Composition
Per 200 mg tablet:
Active ingredient: nevirapine – 200.00 mg.
Auxiliary substances: lactose monohydrate (milk sugar) – 220.10 mg; microcrystalline cellulose-165.00 mg; sodium carboxymethyl starch-22.00 mg; povidone-K 25-22.00 mg; magnesium stearate-6.40 mg; colloidal silicon dioxide-4.50 mg
Pharmacological action
Pharmacotherapy group:
antiviral [HIV] agent
ATX Code: J05AG01
Pharmacological properties
Pharmacodynamics
Nevirapine is a non-nucleoside reverse transcriptase (NNRTI) inhibitor 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 site of this enzyme. Nevirapine does not compete with matrix triphosphates or nucleoside triphosphates. Nevirapine has no significant inhibitory effect on HIV-2 reverse transcriptase and eukaryotic cell DNA polymerases (such as human DNA polymerases α, β, γ or σ).
Nevirapine should not be used as a monotherapy for the treatment of HIV infection or added as the only drug to existing therapy due to the rapid development of viral resistance, which is typical for all other non-nucleoside reverse transcriptase inhibitors.
When choosing antiretroviral drugs that are supposed to be used in combination with nevirapine, the possibility of developing cross-resistance should be taken into account.
In case of discontinuation of an antiretroviral therapy regimen containing nevirapine, it is necessary to keep in mind the long half-life of this drug. If the use of antiretroviral drugs with shorter half-lives than nevirapine is stopped at the same time, then HIV resistance may develop due to a low nevirapine concentration that persists for a week or more.
Pharmacokinetics
Suction
Nevirapine is well absorbed (>90%) after oral use in both healthy volunteers and adult patients with HIV-1 infection. Absolute bioavailability after a single dose of 50 mg nevirapine is 93±9%. The maximum concentration of nevirapine (Cmax) in plasma after a single dose of 200 mg was reached after 4 hours and was 2±0.4 mcg / ml (7.5 microns). After multiple doses, the maximum concentration (Cmax) of nevirapine increased linearly in the dose range from 200 to 400 mg/day. At steady state, Cmax is 5.74 mcg / ml, Cmin is 3.73 mcg / ml, and AUC is 109 h * mcg / ml, which corresponds to an equilibrium concentration of 4.5±1.9 mcg / ml in patients receiving 200 mg of nevirapine twice daily.
Distribution
Nevirapine is highly lipophilic and practically does not ionize at physiological pH. After intravenous use to healthy adult volunteers, the equilibrium volume of distribution of nevirapine (VdSS) was 1.21±0.09 l/kg, indicating a broad distribution of the drug in the human body.
Nevirapine penetrates well through the placental barrier and is detected in breast milk. The binding of nevirapine to plasma proteins is about 60%, its concentration in plasma varies from 1 to 10 micrograms/ml. The concentration of nevirapine in human cerebrospinal fluid is 45% (±5%) of the plasma; this ratio roughly corresponds to the fraction of the drug that is not associated with plasma proteins.
Metabolism and excretion.
In vivo and in vitro studies have shown that nevirapine undergoes intensive biotransformation involving cytochrome P450 isoenzymes (oxidative metabolism) to several hydroxylated metabolites. It is assumed that the oxidative metabolism of nevirapine is mediated by cytochrome P 450 isoenzymes from the CYP3A family of isoenzymes, and other isoenzymes may play an additional role. According to the results of a pharmacokinetic study of the mass / excretion balance (at steady state with 200 mg twice daily followed by 50 mg of 14C-nevirapine), approximately 91.4±10.5% of the isotope-labeled dose of the drug was determined in the urine (81.3±11.1%), indicating a predominant value of renal excretion compared to intestinal excretion (10.1±1.5%).
More than 80% of 14C-nevirapine detected in urine were conjugates of glucuronide and hydroxylated metabolites. Thus, cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion are the primary pathways for biotransformation and elimination of nevirapine in humans. Only a small fraction, less than 5%, of 14C-nevirapine in the urine (corresponding to
Nevirapine is an inducer of cytochrome P450 isoenzymes in the liver. The pharmacokinetics of autoinduction of nevirapine when taken orally as a single dose followed by a two-to four-week dose of 200-400 mg / day is characterized by an increase in clearance by 1.5-2 times.
Autoinduction also leads to a corresponding decrease in the terminal half-life of nevirapine from plasma: from about 45 hours (a single dose) to about 25-30 hours (after repeated use of the drug at doses of 200-400 mg / day).
Renal insufficiency
Renal insufficiency (mild – creatinine clearance 50-80 ml/min, moderate – creatinine clearance 30-50 ml/min or severe – creatinine clearance less than 30 ml/min) does not lead to significant changes in the pharmacokinetics of nevirapine. However, patients with end-stage renal failure requiring hemodialysis showed a 43.5% decrease in the area under the concentration-time curve (AUC) and accumulation of hydroxylated nevirapine metabolites in plasma. Adult patients are recommended to receive adjunctive nevirapine therapy with an additional dose of 200 mg after each dialysis session, which compensates for the effect of dialysis on drug clearance.
Liver failure
Nevirapine is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). Caution should be exercised in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).
Gender, age
Nevirapine clearance in women is 13.8% lower than in men. This difference is not considered clinically significant. Body weight and body mass index (BMI) do not affect the clearance of nevirapine. The pharmacokinetics of nevirapine in HIV-1 infected adult patients do not change with age (in the range of 19-86 years). Special studies of nevirapine use in patients over 65 years of age have not been conducted.
Children
Nevirapine clearance increases with age, which corresponds to an increase in body surface area. A dose of nevirapine 150 mg / m2 twice daily (after an initial two-week introductory period of 150 mg/m2 daily) provided geometric mean values of the minimum nevirapine concentration in the range of 4-6 mcg / ml (which coincides with the data in adults). The body surface area is calculated using the Mosteller formula (section “Dosage and use”).
Indications
Treatment of HIV-1 infection in combination antiretroviral therapy. To prevent mother-to-child transmission of HIV-1 in women who do not receive antiretroviral therapy during childbirth, nevirapine is indicated and can be used in the mother as monotherapy, in the form of a single dose taken orally during childbirth.
Use during pregnancy and lactation
In women taking nevirapine, oral contraceptives and other hormonal methods should not be used as the only method of contraception, as nevirapine can reduce their plasma concentration. For this reason, the use of barrier methods of contraception is recommended. In addition, if hormone therapy is used in the postmenopausal period during treatment with nevirapine, it is necessary to monitor the therapeutic effect of hormone therapy. The safety and efficacy of nevirapine, used to prevent mother-to-child transmission of HIV-1, has been established when the drug is administered once 200 mg orally by the mother during childbirth. Data obtained from pregnant women during the first, second, and third trimesters (according to the US Antiretroviral Pregnancy Registry) indicate that there are no fetal developmental disorders or embryo/fetus toxicity. Specific and well-controlled treatment studies in HIV-1-infected pregnant women have not yet been conducted. Nevirapine should only be used during pregnancy when the potential benefit outweighs the potential risk to the fetus. Use during pregnancy. Studies have shown that during labor in HIV-1-infected women, the half-life of nevirapine, after a single oral dose of 200 mg, is prolonged (up to 60-70 hours), and the clearance varies significantly (2.1±1.5 l/h), which depends on the degree of physiological stress during labor. Nevirapine quickly penetrates the placental barrier. The concentration of nevirapine in the umbilical cord blood after the mother took a dose of 200 mg exceeded 100 ng / ml, and the ratio of concentrations in the umbilical cord blood and in the mother’s blood was 0.84±0.19. Breast-feeding period. HIV-infected mothers should not breastfeed newborns to avoid the risk of postnatal transmission of HIV. Nevirapine passes freely through the placenta and is found in breast milk, so women taking nevirapine should stop breastfeeding. Fertility. In animal reproductive toxicology studies, there was a decrease in fertility in rats.
Contraindications
Hypersensitivity to the active ingredient or any other component of the drug.
Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
Nevirapine should not be re-prescribed to patients who previously, during nevirapine therapy, required its withdrawal due to severe rash, hypersensitivity reactions or the development of clinically pronounced hepatitis caused by taking the drug.
Severe hepatic impairment (Child-Pugh Class C) or cases of an initial increase in aspartate aminotransferase (ACT) or alanine aminotransferase (ALT) activity greater than 5 times the upper limit of normal, until AST/ALT activity decreases steadily to less than 5 times the upper limit of normal.
Nevirapine should not be re-prescribed to patients who have previously experienced an increase in ACT or ALT activity to a level more than 5 times higher than the upper limit of normal, or to patients who have experienced a resumption of liver function disorders after repeated use of nevirapine.
While taking nevirapine, herbal preparations containing St. John’s wort extract (Hypericum perforatum) should not be used, due to the risk of reducing the concentration of nevirapine in plasma and reducing its clinical effect.
Nevirapine is not recommended for use with efavirenz, rifampicin, ketoconazole, delavirdine, etravirine, rilpivirine, elvitegravir (together with cobicistat), boceprevir, as well as with fosamprenavir, saquinavir, atazanavir (if they are not used together with a low dose of ritonavir).
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).
With caution
Mild to moderate hepatic impairment (Child-Pugh class A and B); concomitant use with telaprevir, rifabutin, warfarin, methadone, lopinavir/ritonavir, claritoromycin, fluconazole, itraconazole, ethinylestadiol, indinavir.
Side effects
The most frequently reported adverse reactions associated with nevirapine therapy in all clinical trials were rash, allergic reactions, hepatitis, changes in liver function tests, nausea, vomiting, diarrhea, abdominal pain, fatigue, fever, headache, and myalgia.
According to post-marketing surveillance data, the most serious adverse reactions were: Stevens-Johnson syndrome, toxic epidermal necrolysis, severe hepatitis/liver failure, and drug reaction with eosinophilia and systemic symptoms characterized by a rash with common symptoms such as fever, arthralgia, myalgia, and lymphadenopathy, as well as internal organ involvement, namely the development of hepatitis, pancreatitis, eosinophilia, granulocytopenia and impaired renal function.
The first 18 weeks of therapy are critical and require close monitoring.
The following is the frequency of nevirapine-related adverse events according to the WHO classification: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (
Disorders of the blood and lymphatic system:Often-granulocytopenia, Infrequently-anemia.
Immune system disorders:Often – hypersensitivity (including anaphylactic reactions, angioedema, urticaria), Infrequently – anaphylactic reaction, Rarely – eosinophilia and systemic manifestations.
Nervous system disorders:Often – headache.
Disorders of the gastrointestinal tract:Often – nausea, vomiting, abdominal pain, diarrhea.
Liver and biliary tract disorders:Often – hepatitis (including severe life-threatening hepatotoxicity) (1.9%), Infrequently – jaundice, Rarely – fulminant hepatitis (possible fatal outcome).
Skin and subcutaneous tissue disorders:Very often – rash (12.5%), Infrequently – Stevens-Johnson syndrome, toxic epidermal necrolysis (possible fatal outcome) (0.2%), angioedema, urticaria.
Musculoskeletal and connective tissue disorders:Infrequently-arthralgia, myalgia. Rarely-rhabdomyolysis (in patients who have experienced skin and liver reactions when taking nevirapine).
General disorders and disorders at the injection site often – fever, fatigue. Laboratory and instrumental data Often – increased activity of liver functional tests (alanine aminotransferase, aspartate aminotransferase, transaminases; gamma-glutamyltransferase, liver enzymes; hypertransaminasemia), infrequently – hypophosphatemia, increased blood pressure.
Description of individual adverse reactions
According to the clinical study 1100.1090, from which the majority of adverse reactions were obtained (n=28), patients receiving placebo developed granulocytopenia more often (3.3%) than patients receiving nevirapine (2.5%).
Anaphylactic reactions were observed in the post-marketing period, but were not recorded in randomized controlled clinical trials. The frequency of their development was determined by statistical calculation, based on the total number of patients who participated in randomized controlled clinical trials (n=2718).
An increase in blood pressure and a decrease in blood phosphorus levels were observed during clinical studies with concomitant use of tenofovir or emtricitabine.
Metabolic rates:
Increased weight, blood lipids, and glucose levels have been reported during antiretroviral therapy.
Adverse reactions such as pancreatitis, peripheral neuropathy, and thrombocytopenia have been reported when nevirapine is used in combination with other antiretroviral drugs. These events are often associated with other antiretroviral drugs. They can be expected to occur when nevirapine is used in combination with other drugs; the likelihood of these reactions being associated with nevirapine is low.
HIV-infected patients with severe immunodeficiency may experience inflammatory reactions to non-symptomatic or residual opportunistic sputum organisms at the time of initiation of antiretroviral therapy. Autoimmune diseases (such as Graves ‘ disease) have also been reported to occur with immune reactivation; however, the reported time to onset is very variable, and these events may occur many months after the start of therapy.
Skin and subcutaneous fat:
The most common clinical sign of nevirapine toxicity is a rash. The rash is usually mild to moderate, characterized by maculopapular erythematous elements, accompanied or not accompanied by itching, localized on the trunk, face and limbs.
Allergic reactions (including anaphylaxis, angioedema, and urticaria) have been reported. The rash occurs in isolation or as part of a drug-induced rash with eosinophilia and systemic manifestations, characterized by general symptoms (such as fever, arthralgia, myalgia, and lymphadenopathy) and signs of internal organ damage (such as hepatitis, eosinophilia, granulocytopenia, and kidney dysfunction).
Patients receiving nevirapine may develop severe and life-threatening reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
Deaths from Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic manifestations have also been reported. The greatest risk of developing severe dermatological reactions occurs in the first 6 weeks of nevirapine therapy, some of which require hospitalization. One patient who required surgery was reported.
Liver and biliary tract disorders:
The most common 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 occurrence was an asymptomatic increase in GGT concentration. Isolated cases of jaundice and cases of severe and life-threatening hepatotoxicity, including fatal fulminant hepatitis, have been reported. The best predictor of severe liver complications is an increase in the concentration of biochemical parameters of liver function. Strict monitoring of liver function parameters is recommended at short intervals, depending on the clinical condition of patients, especially during the first 18 weeks of treatment.
Application in pediatrics:
Data on the safety of nevirapine in children were obtained in clinical trials involving 361 patients, most of whom received nevirapine in combination with zidovudine or didanosine, or with zidovudine and didanosine. The most frequently reported nevirapine-related adverse events were similar to those observed in adults, with the exception of granulocytopenia, which was more common in children. In an open-label clinical trial (ACTG 180), the incidence of granulocytopenia assessed as drug-related was 13.5%. In the double-blind placebo-controlled clinical trial ACTG 245, the incidence of granulocytopenia was 1.6%. Isolated cases of Stevens-Johnson syndrome or a transition syndrome between Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.
Interaction
Nevirapine is an inducer of liver cytochrome P 450 isoenzymes (CYP3A, CYP2B) and can lead to a decrease in plasma concentrations of other concomitantly used drugs that are intensively metabolized by CYP3A or CYP2B isoenzymes. Therefore, if a patient who has previously been selected for a dosage regimen of a drug that is metabolized by the CYP3A or CYB2B isoenzyme begins treatment with nevirapine, it may be necessary to adjust the dose of this drug. Maximum induction is observed within 2-4 weeks after the start of therapy. When administered concomitantly with nevirapine, plasma concentrations of drugs that are also metabolized by cytochrome p450 may decrease. Ingestion of food, antacids, or medications that contain an alkaline buffer does not affect nevirapine absorption. Interaction data is presented as a geometric mean with a 90% confidence interval, regardless of the time when this data was received. BUT = not detected, ↑ = increased, ↓ = reduced, ↔ = no exposure.
| Medicinal products | Interactions | Recommendations for use |
| Anti-infective measures | ||
| Antiretroviral drugs | ||
| NRTIs (Nucleoside analogues of reverse transcriptase inhibitors) | ||
| Didanosine 100-150 mg 2 r / day | Didanosine AUC ↔ 1.08 (0.92-1.27)Cmin of didanosine not detectable Cmax 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 CYP450 enzyme in humans | Nevirapine and emtricitabine can be administered simultaneously without dose adjustment |
| Abacavir | Abacavir does not inhibit cytochrome P 450 isoforms in human liver microsomes | Nevirapine and abacavir can be administered simultaneously without dose adjustment |
| Lamivudine 150 mg 2 r / day | There are no changes in the apparent clearance and volume of distribution of lamivudine | Nevirapine and lamivudine can be administered simultaneously without dose adjustment |
| Stavudine 30/40 mg 2 r / day | Stavudine AUC ↔ 0.96 (0.89-1.03)Cmin of stavudine, CMAX of stavudine ↔ 0.94 (0.86-1.03)Nevirapine: compared with retrospective control data, the level remains unchanged | Nevirapine and stavudine can be administered simultaneously without dose adjustment |
| Tenofovir 300 mg daily | When co-administered with nevirapine, tenofovir plasma levels remain unchanged. | Nevirapine and tenofovir can be administered simultaneously without dose adjustment |
| Zidovudine 100-200 mg 3 r / day | Zidovudine AUC ↓ 0.72 (0.60-0.96)Zidovudine cmin, zidovudine cmax ↓ 0.70 (0.49-1.04)Nevirapine: zidovudine has no effect on its pharmacokinetics | Nevirapine and zidovudine can be administered simultaneously without dose adjustment. While taking zidovudine, granulocytopenia often develops, so in such patients, careful monitoring of hematological parameters should be carried out. |
| NNRTIs (Non-nucleoside analogues of reverse transcriptase inhibitors) | ||
| Efavirenz 600 mg daily | Efavirenz AUC ↓ 0.72 (0.66-0.86)Efavirenz Cmin ↓ 0.68 (0.65-0.81)Efavirenz cmax ↓ 0.88 (0.77-1.01) | Concomitant use of efavirenz and nevirapine is not recommended due to increased toxic effects and lack of improvement in efficacy compared to NNRTIs alone. |
| Delavirdin | The interaction was not studied. | Concomitant use of nevirapine and NNRTIS is not recommended |
| Etravirine | Concomitant use of etravirine and nevirapine may cause a significant decrease in plasma concentrations of etravirine and a loss of its therapeutic effect. | Concomitant use of nevirapine and NNRTIS is not recommended |
| Rilpivirine | The interaction was not studied. | Concomitant use of nevirapine and NNRTIs is not recommended |
| by IP (Protease inhibitors) | ||
| Atazanavir / ritonavir 300/100 mg daily 400/100 mg daily | Atazanavir / ritonavir 300/100 mg:Atazanavir / ritonavir AUC ↓ 0.58 (0.48-0.71)Cmin ↓ 0,28 (0,20-0,40)Cmax ↓ 0,72 (0,60-0,86)Atazanavir / ritonavir 400/100 mg:Atazanavir / ritonavir AUC ↓ 0.81 (0.65-1.02)Cmin ↓ 0.41 (0.27-0.60)Cmax ↔ 1.02 (0.85-1.24) (compared to 300/100 mg without nevirapine)Nevirapine AUC ↑ 1.25 (1.17-1.34)Cmin ↑ 1,32 (1,22-1,43)Cmax ↑ 1,17(1,09-1,25) | Concomitant use of atazanavir / ritonavir and nevirapine is not recommended. |
| Darunavir / ritonavir 400/100 mg 2 r / day | Darunavir AUC ↑ 1.24 (0.97-1.57)Cmin ↔ 1.02 (0.79-1.32)Cmax ↑ 1.40 (1.14-1.73)Nevirapine AUC ↑ 1.27 (1.12-1.44)Cmin ↑ 1,47(1,20-1,82)Cmax ↑ 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)Cmin ↓ 0,65 (0,49-0,85)Cmax ↓ 0,75 (0,63-0,89)Nevirapine AUC ↑ 1.29 (1.19-1.40)Cmin ↑ 1,34(1,21-1,49)Cmax ↑ 1,25 (1,14-1,37) | Concomitant use of fosamprenavir and nevirapine is not recommended if fosamprenavir is administered without ritonavir |
| Fosamprenavir / ritonavir 700/100 mg 2 r / day | Amprenavir AUC ↔ 0.89 (0.77-1.03)Cmin ↓ 0,81 (0,69-0,96)Cmax ↔ 0,97 (0.85-1,10)Nevirapine AUC ↑ 1.14 (1.05-1.24)Cmin ↑ 1.22 (1.10-1.35)Cmax↑ 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)Cmin ↓ 0,54 (0,28-0,74)Cmax ↓ 0,81 (0,62-0,95) | When administered concomitantly with nevirapine, it is recommended to increase the dose of lopinavir /ritonavir to 533/133 mg (4 capsules) or 500/125 mg (5 tablets of 100/25 mg each) twice a day with meals. When administered concomitantly with lopinavir, no dose adjustment of nevirapine is required. |
| Lopinavir / ritonavir (oral solution) 300/75 mg / m2 2 r / day | Children:Lopinavir AUC ↓ 0.78 (0.56-1.09)Cmin ↓ 0,45 (0,25-0,82)Cmax ↓ 0,86 (0,64-1,16) | When used concomitantly with nevirapine in children, increasing the dose of lopinavir /ritonavir to 300/75 mg/m2 twice daily should be considered, especially if there is a suspected decrease in sensitivity to lopinavir /ritonavir. |
| Ritonavir 600 mg 2 r / day | Ritonavir AUC ↔ 0.92 (0.79-1.07)Cmin ↔ 0.93 (0.76-1.14)Cmax = 0.93 (0.78-1.07)Nevirapine: concomitant use of ritonavir does not lead to any clinically significant changes in nevirapine plasma levels. | Nevirapine and ritonavir can be administered simultaneously without dose adjustment |
| Saquinavir /ritonavir | Limited data available on the use of soft gel capsules of saquinavir enhanced with ritonavir do not indicate any clinically significant interaction between saquinavir enhanced with ritonavir and nevirapine | Saquinavir / ritonavir and nevirapine may be administered concomitantly without dose adjustment. |
| Tipranavir / ritonavir 500/200 mg 2 r / day | No specific drug interaction studies have been conducted. Limited data obtained in the phase IIa study in patients infected with HIV showed a clinically insignificant 20% decrease in the Cmin of tipranavir. | Tipranavir and nevirapine can be administered simultaneously without dose adjustment. |
| Fusion / penetration inhibitors | ||
| Enfuvirtide | Due to the specific pathways of metabolism, no clinically significant pharmacokinetic interactions are expected between enfuvirtide and nevirapine. | Enfuvirtide and nevirapine can be administered simultaneously without dose adjustment. |
| Maraviroc 300 mg daily | Maraviroc AUC ↔ 1.01 (0.6-1.55)Cmin, vehicle max ↔ 1.54 (0.94-2.52) compared to previously known control data. Nevirapine concentrations have not been measured and no effect is expected. | Maraviroc and nevirapine can be administered simultaneously without dose adjustment. |
| Integrase inhibitors | ||
| Elvitegravir /cobicistat | The interaction was not studied. Cobicistat, an inhibitor of cytochrome P450 – 3A, significantly inhibits liver enzymes, as well as other metabolic pathways. Therefore, when co-administered, changes in plasma levels of cobicistat and nevirapine are likely. | Concomitant use of nevirapine and a combination of elvitegravir and cobicistat is not recommended. |
| Raltegravir 400 mg 2 r / day | There are no available clinical data. Due to the specific pathways of raltegravir metabolism, no interactions are expected. | Raltegravir and nevirapine can be administered simultaneously without dose adjustment. |
| Antibiotics | ||
| Clarithromycin 500 mg 2 r / day | Clarithromycin AUC ↓ 0.69 (0.62-0.76)Cmin ↓ 0,44 (0,30-0,64)Cmax ↓ 0,77 (0,69-0,86)Clarithromycin 14-OH metabolite AUC ↑ 1.42(1.16-1.73)Cmin ↔ (0,68-1,49)Cmax ↑ 1,47 (1,21-1,80)Nevirapine AUC ↑ 1.26 Cmin ↑ 1.28 Cmax ↑ 1.24 Compared to available historical control data. | Clarithromycin concentrations were significantly reduced, while concentrations of the 14-OH metabolite were significantly increased. Since the effect of the active clarithromycin metabolite on Mycobacterium avium-intracellulare complex was reduced, the overall activity against pathogens may vary. Alternative medications such as azithromycin should be considered. Careful monitoring of liver changes is recommended. |
| Rifabutin 150 or 300 mg daily | Rifabutin AUC ↑ 1.17 (0.98-1.40)Cmin ↔ 1,07 (0,84-1,37)Cmax ↑ 1,28 (1,09-1,51)Metabolite of 25-O-Deacetylrifabutine AUC ↑ 1.24 (0.84-1.84)Cmin ↑ 1,22 (0,86-1,74)Cmax ↑ 1,29 (0,98-1,68)A clinically insignificant increase in the apparent clearance of nevirapine (by 9%) compared to previously known data has been reported. | No significant effect on the pharmacokinetic parameters of rifabutin and nevirapine was observed. Rifabutin and nevirapine can be administered simultaneously without dose adjustment. However, due to the high inter-individual variability, some patients may experience increased rifabutin action, which may lead to an increased risk of developing toxic effects of rifabutin. Therefore, caution should be exercised when prescribing concomitantly. |
| Rifampicin 600 mg daily | Rifampicin AUC↔ 1.11 (0.96-1.28)Cmax ↔ 1.06 (0.91-1.22)Nevirapine AUC ↓ 0.42 Cmin ↓ 0.32 Cmax ↓ 0.50 compared to previously known control data. | Concomitant use of rifampicin and nevirapine is not recommended. For the treatment of patients with tuberculosis infection, the use of rifabutin instead of rifampicin should be considered. |
| Antifungal medications | ||
| Fluconazole 200 mg daily | Fluconazole AUC ↔ 0.94 (0.88-1.01)Cmin ↔ 0,93 (0,86-1,01)Cmax ↔ 0,92 (0,85-0,99)Nevirapine: exposure: ↑ 100% compared to previously known data when only nevirapine alone was prescribed. | Risk of increased nevirapine action. Patients should be closely monitored. |
| Itraconazole 200 mg daily | Itraconazole AUC ↓ 0.39 Cmin ↓ 0.13 Cmax ↓ 0.62 Nevirapine: there was no significant difference in the pharmacokinetic parameters of nevirapine. | Increasing the dose of itraconazole should be considered when these two drugs are co-administered. |
| Ketoconazole 400 mg daily | Ketoconazole AUC ↓ 0.28 (0.20-0.40)Cmin, NOSmax ↓ 0.56 (0.42-0.73) Nevirapine: plasma levels: ↑ 1.15-1.28 compared to previously known control data. | Concomitant use 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 reduction in efficacy is expected. Adefovir does not affect the usual isoforms of CYP, which are known to be involved in drug metabolism in humans, and is excreted by the kidneys. No clinically significant drug interaction is expected. | Adefovir and nevirapine can be administered simultaneously without dose adjustment. |
| Boceprevir | Boceprevir is partially metabolized by the enzyme CYP3A4 / 5. Concomitant use with drugs that activate or inhibit the CYP3A4/5 isoenzyme may increase or decrease exposure. Residual plasma concentrations of boceprevir were reduced by use of NNRTIs with a similar metabolic pathway as nevirapine. The clinical outcome of this reduction in the residual concentration of boceprevir has not been directly studied. | Concomitant use of boceprevir and nevirapine is not recommended. |
| Entecavir | Entecavir is not a cytochrome P450 substrate, inducer, or inhibitor. Due to the specific pathways of entecavir metabolism, no clinically significant interactions are expected. | Entecavir and nevirapine can be administered simultaneously without dose adjustment. |
| Interferons (pegylated interferons alpha 2A and alpha 2b) | Interferons have no known effects on CYP 3A4 or 2B6. No clinically significant interactions are expected. | Interferons and nevirapine can be administered simultaneously without dose adjustment. |
| Ribavirin | Ribavirin does not inhibit cytochrome P 450. Ribavirin did not induce liver enzymes in toxicity studies. No clinically significant interactions are expected. | Ribavirin and nevirapine can be administered simultaneously without dose adjustment. |
| Telaprevir | Telapreir is metabolized in the liver by the enzyme CYP3A and is a P-glycoprotein substrate. Other enzymes may also be involved in this metabolism. Concomitant use of telaprevir and drugs that induce CYP3A and / or P-glycoprotein may reduce plasma concentrations of telaprevir. No studies on the interaction of telaprevir and nevirapine have been conducted, however, studies on the interaction of NNRTIs with a similar nevirapine metabolism pathway have shown a decrease in the level of both drugs. | Caution should be exercised when telaprevir and nevirapine are co-administered, and the possibility of adjusting the dose of telaprevir should be taken into account. |
| Telbivudine | Telbivudine is not a cytochrome P450 substrate, inducer, or inhibitor. Due to the specific pathways of telbivudine metabolism, no clinically significant interactions are expected. | Telbivudine and nevirapine can be administered simultaneously without dose adjustment. |
| Antacids | ||
| Cimetidine | Cimetidine: no significant effect on the pharmacokinetic parameters of cimetidine was observed. Nevirapine Cmin ↑ 1.07 | Cimetidine and nevirapine can be administered simultaneously without dose adjustment. |
| Anticoagulants | ||
| Warfarin | The interaction between the anticoagulant warfarin and nevirapine is complex; however, there is a possibility of both an increase and a decrease in clotting time when they are used simultaneously. | Careful monitoring of clotting levels is required. |
| Contraceptives | ||
| Depot-Medroxyprogesterone acetate (DMPA) 150 mg every 3 months | DMPA AUC Cm Cmin ↔Cmax↔Nevirapine AUC ↑ 1.20 Cmax ↑ 1.20 | When administered concomitantly, nevirapine does not affect the suppression of ovulation caused by DMPA. DMPA and nevirapine can be administered simultaneously without dose adjustment. |
| Ethinyl Estadiol (EE) 0.035 mg | EE AUC ↓ 0.80 (0.67-0.97)Cmin Max ↔ 0.94 (0.79-1.12) | Oral hormonal contraceptives should not be used as the only method of contraception for women taking nevirapine. The safety and efficacy of acceptable doses of hormonal contraceptives (oral or other forms of use) other than DMPA have not been established. |
| Norethindrone (NET) 1.0 mg per day | NET AUC ↓ 0.81 (0.70-0.93)Cmin HOCmax ↓ 0,84 (0,73-0,97) | |
| Analgesics /Opioids | ||
| Methadone, individual dosage | Methadone AUC ↓ 0.40 (0.31-0.51)Cmin, max HOC 0.58 (0.50-0.67) | Patients taking methadone should be monitored for withdrawal symptoms prior to nevirapine therapy, and the dose of methadone should be adjusted accordingly. |
| Herbal preparations | ||
| St. John’s wort (Hypericum perforatum) | With simultaneous use of the herbal preparation of St. John’s wort (Hypericum perforatum) serum nevirapine levels may decrease. | You can not simultaneously prescribe herbal preparations of St. John’s wort and nevirapine. If the patient is already taking these medications, nevirapine concentrations and, if possible, viral load levels should be checked, and medications containing St. John’s wort extract should be discontinued. After their withdrawal, the concentration of nevirapine may increase. It may be necessary to change the dose of nevirapine. After discontinuation of medications containing St. John’s wort extract, the inducing effect may persist for at least 2 weeks. |
How to take, course of use and dosage
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Nevirapine should be prescribed by a doctor who has experience in treating HIV infection. The drug should only be taken in combination with at least two additional antiretroviral drugs.
Tablets should be taken with water, not broken or chewed. Nevirapine can be taken regardless of food intake.
The total daily dose for any patient should not exceed 400 mg.
Treatment of HIV infection:
Patients over 16 years of age with a body weight of more than 50 kg or with a body surface area (PP’G according to the Mosteller formula) of more than 1.25 m2
The recommended dose of nevirapine is 200 mg for the first 14 days of treatment (it has been shown that the use of such an introductory period reduces the frequency of rash), followed by switching to taking 200 mg tablets twice a day in combination with at least two additional antiretroviral drugs.
If the patient has missed the next dose of the drug, and no more than 8 hours have passed since the missed dose, you should take the missed dose as soon as possible.
If the next dose is missed for more than 8 hours, the patient should only take the next dose at the usual time. If a skin rash develops during this period, then you should 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 (Mosteller’s formula) are recommended to use the suspension for oral use.
General recommendations:
Patients who develop a skin rash during the initial 14-day introductory period of taking the drug at a dose of 200 mg per 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 with the use of 200 mg of the drug once a day should not last more than 28 days, by which time alternative therapy should be selected in a timely manner, due to the risk of developing resistance against the background of insufficient doses of the drug.
Patients who have stopped taking the drug for more than 7 days should start therapy again with a two-week introductory period of 200 mg once a day.
Preventing mother-to-child transmission of HIV-1:
To prevent vertical transmission of HIV-1 infection during labor, a pregnant woman should receive a single 200 mg tablet as soon as possible after the start of labor.
Special patient groups:
Elderly patients:
Special studies of nevirapine use in patients over 65 years of age have not been conducted.
Impaired renal function
In patients with impaired renal function requiring hemodialysis (creatinine clearance < 20 ml/min), an additional 200 mg of the drug is recommended after each hemodialysis procedure. Patients with creatinine clearance greater than 20 ml/min do not need to adjust the dose of nevirapine.
Liver function disorders
Nevirapine is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), no dose adjustment is required, but such patients should be closely monitored for adverse reactions.
Overdose
There is no specific antidote for nevirapine overdose. When nevirapine overdosed (taking 800 to 6000 mg per day for up to 15 days), the following symptoms were observed: edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, infiltrates, rash, dizziness, vomiting, increased activity of “liver” transaminases and weight loss. Treatment: discontinuation of the drug.
Special instructions
The first 18 weeks of nevirapine therapy are critical and require close monitoring of patients for possible severe and life-threatening skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) and serious hepatic / renal failure. The greatest risk of developing liver and skin reactions occurs in the first 6 weeks of therapy.
Also keep in mind that nevirapine does not prevent HIV-1 transmission.
Clinical biochemical tests, including liver function tests, should be performed before starting nevirapine therapy 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. Liver tests should be monitored if the patient has symptoms or signs of hepatitis and / or hypersensitivity.
If the activity of ACT or ALT enzymes is more than 2.5 times higher than the upper limit of normal before or during treatment, liver function indicators should be monitored more often during regular examinations. Nevirapine should not be administered to patients with an increase in ACT or ALT activity of more than 5 times the upper limit of normal until the initial values of ACT or ALT are stabilized to a level less than 5 times the upper limit of normal.
Liver diseases:
Nevirapine should not be used in patients with severe hepatic impairment (Child-Pugh Class C).
All patients, especially those with mild to moderate hepatic insufficiency, should be closely monitored for timely detection of toxic reactions, since the risk of any liver reactions persists even after the first 18 weeks of therapy, so monitoring should be continued at frequent intervals. Patients with chronic hepatitis B or C receiving combination antiretroviral therapy are at an increased risk of severe and life-threatening adverse events from the hepatobiliary system. In the case of simultaneous use of antiviral drugs for the treatment of viral hepatitis B or C, you should follow the information in the instructions for use of these drugs.
Patients with pre-existing hepatic impairment, including the active form of chronic hepatitis, show an increase in the incidence of hepatic impairment with combined antiretroviral therapy. Such patients should be monitored in accordance with standard clinical practice. Consideration should be given to suspending or discontinuing treatment in the event of worsening liver disease in such patients.
Being female and/or having an increased CD4 cell count (>250/mm3 in adult women and 400/mm3 in adult men) at the start of nevirapine therapy is associated with a higher risk of hepatic adverse reactions if HIV RNA is detected in the patient’s plasma, i. e. a concentration of ≥50 copies / ml at the start of nevirapine therapy.
Due to the possible development of severe and life-threatening hepatotoxic reactions, nevirapine therapy should not be initiated in adult women with a CD4 cell count of more than 250 in 1 ml3 or adult men with a CD4 cell count of more than 400 in 1 mm3, in whom HIV-1 RNA is detected in plasma, if the benefit does not outweigh the risk.
Rhabdomyolysis: In rare cases, rhabdomyolysis has been observed in patients with skin and liver reactions associated with nevirapine use.
Osteonecrosis: Cases of osteonecrosis have been reported, especially in patients with established risk factors, progressing HIV infection, or receiving long-term combination antiretroviral therapy. The frequency of development is unknown. Patients should be advised to seek medical attention if they experience aches and pains in their joints or difficulty moving.
Skin reactions: nevirapine should be discontinued in any patient who develops a severe rash or rash accompanied by general symptoms (fever, blistering, changes in the oral mucosa, conjunctivitis, facial edema, joint and muscle pain, general malaise), Stevens-Johnson syndrome, or toxic epidermal necrolysis. Nevirapine should be discontinued and should not be re-prescribed in any patient who develops a hypersensitivity reaction characterized by rash and general symptoms of internal organ damage, such as hepatitis, eosinophilia, granulocytopenia and impaired renal function, as well as in the case of other internal organ changes.
Patients should be informed that the main manifestation of nevirapine toxicity is rash. An introductory initial treatment period should be used, as this has been found to reduce the frequency of 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 carefully monitored for dermatological reactions. Patients should be advised that if any rash develops during the initial introductory treatment period, the dose of the drug should not be increased to twice a day until the rash disappears. The dosage regimen with 200 mg of the drug once a day should not last more than 28 days, by which time a different regimen should be developed. In rare cases, rhabdomyolysis has been observed in patients with skin and liver reactions associated with nevirapine use.
It has been shown that concomitant use of prednisone (40 mg / day, during the first 14 days of nevirapine use) 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 developing serious skin reactions is violation of the recommendation to use the drug at a dose of 200 mg per day during the initial initial treatment period. The risk of developing more serious outcomes of dermatological reactions increases if there is a delay in seeking medical advice after the onset of symptoms. The risk of developing a rash in women is higher than in men, both with nevirapine and with nevirapine-free therapy.
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 people, have an increased risk of developing granulocytopenia. In such patients, blood counts should be monitored periodically.
Liver reactions: it is necessary to inform the patient that liver reactions are the main type of toxicity of nevirapine. Patients who show signs or symptoms of hepatitis should stop taking the drug and immediately contact a medical institution for examination, which should include an assessment of liver function indicators. When using multiple doses of nevirapine for post-exposure prophylaxis in people who were not infected with HIV, severe manifestations of hepatotoxicity, including the development of liver failure requiring liver transplantation, have been reported.
Post-exposure prophylaxis for people who have not been infected with HIV is not an approved indication for the use of the drug and is therefore strongly discouraged.
A high risk of adverse liver reactions during any antiretroviral therapy (including nevirapine-based therapy) is observed when the initial increase in the activity of ACT or ALT enzymes is more than 2.5 times higher than the upper limit of normal, and/or in the presence of hepatitis B and / or C.
Liver condition monitoring: an asymptomatic increase in the activity of liver enzymes and gamma-glutamyltransferase (GGT) is often described and is not an absolute contraindication for the use of nevirapine.
Strict monitoring of liver function parameters is recommended at short intervals, depending on the clinical condition of patients, especially during the first 18 weeks of treatment. Clinical and laboratory monitoring should continue throughout the entire treatment period. Doctors and patients should be wary of prodromal signs or symptoms of hepatitis such as anorexia, nausea, jaundice, bilirubinemia, fecal discoloration, hepatomegaly, or liver soreness. Patients should be informed about the need to seek medical advice in such cases.
If the activity of ACT or ALT enzymes is more than 2.5 times higher than the upper limit of normal before or during treatment, liver function indicators should be monitored more often during regular examinations.
Nevirapine should not be used in patients whose initial ACT or ALT activity is more than 5 times the upper limit of normal (until it consistently decreases to less than 5 times the upper limit of normal).
If the activity of ACT or ALT enzymes increases more than 5 times the upper limit of normal during treatment, nevirapine should be immediately discontinued. If the activity of the ACT and ALT enzymes returns to the initial values and if the patient does not experience any clinical signs or symptoms of hepatitis, or general symptoms or other phenomena indicating impaired internal organ function, the use of nevirapine may be resumed (if there is a clinical need). This decision should be made on a case-by-case basis, based on clinical necessity. Repeated use of nevirapine should be carried out in conditions of increased clinical and laboratory alertness, at an initial dose of 200 mg / day (for 14 days), followed by its increase to 400 mg/day. If liver dysfunction persists, nevirapine should be permanently discontinued.
Nevirapine should be permanently discontinued if hepatitis develops with clinical manifestations such as anorexia, nausea, vomiting, jaundice and changes in laboratory parameters (moderate or significant changes in liver function indicators, without taking into account gamma-glutamyltransferase activity). Nevirapine should not be re-administered to those patients who have required its withdrawal due to the development of clinically pronounced hepatitis caused by nevirapine.
Weight and metabolic parameters: against the background of ongoing antiretroviral therapy, an increase in body weight and an increase in the concentration of glucose and lipids in the blood can be observed. These changes may be partly related to the disease itself and lifestyle. In some cases, the effect of therapy on increasing the concentration of lipids has been proven, but there is no convincing data indicating the effect of therapy on weight gain. Monitoring of glucose and lipid concentrations in the blood should be carried out in accordance with the recommendations for the treatment of HIV infection. Lipid metabolism disorders should be corrected if clinically necessary.
Immune recovery syndrome: HIV-infected patients with severe immunodeficiency may experience inflammatory reactions to non-symptomatic or residual opportunistic microorganisms at the time of use of combined antiretroviral therapy, which may lead to the development of serious clinical conditions or worsen the symptoms of the disease. Usually, such reactions were observed within the first few weeks or months after the start of combined antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and / or local mycobacterial infections, and pneumonia caused by Pneumocystis jirovecii. Any inflammatory symptoms should be identified and treatment should be initiated if necessary. Autoimmune diseases (such as Graves ‘ disease) have also been reported to occur with immune reactivation: however, the reported time to onset is very variable and these events may occur many months after the start of therapy.
Nevirapine is not recommended for use with efavirenz, rifampicin, ketoconazole, delavirdine, etravirine, rilpivirine, elvitegravir (together with cobicistat), boceprevir, as well as with fosamprenavir, saquinavir, atazanavir (if they are not used together with a low dose of 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 nevirapine does not prevent transmission of HIV-1 to healthy people through blood and unprotected sexual contact.
Influence on the ability to drive vehicles and mechanisms
No special studies have been conducted on the ability to drive motor vehicles and manage mechanisms. However, patients should be advised that adverse reactions such as fatigue and headache may occur during treatment with nevirapine, and that driving vehicles or operating machinery should be avoided.
Storage conditions
At a temperature not exceeding 25 °C. Keep out of reach of children.
Shelf
life is 3 years. Do not use the product after the expiration date.
Active ingredient
Nevirapine
Conditions of release from pharmacies
By prescription
Dosage form
Tablets
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