Nevirapine

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Nevirapine: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Nevirapine

ATX code: J05AG01

Active ingredient: nevirapine (Nevirapine)

Manufacturer: Ozone LLC (Russia); Drug Technology LLC (Russia); Emkyur Pharmaceuticals, Ltd. (Emcure Pharmaceuticals, Ltd.) (India); Aurobindo Pharma, Ltd (India)

Description and photo update: 2019-15-03

Nevirapine is an antiviral drug that is active against the human immunodeficiency virus (HIV).

Release form and composition

The drug is released in the form of tablets: a dosage of 100 or 200 mg - almost white or white, flat-cylindrical, round, with a risk on one side and a chamfer; dosage of 200 mg - almost white or white, biconvex, oval, on one side there is an engraving "C" and "35" and a risk between them, and on the other side there is only a risk; dosage 200 mg - from pale yellow to white, biconvex, oval, capsule-shaped, on one side with NVR engraving, on the other side with a line [100/200 mg tablets - 7, 10, 20, 25 or 30 pcs. … in a contour acheikova packing / 10, 20, 30, 40, 50, 60, 100 or 120 pcs. in a polypropylene or polyethylene terephthalate can, in a cardboard box 1, 2, 3, 4, 6, 10 or 12 packages / 1 can; tablets 200 mg - 60 pcs. in a high density polyethylene container / 30 or 60 pcs.in a bottle (can), polymer or plastic / 10 pcs. in a blister, in a cardboard box 1 bottle (can) / 1 container / 2 blisters. Each pack also contains instructions for the use of Nevirapin].

Other packaging and appearance options are available depending on the manufacturer.

1 tablet contains:

active substance: nevirapine - 100 or 200 mg;
additional components: sodium carboxymethyl starch, lactose monohydrate (milk sugar), microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate; depending on the manufacturer - additionally povidone K25 / povidone K30, for 200 mg tablets - pregelatinized starch, sodium lauryl sulfate, talc.

Pharmacological properties

Pharmacodynamics

Nevirapine belongs to HIV type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs). The active substance directly forms a bond with reverse transcriptase and inhibits the activity of DNA-dependent and RNA-dependent DNA polymerase, leading to the destruction of the active center of this enzyme. The active ingredient does not compete with matrix nucleoside triphosphates or triphosphates, does not exhibit a pronounced inhibitory effect on HIV-2 reverse transcriptase and DNA polymerase of eukaryotic cells (including human DNA polymerases α, β, γ or σ).

It is not recommended to use nevirapine as a monotherapy for the treatment of HIV infection or to add it to the existing treatment regimen as the only drug, due to the rapid development of viral resistance, which is typical for all other NNRTIs. Consideration should be given to the likelihood of developing cross-resistance when selecting antiretroviral drugs to be used in combination with nevirapine. If it is necessary to cancel the antiretroviral therapy regimen that includes nevirapine, the long half-life (T _1/2) of the latter should be taken into account. If antiretrovirals with shorter T _1/2 should be discontinued concurrently with the drugthan nevirapine, HIV resistance may develop due to its low concentration for 7 days or more.

Pharmacokinetics

When taken orally, Nevirapine in healthy volunteers, as well as in HIV-1 infected adults, is well and quickly absorbed - over 90% of the dose taken. The absolute bioavailability after using the active substance in a single dose of 50 mg can be equal to 93 ± 9%, the maximum concentration (C _max) in plasma after a single dose of nevirapine 200 mg was observed 4 hours later and was 2 ± 0.4 μg / ml (7, 5 μM). During course use, a linear increase in the plasma C _{max of the} drug was recorded in the range of daily doses from 200 to 400 mg. Upon reaching the equilibrium state, C _{max of} nevirapine was 5.74 μg / ml, and C _min- 3.73 μg / ml. The area under the concentration-time curve (AUC) reached 109 h × μg / ml (96.0-143.5 h × μg / ml), which corresponded to an equilibrium concentration of 4.5 ± 1.9 μg / ml in patients taking the drug 2 times a day, 200 mg.

Nevirapine is a lipophilic substance and is essentially not ionized at physiological pH. The equilibrium volume of distribution of the active substance (V _dss) after intravenous (iv) administration to adult volunteers was 1.21 ± 0.09 l / kg, which indicated its wide distribution in the human body.

The substance passes well through the placental barrier and is found in breast milk, binds to plasma proteins by about 60%, its plasma level can range from 1 to 10 μg / ml. The concentration in the cerebrospinal fluid is 45% (± 5%) of that in the blood plasma, this ratio approximately corresponds to the content of the non-associated plasma fraction of nevirapine.

In the course of in vivo and in vitro studies, it was found that the intensive metabolic transformation of nevirapine occurs with the participation of cytochrome P ₄₅₀ isoenzymes, mainly from the CYP3A family (oxidative metabolism), as a result of which several hydroxylated metabolites are formed. Presumably, other isozymes can also have an additional effect on this process.

According to the results of a pharmacokinetic study (using ¹⁴ C-nevirapine), approximately 81.3 ± 11.1% of the isotope-labeled dose was detected in urine, indicating a dominant role for renal excretion compared with excretion (10.1 ± 1.5%) intestines. Conjugates of hydroxylated metabolites and glucuronide accounted for over 80% of ¹⁴ C-nevirapine detected in urine, and only a small amount of the drug (less than 3% of the total dose) was eliminated unchanged.

Nevirapine belongs to the inducers of cytochrome P ₄₅₀ isoenzymes in the liver. With oral administration of a single dose and further two to four weeks of taking the drug in a daily dose of 200–400 mg, the pharmacokinetics of its autoinduction is characterized by an increase in clearance by 1.5–2 times. Also, autoinduction causes a corresponding decrease in the terminal phase of the T _{1/2 of the} drug from the plasma - from approximately 45 hours with a single dose, up to 25-30 hours with a course of treatment in daily doses of 200-400 mg.

In women, the clearance of nevirapine is slightly lower (by 13.8%) than in men, but this difference is not clinically significant. Body mass index (BMI) and body weight do not affect vehicle clearance. In HIV-1 infected adults, the pharmacokinetics of nevirapine does not change with age (19 to 86 years).

Indications for use

treatment of HIV-1 infection as part of combination antiretroviral therapy (ART);
prevention of mother-to-child transmission of HIV-1 in women who do not receive ART during labor (Nevirapine is indicated and can be used by the mother as monotherapy as a single dose taken by mouth during labor).

Contraindications

Absolute:

lactase deficiency, glucose-galactose malabsorption, lactose intolerance;
severe hepatic impairment (class C according to the Child-Pugh classification) or cases of an initial increase in the concentration of aspartate aminotransferase (ACT) / alanine aminotransferase (ALT), more than 5 times higher than the upper limit of normal (ULN);
an increase in the activity of ACT or ALT recorded against the background of previous treatment with the drug to a level more than 5 times higher than the ULN, or the resumption of abnormalities in liver function in the case of repeated administration of the drug;
severe rash, hypersensitivity reactions or the occurrence of clinically pronounced hepatitis caused by taking the drug, which arose during previous therapy and required its cancellation;
under 16 years of age, body weight less than 50 kg or body surface area (BSP) less than 1.25 m²;
combined intake with herbal remedies containing St. John's wort extract (Hypericum perforatum) (due to the increased risk of reducing the plasma level of nevirapine and weakening its clinical effect);
combined use with drugs such as delavirdine, efavirenz, etravirine, ketoconazole, rifampicin, rilpivirine, boceprevir, elvitegravir (in combination with cobicistat), saquinavir, fosamprenavir, atazanavir (provided that they are not used at a low dose with ritonavir)
hypersensitivity to any of the constituents of the drug.

Relative (Nevirapine must be used with extreme caution):

functional disorders of the liver of mild / moderate severity (class A / B according to the Child-Pugh classification);
combination therapy with rifabutin, telaprevir, methadone, warfarin, lopinavir / ritonavir, fluconazole, clarithoromycin, ethinylestadiol, itraconazole, indinavir.

Nevirapine, instructions for use: method and dosage

Nevirapine tablets are taken orally. A doctor with experience in treating HIV infection should prescribe the drug and conduct therapy.

The tablets are taken regardless of the mealtime, swallowed whole, without breaking or chewing, washed down with water. Nevirapine should only be used in combination with at least two additional antiretroviral drugs. The maximum daily dose should not exceed 400 mg.

Treatment of HIV infection

The recommended dose of Nevirapine in patients over 16 years of age with a body weight of more than 50 kg or with a PPT of more than 1.25 m² (calculated according to the Mosteller formula), during the first 14 days of the course is 200 mg, taken daily 1 time per day. It was found that with such treatment in the initial period, the incidence of rash is reduced. After 14 days of therapy, a transition is made to the use of 200 mg tablets 2 times a day in combination with 2 or more additional antiretroviral drugs.

In the case when the next dose of nevirapine was missed, and no more than 8 hours have passed since the pass, this dose must be taken as soon as possible. If more than 8 hours have passed since the skipping, you should use only the next dose at the usual time, without doubling it.

If during the 14-day initial period of taking the drug in a daily dose of 200 mg, the development of a skin rash was observed, it is impossible to increase the dose of nevirapine until this adverse reaction is resolved. When a rash appears while taking the drug, it is necessary to establish careful monitoring of the patient's condition.

The dosage regimen using a dose of 200 mg 1 time per day should not last more than 28 days, at the end of this period it is necessary to choose an alternative treatment due to the risk of resistance on the background of taking insufficient doses of the drug. If the course is interrupted for more than 7 days, it is required to start therapy again with an introductory 14-day period using a dose of 200 mg per day.

Children and adolescents under 16 years of age with a body weight of less than 50 kg or a PPT of less than 1.25 m² should use an oral nevirapine suspension.

PPT (Mosteller's formula) = √ [weight (kg) × height (cm) / 3600]

Preventing mother-to-child transmission of HIV-1

In order to prevent the vertical transmission of HIV-1 from mother to child during childbirth, a woman is recommended to take a single dose of Nevirapine at a dose of 200 mg, as early as possible after the onset of labor.

Side effects

immune system: often - hypersensitivity (including urticaria, angioedema, anaphylactic reactions); rarely - systemic manifestations and eosinophilia;
blood and lymphatic system: often - granulocytopenia; infrequently - anemia;
nervous system: often - headache;
liver and biliary tract: often - hepatitis (including severe life-threatening hepatotoxicity); infrequently - jaundice; rarely - fulminant hepatitis (with the threat of death);
digestive tract: often - abdominal pain, vomiting, diarrhea, nausea;
musculoskeletal system and connective tissue: infrequently - myalgia, arthralgia; rarely - rhabdomyolysis (in case of liver and skin reactions during therapy);
skin and subcutaneous tissues: very often - a rash (usually mild / moderately pronounced, characterized by maculopapular erythematous elements with or without itching, localized on the face, limbs and trunk); infrequently - urticaria, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis (with a possible fatal outcome);
general disorders: often - fatigue, fever;
laboratory and instrumental data: often - increased activity of liver function tests: transaminases ACT, ALT, gamma-glutamyl transferase (GGT), other liver enzymes; hypertransaminasemia; infrequently - increased blood pressure (BP), hypophosphatemia.

According to the results of post-marketing observation, the most serious side effects associated with therapy were the following disorders: toxic epidermal necrolysis, Stevens-Johnson syndrome, liver failure / severe hepatitis, drug-related eosinophilia with systemic symptoms that differ in the development of rash in combination with such reactions as myalgia, arthralgia, fever and lymphadenopathy, and signs of internal organ damage (including pancreatitis, hepatitis, eosinophilia, granulocytopenia and renal impairment).

During the antiretroviral therapy regimen, cases of weight gain, an increase in glucose and blood lipids were recorded.

Phenomena such as pancreatitis, thrombocytopenia and peripheral neuropathy were most often associated with the use of other antiretroviral drugs during the combined ART period. The chances of these disorders occurring as a result of taking nevirapine are low.

At the time of initiation of ART in HIV-infected patients with severe immunodeficiency, inflammatory reactions to microorganisms with residual opportunistic or non-initiating symptoms may occur.

Overdose

In case of an overdose of nevirapine, in the case of taking a daily dose of 800 to 6000 mg for a period not exceeding 15 days, the following effects were recorded: fatigue, dizziness, insomnia, headache, fever, vomiting, nausea, weight loss, rash, erythema nodosum, edema, infiltrates, increased activity of hepatic transaminases.

In this condition, it is required to cancel therapy. The specific antidote for nevirapine is currently unknown.

special instructions

The first 18 weeks of using Nevirapine are critical, and therefore, during this period, careful monitoring of the patient's condition is required in order to detect possible severe hepatic / renal failure and severe / life-threatening skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome). In the first 6 weeks of treatment, there is the greatest likelihood of skin and hepatobiliary disorders.

Due to the increased risk of severe hepatotoxic reactions, it is not recommended to start therapy with the drug in adult men and women with a CD4 + cell count of more than 400 in 1 mm³ and more than 250 in 1 mm³, respectively, in which HIV-1 RNA is detected in plasma, if the benefits of treatment does not outweigh the risk.

During the period of drug therapy, cases of osteonecrosis were recorded, mainly in patients with progression of HIV infection, identified risk factors or on the background of prolonged combined ART. The incidence of these complications has not been established. You should urgently seek medical attention if you experience joint pain and aches or difficulty moving.

If a severe rash or rash appears, which is accompanied by general symptoms such as malaise, changes in the oral mucosa, fever, blistering, facial edema, conjunctivitis and pain in joints and muscles, nevirapine should be discontinued. It is also required to stop treatment with the drug if a hypersensitivity reaction develops, characterized by a rash and general signs of damage to internal organs. It was found that the simultaneous use of prednisone (in a daily dose of 40 mg during the first 2 weeks of the course) does not reduce the incidence of rash, but, on the contrary, may increase the frequency of dermatological reactions during the first 6 weeks of combined treatment.

The risk of rash, the main manifestation of drug toxicity, is higher in women than in men.

It is necessary to carry out strict monitoring of indicators of liver activity at short intervals taking into account the clinical condition, especially during the first 18 weeks of therapy. Laboratory and clinical control should be carried out during the entire period of treatment. In the case of the development of such prodromal signs or symptoms of hepatitis as nausea, discoloration of feces, bilirubinemia, hepatomegaly, jaundice, liver soreness, it is necessary to urgently consult a specialist.

It is important to remember that the use of nevirapine does not reduce the risk of HIV-1 transmission through unprotected sex or blood.

Influence on the ability to drive vehicles and complex mechanisms

There have been no studies examining the effect of nevirapine on the ability to concentrate and psychomotor speed. Patients should avoid potentially hazardous activities, including driving vehicles or other complex machinery and equipment, if disorders such as headache and excessive fatigue develop during therapy.

Application during pregnancy and lactation

Women receiving nevirapine are not advised to use oral contraceptives and other hormonal systemic contraception as the only method, as the drug may decrease their plasma concentrations. As a result, during therapy, it is recommended to use barrier methods of preventing pregnancy. Against the background of treatment in the postmenopausal period, in the case of hormone therapy, it is necessary to monitor its effectiveness.

To date, no special and adequately controlled studies of therapy in HIV-1-infected pregnant women have been conducted. The efficacy and safety of nevirapine, used to prevent transmission of HIV-1 from mother to child, when used by the mother at a dose of 200 mg once during childbirth, has been documented. According to reports received during observations of the course of pregnancy in the I-III trimesters (according to the US Antiretroviral Pregnancy Registry), toxicity in relation to the development of the embryo / fetus or fetal development disorders was not revealed.

Nevirapine tablets should be used in pregnant women only in cases where the expected benefit significantly exceeds the possible threat to the fetus.

According to the results of studies in HIV-1-infected women during labor, T _{1/2 of} nevirapine after a single oral dose of 200 mg is extended to 60-70 hours, and the clearance can change significantly (2.1 ± 1.5 l / h), depending on the degree of physiological stress during childbirth.

To avoid the risk of postnatal transmission of the virus, HIV-infected mothers should not breastfeed their newborns. The drug easily crosses the placenta and is excreted in breast milk, therefore women taking NVP should not breastfeed.

Pediatric use

Nevirapine is contraindicated for persons under 16 years of age, with a body weight of less than 50 kg, or a PPT of less than 1.25 m².

With impaired renal function

There were no significant changes in the pharmacokinetic parameters of nevirapine in the presence of renal failure of any severity. At the same time, in end-stage renal failure, with the need for hemodialysis, a 43.5% decrease in AUC and plasma accumulation of hydroxylated metabolites of nevirapine were observed.

Patients undergoing hemodialysis treatment with creatinine clearance (CC) ≤ 20 ml / min are recommended adjuvant therapy with nevirapine with the introduction of an additional dose of 200 mg after each hemodialysis session. Patients with CC above 20 ml / min do not need to change the dose of the drug.

For violations of liver function

Nevirapine therapy is contraindicated in the presence of severe liver dysfunction (Child-Pugh class C). Patients with mild / moderate hepatic impairment (class A / B according to the Child-Pugh classification) do not need individual dose selection, but monitoring of the condition is necessary to timely detect possible side effects. The greatest threat of the development of adverse events from the liver can be observed in the first 6 weeks of therapy, but the likelihood of occurrence of such disorders remains in the course of further treatment.

The risk of adverse reactions from the liver is exacerbated if the activity of the ACT / ALT enzymes is exceeded by more than 2.5 times before or during therapy when compared with VGN. With an increase in ACT / ALT activity higher than 5 times from VGN, nevirapine is contraindicated. Only with a steady decrease in these enzymes to a level exceeding VGN by less than 5 times, the use of the drug can be resumed in an initial daily dose of 200 mg over a 14-day period, and with a subsequent increase to 400 mg. If the resumption of liver dysfunction is recorded, nevirapine must be canceled completely.

Functional liver tests are recommended to be performed before the start of the course of treatment, during the first 2 months of the course every two weeks, then regularly during the entire period of therapy with nevirapine. Monitoring of liver function tests is required if there are symptoms or signs of hepatitis and / or hypersensitivity.

Combined ART in patients with chronic hepatitis B or C increases the risk of developing serious and life-threatening reactions from the hepatobiliary system. In patients with initial functional disorders of the liver, including those with an active form of chronic hepatitis, an increase in the frequency of liver dysfunctions is recorded during ART. Patients in this risk group require supervision in accordance with standard clinical practice. If liver disease worsens, it is necessary to suspend or discontinue drug treatment. In the event of hepatitis, accompanied by manifestations in the form of vomiting, anorexia, nausea, jaundice, as well as changes in laboratory parameters (moderate / significant changes in liver activity indicators, without considering the activity of GGT),nevirapine therapy should be permanently withdrawn.

Use in the elderly

Special studies of the use of nevirapine in elderly patients (over 65 years of age) have not been conducted.

Drug interactions

drugs metabolized by the isoenzyme CYP3A or CYP2: a decrease in their plasma concentrations is possible, since nevirapine is an inducer of CYP3A and CYP2B isoenzymes; dose adjustment of these drugs may be required;
didanosine (100-150 mg 2 times a day), abacavir, emtricitabine, lamivudine (150 mg 2 times a day), tenofovir (300 mg daily), stavudine (30/40 mg 2 times a day) (nucleoside analogs of reverse transcriptase): no dose adjustment of nevirapine and these drugs is required in combined use;
zidovudine (100-200 mg 3 times a day): no dose adjustment required; due to the frequent development of granulocytopenia with this combination, careful monitoring of hematological parameters is necessary;
efavirenz (600 mg daily), rilpivirine, etravirine, delavirdine (NNRTI): simultaneous use of the drug and NNRTI is not recommended;
atazanavir / ritonavir (300/100 mg and 400/100 mg, respectively, daily): the combined use of this combination at the same time as nevirapine is not recommended;
tipranavir / ritonavir (500/200 mg twice a day), darunavir / ritonavir (400/100 mg twice a day), fosamprenavir / ritonavir (700/100 mg twice a day), ritonavir (600 mg twice a day), saquinavir / ritonavir (protease inhibitors); maraviroc (300 mg daily), enfuvirtide (fusion / penetration inhibitors); raltegravir (400 mg twice daily): these drugs and nevirapine can be used without dose adjustment;
lopinavir / ritonavir (capsules) (400/100 mg twice daily): an increase in the dose of these drugs is recommended; when combined with lopinavir, it is not necessary to change the dose of nevirapine;
clarithromycin (500 mg 2 times a day): there was a significant decrease in the concentration of this substance and an increase in the metabolite of 14-OH, the total activity against pathogens may change; the use of alternative drugs (azithromycin) should be considered, careful monitoring of liver activity is needed;
rifabutin (150/300 mg daily): concomitant use is permissible without dose adjustment; caution should be exercised, since, due to the high variability, it is possible to enhance the effect of this agent and aggravate the risk of developing its toxic effects;
rifampicin (600 mg daily): combination therapy with this substance is not recommended;
fluconazole (200 mg daily): the effect of nevirapine may increase, close observation is necessary;
itraconazole (200 mg daily): when used together, the likelihood of increasing the dose of this substance should be considered;
ketoconazole: the plasma concentration of nevirapine increases, concomitant use is not recommended;
adefovir, entecavir, interferons (pegylated interferons alpha 2a and alpha 2b), ribavirin, telbivudine (antiviral agents for the treatment of chronic hepatitis B and C): simultaneous administration is possible without changing the dose;
telaprevir: with simultaneous use, caution should be exercised and the possibility of changing the doses of these funds should be taken into account;
cimetidine: no dose adjustment is required in combination therapy;
warfarin: close monitoring of clotting levels is necessary; there may be both an increase and a decrease in clotting time;
methadone (individual dosage): cases of withdrawal have been reported; it is required to monitor the patient's condition and, if necessary, change the methadone dose accordingly
norethindrone, ethinyl estradiol (hormonal contraceptives for oral administration): there may be a decrease in their plasma levels and a decrease in effectiveness.

Analogs

The analogues of Nevirapin are Viramune, Nevirapin-TL, Nevirpin.

Terms and conditions of storage

Store in a place protected from light, out of reach of children, at a temperature not exceeding 25 ° C.

The shelf life is 3 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Nevirapin

According to reviews, Nevirapine in combination ART generally shows good results in the treatment of HIV-1 infection, helping to reduce the HIV load. The drug also demonstrates efficacy when used once during childbirth to prevent mother-to-child transmission of HIV during delivery in women who do not receive ART.

At the same time, during HIV therapy with nevirapine in combination with other antiretroviral drugs, many patients note the development of side reactions in the form of fatigue, severe rash, myalgia, as well as the appearance of undesirable hepatobiliary events, sometimes of a severe degree.

Price for Nevirapine in pharmacies

The price of Nevirapine 200 mg can be 550 rubles. per pack containing 60 tablets.

Maria Kulkes Medical journalist About the author

Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!