on the pharmacokinetics of fluconazole. Due to the risk of increased exposure to nevirapine while using these drugs, care must be taken and the patients' condition carefully monitored.

Itraconazole: with simultaneous application of itraconazole and nevirapine, a decrease in AUC, C_max and C_mi_n itraconazole. Significant effects on the pharmacokinetic parameters of nevirapine itraconazole does not render. If it is necessary to simultaneously prescribe drugs, it is necessary to monitor the concentrations of itraconazole in the plasma and, if necessary, adjust the dosage of itraconazole. Consider the possibility of prescribing alternative antifungal drugs.

Pegylated interferons alpha-2a and alpha-2b: no effect of interferons on the activity of isoenzymes CYP2B6, CYP3A4. Therefore, clinically significant interaction between pegylated interferons alpha-2a and alpha-2b and nevirapine is not expected.With the simultaneous use of nevirapine with these drugs, correction of the dosing regimen is not required.

Other types of interaction

Antacids / Cimetidine: clinically significant interaction between cimetidine and nevirapine was not detected. With simultaneous use of nevirapine with cimetidine, correction of the dosing regimen is not required.

Anticoagulants

Warfarin: the observed in vitro interaction between nevirapine and warfarin is complex. As a result of the interaction, in the case of joint use of these drugs, the concentration of warfarin in the plasma can vary in such a way that there is a risk of both increasing and decreasing the clotting time. The resulting effect of this interaction may change during the first weeks of simultaneous use of drugs or after the withdrawal of nevirapine. In the case of simultaneous use of warfarin and nevirapine, frequent monitoring of prothrombin time is necessary.

Inductors of enzymes of the system cytochrome P450

Rifampicin: nevirapine does not have a significant effect on C_max and AUC of rifampicin. Rifampicin significantly reduces AUC (by 58%), C_max (by 50%) and C_min (by 68%) of nevirapine compared to baseline data. therefore rifampicin and nevirapine should not be applied simultaneously. If it is necessary to treat mycobacterial infections in patients taking nevirapine, rifabutin should be considered instead of rifampicin.

Rifabutin. With the simultaneous administration of nevirapine at a dose of 200 mg twice daily and rifabutin 300 mg once daily (or 150 mg once daily with zidovudine or protease inhibitors), an unreliable change in the concentrations of rifabutin (an increase in the median AUC of rifabutin by 12% and a decrease in the median C_min ss rifabutin by 3%) and to a significant increase in the median C_max ss by 20%. Significant changes in the concentrations of the active metabolite, 25-O-deacetyl-rifabutin, have not been established. There was a significant interindividual variability of the results.

In some patients, a significant increase in rifabutin concentrations is possible, which increases the risk of toxicity. Simultaneous use with rifabutin led to a clear and significant increase in the systemic clearance of nevirapine (by 9% compared with the control). However, none of these changes were clinically significant.

St. John's wort perforated (Hypericum perforatum): patients receiving nevirapine, should not take drugs / products containing St. John's wort, as it is expected that this can lead to a reduction in plasma nevirapine. This effect is due to induction of the isoenzyme CYP3A4 and can lead to loss of therapeutic effectiveness and development of resistance to nevirapine or to the entire class of NNRTIs. The induction effect of St. John's wort can be preserved for 2 weeks after its cancellation.

Inhibitors of the enzymes of the cytochrome P450 system

Clarithromycin: with simultaneous administration of nevirapine and clarithromycin, there is a significant decrease in AUC (by 30%), C_max (by 21%) and C_min (by 46%) of clarithromycin, but at the same time AUC (by 58%) and C_max (62%) of its active metabolite, 14-OH clarithromycin. There was a significant increase in C_min (by 28%) of nevirapine and an unreliable increase in its AUC (by 26%) and C_max(by 24%). These the data suggest that with the simultaneous use of these drugs, no change in their dosage is required. However, in the treatment of a patient with infection caused by the Mycobacterium avium-intracellulare complex, the use of an alternative drug (eg, azithromycin) should be considered, since the active metabolite of clarithromycin is ineffective in this case.

In addition, careful monitoring of liver function is recommended.

Oral contraceptives

Nevirapine (200 mg twice daily) was administered concomitantly with a contraceptive containing ethinyl estradiol 0.035 mg and norethidone 1.0 mg, taken only once inside. Compared to plasma concentrations established prior to the use of nevirapine, the median AUC 17-alpha-ethinyl estradiol after 28 days of the use of nevirapine significantly decreased (by 29%). There was also a significant decrease in the mean values of the circulation time and T_1/2 ethinylestradiol. A significant decrease (by 18%) in the medians AUC norethrodine (in the absence of changes in the mean values of the circulation time or T_1/2). The degree of these changes may indicate the need for correcting the dose of oral contraceptive in the case its use not for the purpose of contraception, but for other indications (for example, for the treatment of endometriosis) if it is used in conjunction with nevirapine. However, when using oral contraceptives containing estrogen / progesterone, there is also a risk of ineffective contraception.In the appointment of nevirapine to women with the ability to conceive, the use of other methods of contraception (for example, barrier methods) is recommended. In case of use in patients receiving nevirapine, oral contraceptive pills for other medical indications, it is necessary to monitor their therapeutic effect.

Other information

Research in vitro using human liver microsomes have shown that the formation of hydroxylated nevirapine metabolites in the presence of dapsone, rifabutin, rifampin and trimethoprim / sulfamethoxazole does not change. Ketoconazole and erythromycin significantly inhibited the formation of hydroxylated metabolites of nevirapine.

It should be taken into account that in the case of simultaneous application with nevirapine of other compounds that are substrates for isozymes of the subfamilies CYP3A or CYP2B, it is possible to reduce their concentrations in the plasma. Given the known information about the metabolism of methadone, it can not be ruled out that nevirapine can reduce the concentration of methadone in the plasma, by increasing its metabolism in the liver.There was reported the development of withdrawal syndrome in patients receiving concomitantly nevirapine and methadone. Patients receiving methadone should be monitored after initiating nevirapine therapy to identify withdrawal symptoms and, if necessary, they can be increased in methadone dose to reduce the symptoms.

Special instructions:

Critical is the first 18 weeks of therapy with nevirapine. During this period, careful monitoring of patients is required to identify possible severe and life-threatening skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) or severe hepatitis / liver failure. The greatest risk of unwanted reactions from the liver and dermatological reactions exists in the first 6 weeks of therapy. The risk of adverse events from the liver is elevated in women and in patients with a higher number CD4 + cells. It is necessary to adhere strictly to the recommended regimen of therapy, especially during the initial 14-day period.

Reactions from the skin

In patients who received nevirapine, there were serious and life-threatening dermatological reactions, including fatalities. There were cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome characterized by a rash, general reactions and internal organ damage. Careful observation of patients during the first 18 weeks of treatment is necessary. Careful observation is required in the case of development of an isolated rash. Nevirapine should be withdrawn from any patient in the event of a severe rash or rash accompanied by common symptoms (fever, blistering, changes in the oral cavity, conjunctivitis, facial edema, joint or muscle pain, general malaise), with Stevens-Johnson syndrome or toxic epidermal necrolysis. Nevirapine should be abolished in any patient in case of development of hypersensitivity reactions characterized by a rash and general symptoms, as well as changes in internal organs, including hepatitis, eosinophilia, granulocytopenia and renal dysfunction, or other signs of internal organ damage (see section "Side effect ").

Patients should be informed that the main manifestation of the toxicity of nevirapine is a rash. An initial treatment period should be used, since it is determined that this reduces the frequency of the rash (see the section on "Dosage and use"). In most cases, the rash associated with taking nevirapine occurs in the first six weeks of therapy. Therefore, during this period, careful monitoring of patients with dermatological reactions is necessary. Patients should be informed that if any rash develops during the initial treatment period, the dose should not be increased until the rash disappears. It was shown that the simultaneous use of prednisone (40 mg per day, during the first 14 days of taking nevirapine) does not reduce the incidence of rash, but, on the contrary, may increase 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 initial period of therapy. 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 appears to be greater than that of men, both in the case of nevirapine and in therapy not containing nevirapine.

A patient who develops a severe rash or rash accompanied by common symptoms (fever, blistering, changes in the oral cavity, conjunctivitis, facial edema, joint or muscle pain, general malaise) should stop taking the drug and consult a doctor. Repeated use of nevirapine in these patients is not allowed. If a patient has a rash and there is a suspicion of a relationship with taking nevirapine, a study of liver function should be performed. In patients with moderate or severe impairment (activity indicators ACT or ALT exceeds the upper limit of the norm by more than 5 times), nevirapine should be canceled.

In the case of hypersensitivity reactions characterized by a rash accompanied by common symptoms (fever, arthralgia, myalgia and lymphadenopathy) in combination with signs of internal organ damage, eg hepatitis, eosinophilia, granulocytopenia and kidney dysfunction, nevirapine must be canceled; repeated use of nevirapine is not allowed.

Reactions from the liver

Patients treated with nevirapine experienced serious or life-threatening hepatotoxicity, including fatal fulminant hepatitis. Critical is the first 18 weeks of treatment, during which careful monitoring is necessary. The highest risk of reactions from the liver is noted in the first 6 weeks of therapy. An increased risk of unwanted liver reactions is observed in women and patients with a higher number CD4 + cells. This risk persists in the future, so frequent monitoring should continue throughout the treatment. It is necessary to inform patients that liver reactions are the main type of nevirapine toxicity and that the appearance of signs indicating the development of hepatitis should be an occasion for prompt consultation with the doctor.

Serious hepatotoxicity, including the development of liver failure requiring liver transplantation, has been reported using multiple doses of nevirapine for postexposure prophylaxis of individuals who have not been infected with HIV, which is not an approved indication for the use of this drug.A higher risk of unwanted reactions from the liver during any antiretroviral therapy, including during the application of regimens that include nevirapine, is noted at the initial increase in activity ACT or ALT by more than 2.5 times compared with the upper limit of the norm and / or in the presence of hepatitis B and / or C. The risk of developing unwanted reactions from the liver associated with a rash in women appears to be three times higher , than for men (4.6% compared to 1.5%). The risk of developing unwanted liver reactions associated with a rash in the treatment with nevirapine may also be higher in patients with a higher number CD4 + cells. According to a retrospective analysis, in women with a number CD4 + cells more than 250 cells / mm³, the risk of hepatotoxic reactions associated with a rash was 9 times higher than in women with a number CD4 + cells less than 250 cells / mm³ (8.4% compared with 0.9%). Increased risk was observed in men with a number CD4 + cells> 400 cells / mm³ compared with men with a number CD4 + cells <400 cells / mm³ (4.5% compared to 0.7%).

Monitoring the liver

With the use of nevirapine, it was reported changes in liver function indicators, sometimes occurring in the first weeks of therapy.The asymptomatic increase in the activity of liver enzymes is described often and is not an unconditional contraindication for the use of nevirapine. Asymptomatic increase in gamma-glutamyl transferase is not a contraindication to the continuation of therapy. 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 with nevirapine. Doctors and patients should be wary of such prodromal signs or symptoms of hepatitis, as anorexia, nausea, jaundice, bilirubinemia, achalemic stool, hepatomegaly or liver tenderness. Patients should be informed of the need to seek medical advice in such cases.

In case of increased activity ACT or ALT is more than 2.5 times higher than the upper limit of the norm before or during treatment, liver function indicators should be checked more often during regular clinical visits. Nevirapine should not be administered to patients who have a baseline activity ACT or ALT is more than 5 times higher than the upper limit of the norm (until it steadily decreases to less than 5 times the upper limit of the norm).

If activity indicators ACT or ALT increase more than 5 times higher than the upper limit of the norm during treatment, nevirapine must be immediately canceled. If activity indicators ACT and ALT return to baseline values, and if the patient does not develop any clinical signs or symptoms of hepatitis, general symptoms or other phenomena that indicate abnormalities in the function of the internal organs, the use of nevirapine may be resumed (if there is a clinical need). A decision on this should be made in each case, based on clinical considerations. Repeated administration of nevirapine should be performed 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 liver function are resumed, nevirapine must be finally canceled.

If hepatitis occurs, accompanied by such clinical manifestations as anorexia, nausea, vomiting, jaundice, and laboratory disorders (moderate or significant changes in liver function parameters, without taking into account GGT), 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.

Rhabdomyolysis

In rare cases, in patients with skin and liver reactions associated with the use of nevirapine, rhabdomyolysis was observed. Patients should be warned that the first signs of muscle pain and weakness or darkening of urine should immediately stop taking the drug and contact your doctor to determine the level of creatine kinase in the blood.

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (for example, taking corticosteroids, drinking alcohol, acute immunosuppression, increased body mass index play an important role in the development of this complication), there are reports of such cases, especially in patients with progressive HIV infection / or long-term antiretroviral therapy.Patients should seek medical advice from a physician if symptoms such as lethargy, stiffness, joint pain or difficulty with movement occur. Lipodystrophy

In patients receiving antiretroviral therapy, there was a redistribution / accumulation of fatty tissue, including obesity of the central type, an increase in adipose tissue in the dorso-cervical region ("buffalo buffalo"), a reduction in the volume of peripheral adipose tissue, a reduction in subcutaneous fat in the face, mammary hypertrophy and "Cushingoid appearance." The mechanism of development and the long-term effects of these effects are currently unknown, their cause-and-effect relationship with the use of certain antiretroviral drugs has not been established.

Immunodeficiency Syndrome

In HIV-infected patients receiving combined antiretroviral therapy, the immune reconstitution syndrome was observed. In patients with severe immunodeficiency, an inflammatory response may occur in response to asymptomatic or residual opportunistic infections, which can lead to the development of serious clinical conditions or increased symptom severity.Such reactions are usually observed in the first few weeks or months of antiretroviral therapy. Examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumonia caused by Pneumocystis jirovecii. Any symptomatology of an inflammatory nature requires an appropriate evaluation and, if necessary, the initiation of treatment. Patients should be under close clinical supervision of specialists with experience in the treatment of patients with HIV disease. Autoimmune diseases (such as Graves' disease, Wagner's syndrome, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

Diseases of the liver

The results of pharmacokinetic studies indicate the need for caution when prescribing nevirapine to patients with moderate hepatic impairment (Child-Pugh class B). Nevirapine should not be administered to patients with severe impairment of liver function (Child-Pugh class C).

The risk of hepatotoxic effect of antiretroviral drugs in patients with co-infected HIV infection and the hepatitis B or C virus is higher than in the presence of only HIV infection. Therefore, patients with chronic hepatitis B or C who simultaneously take antiretroviral drugs are at increased risk of adverse effects on the liver with possible fatal outcome. These patients should be carefully monitored, both clinically and laboratory.

A higher risk of adverse reactions from the liver during any antiretroviral therapy, incl. and during the application of regimes including nevirapine, it is noted in patients with initial liver diseases, incl. with chronic active hepatitis. For patients with liver disease receiving nevirapine in combination antiretroviral therapy, careful monitoring should be conducted; if signs of impaired liver function appear, consideration should be given to the possibility of interrupting or canceling therapy.

Granulocytopenia

Granulocytopenia is usually associated with zidovudine.The risk of developing granulocytopenia is increased in patients receiving concomitantly nevirapine and zidovudine (especially in patients receiving zidovudine in high doses and patients with a reduced reserve of bone marrow). Such patients need careful monitoring of hematological parameters.

Other caveats

In the case of the use of nevirapine in combination with other antiretroviral drugs, the development of such undesirable reactions 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 nevirapine in combination with other drugs; the likelihood of the relationship of these reactions with the use of nevirapine is low.

Information on the ability of nevirapine to reduce the risk of horizontal transmission of HIV-1 to others is not available.

Although the ability of nevirapine to prevent mother-to-child transmission of HIV-1 (in women who have not received other antiretroviral drugs) is established to minimize the possibility of HIV-1 transmission to a child, more intensive mother-to-child treatment with antiretroviral drug combinations is recommended (when this is possible).

Pharmacokinetic studies performed in patients with impaired renal function on hemodialysis showed that adjuvant therapy with nevirapine supplemented with a dose of 200 mg after each dialysis session can help offset the effect of dialysis on nevirapine clearance. Thus, in patients with creatinine clearance greater than 20 mL / min, no dosage changes of nevirapine are required.

In women receiving nevirapine, oral contraceptives and other hormonal methods should not be used as the main method, since nevirapine can reduce the concentration of these drugs in the plasma. In addition, in the case of using nevirapine in oral contraceptives for hormonal regulation during therapy, monitoring of the therapeutic effect of hormonal treatment is necessary.

Existing data of pharmacokinetic studies indicate the inexpediency of simultaneous use of rifampicin and nevirapine. If it is necessary to treat concomitant tuberculosis in patients receiving treatment, including nevirapine, the possibility of using rifabutin may be considered. Rifabutin and nevirapine can be used together without changing the dosing.

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

Special studies to study the effect of the drug on the ability to drive and move vehicles have not been carried out. However, when evaluating a patient's ability to control a car and moving machinery, his general condition, as well as the nature of unwanted nevirapine reactions, should be taken into account.

Form release / dosage:

Tablets, film-coated, 100 mg and 200 mg each.

Packaging:

Primary packaging of medicinal product.

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30, 60, 100 or 500 tablets (for hospitals) in a can of polymer with a cover pulled with the control of the first opening. Free space is filled with cotton wool. On cans are labeled with paper label or from polymer materials, self-adhesive.

Secondary packaging of medicinal product.

For 3, 6 or 10 contour squares, together with the instruction for use, they are placed in a pack of cardboard for consumer packaging of subgroups chrome or chrome-ersatz, or of another similar quality. The packets are placed in a group package.

Banks, together with an equal number of instructions for use, are placed in a group package.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

4 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002406

Date of registration:21.03.2014 / 05.02.2016

Expiration Date:21.03.2019

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp26.06.2018

Illustrated instructions

Instructions

Nevirpin (Nevirpine)