Nevirapine, 200 mg 60 pcs

Pharmacotherapeutic group:

antiviral [HIV] medicine

ATX code: J05AG01

Pharmacological properties

Pharmacodynamics

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Nevirapine binds directly to reverse transcriptase and blocks the activity of RNA-dependent and DNA-dependent DNA polymerase, causing destruction of the active center 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 DNA polymerases (such as human α, β, γ or σ DNA polymerases).

Nevirapine should not be used as monotherapy for the treatment of HIV infection or added as a single drug to existing therapy because of the rapid development of virus resistance that is common with all other non-nucleoside reverse transcriptase inhibitors.

When selecting antiretroviral drugs to be used in combination with nevirapine, the possibility of cross-resistance should be considered.

If an antiretroviral therapy containing nevirapine is discontinued, the long half-life of the drug must be kept in mind. If antiretrovirals with shorter half-lives than nevirapine are discontinued at the same time, resistance to HIV may develop because of the low concentration of nevirapine that persists for a week or more.

Pharmacokinetics

Intake

Nevirapine is well (>90%) absorbed after oral administration in both healthy volunteers and adult patients with HIV-1 infection. Absolute bioavailability after a single dose of 50 mg of nevirapine is 93±9%. Maximum plasma concentration of nevirapine (Cmax) after a single dose of 200 mg was reached 4 hours later and was 2±0.4 µg/ml (7.5 µM). After multiple doses, the maximum concentration (Cmax) of nevirapine increased linearly in the dose range from 200 to 400 mg/day. At equilibrium, Cmax was 5.74 mcg/mL and Cmin was 3.73 mcg/mL with an AUC of 109 h*mcg/mL, corresponding 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 virtually non-ionizing at physiologic pH. After intravenous administration in healthy adult volunteers, the equilibrium volume of distribution of nevirapine (VdSS) was 1.21±0.09 L/kg, indicating wide distribution of the drug in humans.

Nevirapine penetrates well through the placental barrier and is detected in breast milk. Binding of nevirapine to plasma proteins is about 60%, its concentration in plasma varies from 1 to 10 mcg/ml. The concentration of nevirapine in human cerebrospinal fluid is 45% (±5%) of plasma; this ratio approximately corresponds to the fraction of the drug not bound to plasma proteins.

Metabolism and excretion.

In in vivo and in vitro studies, it has been shown that nevirapine undergoes intense biotransformation involving cytochrome P450 isoenzymes (oxidative metabolism) to several hydroxylated metabolites. It is assumed that oxidative metabolism of nevirapine is mediated by cytochrome P450 isoenzymes of CYP3A isoenzyme family, other isoenzymes may play an additional role. According to the results of a mass/elimination balance pharmacokinetic study (at equilibrium when taking 200 mg twice daily followed by 50 mg of 14C-nevirapine), approximately 91.4±10.5% of the isotope-labeled drug dose was determined in urine (81.3±11.1%), indicating predominant renal excretion compared with excretion through the gut (10.1±1.5%).

More than 80% of the 14C-nevirapine determined in the urine were conjugates of glucuronide and hydroxylated metabolites. Thus, metabolism by cytochrome P450, conjugation to glucuronide, and excretion with the urine are the primary biotransformation and excretion pathways of nevirapine in humans. Only a small proportion, less than 5%, of 14C-nevirapine in the urine (corresponding to <3% of the total dose) was excreted unchanged.

Nevirapine is an inducer of cytochrome P450 isoenzymes in the liver. The pharmacokinetics of autoinduction of nevirapine when administered orally as a single dose followed by two to four weeks of 200-400 mg/day dose is characterized by a 1.5-2-fold increase in clearance.

The autoinduction also results in a corresponding decrease in the terminal phase of the plasma half-life of nevirapine: from approximately 45 hours (single dose) to approximately 25-30 hours (after multiple doses of 200-400 mg/day).

Inadequate renal function

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 result in significant changes in the pharmacokinetics of nevirapine. However, in patients with terminal renal failure requiring hemodialysis, a 43.5% decrease in the area under the curve “concentration-time” (AUC) and accumulation of hydroxylated metabolites of nevirapine in plasma was noted. In adult patients, adjunctive therapy with nevirapine is recommended with an additional dose of 200 mg after each dialysis session to compensate for the effect of dialysis on drug clearance.

Hepatic impairment

Nevirapine is contraindicated in patients with severe hepatic impairment (Child-Pugh class C). Caution should be used in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B).

Gender, age

The clearance of nevirapine in women is 13.8% less than in men. This difference is not considered clinically significant. Body weight and body mass index (BMI) have no effect on the clearance of nevirapine. The pharmacokinetics of nevirapine in HIV-1-infected adult patients do not change with age (range 19-86 years). There have been no specific studies on the use of nevirapine in patients over 65 years of age.

Children

The clearance of nevirapine increases with age, corresponding to an increase in body surface area. The twice-daily dose of nevirapine 150 mg/m² (after an initial two-week introductory period of 150 mg/m² daily) provided geometric mean minimum nevirapine concentrations of between 4-6 µg/mL (which is consistent with data in adults). Body surface area was calculated using Mosteller’s formula (section “Administration and Doses”).

Indications

Active ingredient

Composition

Active ingredient: nevirapine – 200.00 mg.

Excipients: lactose monohydrate (milk sugar) – 220.10 mg; microcrystalline cellulose – 165.00 mg; sodium carboxymethyl starch – 22.00 mg; povidone-C25 – 22.00 mg; magnesium stearate – 6.40 mg; colloidal silicon dioxide – 4.50 mg.

How to take, the dosage

Ingestion.

Nevirapine should be prescribed by a doctor experienced in treating HIV infection. The drug should only be taken in combination with at least two additional antiretrovirals.

The tablets should be taken with water, not broken or chewed. Nevirapine can be taken regardless of meals.

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

The treatment of HIV infection:

Patients 16 years of age or older with a body weight greater than 50 kg or a body surface area (BP’G by Mosteller’s formula) greater than 1.25 m²

. The recommended dose of nevirapine is 200 mg for the first 14 days of treatment (using this introductory period has been shown to reduce the incidence of rash), followed by switching to 200 mg tablets twice daily in combination with at least two additional antiretrovirals.

If a patient has missed another dose of the medication and it has not been more than 8 hours since the dose was missed, the missed dose should be taken as soon as possible.

If more than 8 hours have passed since the next dose was missed, the patient should only take the next dose at the usual time. If a skin rash develops during this period, see a doctor immediately 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 (PPT according to Mosteller’s formula) are recommended for oral suspension.

General recommendations:

Patients who develop a skin rash during the initial 14-day introductory dose of 200 mg per day should not increase the dose of nevirapine until the rash disappears. The appearance of a rash while taking nevirapine always requires close monitoring.

The dosing regimen of 200 mg once daily should not continue for more than 28 days, at which time alternative therapy should be chosen promptly, because of the risk of resistance with inadequate doses of the drug.

Patients who interrupted therapy for more than 7 days should begin therapy again with a two-week introductory period of 200 mg once daily.

Prevent mother-to-child transmission of HIV-1:

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

Particular patient groups:

Elderly patients:

There have been no special studies of the use of nevirapine in patients over 65 years of age.

Patients with impaired renal function who require hemodialysis (creatinine clearance ≤20 mL/min) are recommended to take an additional 200 mg of the drug after each hemodialysis procedure. Patients whose creatinine clearance is greater than 20 ml/min do not require dose adjustment of nevirapine.

Hepatic disorders

The use of 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 necessary, but these patients should be monitored closely to monitor for adverse reactions.

Interaction

Nevirapine is an inducer of hepatic cytochrome P450 isoenzymes (CYP3A, CYP2B) and may lead to decreased plasma concentrations of other concomitant drugs that are extensively metabolized by CYP3A or CYP2B isoenzymes. Therefore, if a patient who has been previously dosed with 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 initiation of therapy.
When concomitantly administered with nevirapine, plasma concentrations of drugs that are also metabolized by cytochrome P450 may decrease.
Intake of food, antacids or drugs containing alkaline buffer do not affect absorption of nevirapine.
Interaction data are presented as a geometric mean with a 90% confidence interval, regardless of when these data were obtained. BUT = not determined, ↑ = increased, ↓ = decreased, ↔ = no effect.

Special Instructions

The first 18 weeks of therapy with nevirapine 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 is in the first 6 weeks of therapy.

You should also remember that nevirapine does not prevent HIV-1 transmission.

Clinical biochemical tests, including liver function tests, should be performed before starting therapy with nevirapine and at intervals during therapy every two weeks during the first 2 months of therapy, 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 ACT or ALT enzyme activity is more than 2.5 times higher than the upper limit of normal before or during treatment, liver function parameters should be monitored more frequently during regular examinations. Nevirapine should not be administered to patients with ACT or ALT elevations greater than 5 times the upper limit of normal before the baseline ACT or ALT values stabilize to less than 5 times the upper limit of normal.

Hepatic diseases:

Nevirapine should not be used in patients with severe hepatic impairment (Child-Pugh class C).

All patients, and especially those with mild to moderate hepatic impairment, should be closely monitored for timely detection of toxic reactions, as the risk of any liver reactions remains after the first 18 weeks of therapy, so monitoring should continue at frequent intervals. Patients with chronic hepatitis B or C who receive combined antiretroviral therapy are at increased risk of serious and life-threatening adverse events to the hepatobiliary system. If antiviral drugs for treatment of viral hepatitis B or C are used concomitantly, the information in the instructions for use of these drugs should be followed.

In patients with pre-existing liver function impairment, including active chronic hepatitis, there is an increased incidence of liver function impairment with antiretroviral combination therapy. These patients need to be monitored according to standard clinical practice. Suspension or discontinuation of treatment should be considered in the case of worsening liver disease in these patients.

Women and/or higher CD4 cell counts (>250/mm3 in adult women and 400/mm3 in adult men) at initiation of nevirapine therapy are associated with a higher risk of adverse liver reactions if the patient has plasma HIV RNA. ie, a concentration of ≥50 copies/mL at initiation of nevirapine therapy.

Because of the potential for severe and life-threatening hepatotoxic reactions, therapy with nevirapine should not be started in adult women with CD4 cell counts greater than 250 in 1 ml³ or in adult men with CD4 cell counts greater than 400 in 1 mm³ who have HIV-1 RNA determined in plasma, unless the benefit exceeds 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, particularly in patients with established risk factors, progression of HIV infection, or long-term recipients of combination antiretroviral therapy. The frequency of development is unknown. Patients should be advised to seek medical attention if they experience joint stiffness and pain 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, oral mucosa changes, conjunctivitis, facial edema, joint and muscle pain, general malaise), Stevens-Johnson syndrome or toxic epidermal necrolysis. Nevirapine should be discontinued and should not be prescribed again in any patient if a hypersensitivity reaction characterized by rash and general symptoms of internal organ damage, such as hepatitis, eosinophilia, granulocytopenia and impaired renal function, or other internal organ changes develop.

Patients should be informed that the main manifestation of the toxicity of nevirapine is rash. An introductory initial period of treatment should be used because it has been found to reduce the incidence of rash. In most cases, rash associated with taking the drug occurs in the first six weeks of therapy, so it is during this period that patients should be closely monitored for dermatologic reactions. Patients should be informed that if any rash develops during the initial introductory period of treatment, the dose of the drug should not be increased up to twice daily until the rash disappears. A dosing regimen using 200 mg of the drug one rad daily should not be continued for more than 28 days; another regimen should be developed by that time. In rare cases, rhabdomyolysis has been observed in patients with skin and liver reactions associated with nevirapine use.

The concomitant use of prednisone (40 mg/day, during the first 14 days of nevirapine) has not been shown to reduce the incidence of rash, but instead may increase the incidence of dermatologic reactions during the first 6 weeks of therapy. Risk factors for serious skin reactions include violating the recommendation to use the drug at a dose of 200 mg daily during the introductory initial treatment period. The risk of developing more serious dermatologic reaction outcomes increases if there is a delay in seeking medical advice after the onset of symptoms. The risk of rash is higher in women than in men, both with nevirapine and with non-nevirapine 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, particularly HIV-infected patients have an increased risk of granulocytopenia. Blood values should be periodically monitored in such patients.

Hepatic reactions: Patients should be informed that hepatic reactions are the main type of toxicity of nevirapine. Patients with signs or symptoms of hepatitis should stop taking the drug and immediately go to a medical facility for evaluation, which should include evaluation of liver function. Severe manifestations of hepatotoxicity, including development of liver failure requiring liver transplantation, have been reported when multiple doses of nevirapine have been used for post-exposure prophylaxis in persons who have not been infected with HIV.

Post-exposure prophylaxis for persons who have not been infected with HIV is not among the approved indications for use of the drug and therefore is categorically not recommended.

High risk of adverse liver reactions during any antiretroviral therapy (including during therapy that includes nevirapine) is when there is a baseline increase in ACT or ALT enzyme activity of more than 2.5 times the upper limit of normal, and/or when hepatitis B and/or C is present.

Hepatic monitoring: Asymptomatic elevations in liver enzyme activity and gamma-glutamyltransferase (GGT) are frequently described and are not unconditional contraindications for the use of nevirapine.

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

If ACT or ALT enzyme activity increases more than 2.5 times the upper limit of normal before or during treatment, liver function parameters should be monitored more frequently during regular examinations.

Nevirapine should not be administered to patients whose baseline ACT or ALT activity is more than 5 times the upper limit of normal (until it has steadily decreased to less than 5 times the upper limit of normal).

If ACT or ALT enzyme activity increases more than 5 times the upper limit of normal during treatment, nevirapine should be stopped immediately. If ACT and ALT activity return to baseline values and if the patient does not have any clinical signs or symptoms of hepatitis or general symptoms or other phenomena suggestive of internal organ dysfunction, nevirapine may be restarted (if clinically necessary). This must be decided on a case-by-case basis, based on clinical necessity. Re-prescribing nevirapine should be done with increased clinical and laboratory alertness, at an initial dose of 200 mg/day (for 14 days), rising to 400 mg/day thereafter. If liver dysfunction recurs, nevirapine should be permanently withdrawn.

If hepatitis develops with clinical manifestations such as anorexia, nausea, vomiting, jaundice, and changes in laboratory values (moderate to significant changes in liver function, not including gamma-glutamyltransferase activity), nevirapine should be permanently withdrawn. Nevirapine should not be re-prescribed in patients who have required withdrawal due to the development of clinically significant hepatitis caused by nevirapine.

Weight and metabolic parameters: There may be an increase in body weight and elevated blood glucose and lipid concentrations with antiretroviral therapy. These changes may be partly related to the disease itself and lifestyle. In some cases, it has been shown that therapy has an effect on increasing lipid concentrations, but there is no conclusive evidence that therapy has an effect on weight gain. Blood glucose and lipid concentrations should be monitored according to HIV treatment guidelines. Lipid metabolism disorders should be corrected if clinically necessary.

Immune reconstitution syndrome: HIV-infected patients with severe immunodeficiency at the time of administration of combination antiretroviral therapy may have inflammatory reactions to non-symptomatic or residual opportunistic pathogens, which may result in serious clinical conditions or worsen disease symptoms. Usually such reactions have been observed within the first few weeks or months after initiation of combination antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and pneumonia caused by Pneumocystis jirovecii. Any inflammatory symptoms should be identified, and treatment should be initiated if necessary. The development of autoimmune diseases (such as Graves’ disease) has also been reported, which appeared on the background of immune reactivation: however, the described time to onset is highly variable and these phenomena may appear many months after initiation of therapy.

. Nevirapine should not be used with efavirenz, rifampicin, ketoconazole, delavirdine, etravirine, rilpivirine, elvitegravir (together with cobicistat), boceprevir, and fosamprenavir, saquinavir, atazanavir (in case they are not used together with low-dose ritonavir). Nevirapine should not be used as a single drug (monotherapy) for the treatment of HIV-1 infection because of the possibility of resistance development. Keep in mind that nevirapine does not prevent transmission of HIV-1 to healthy people through blood and unprotected sexual intercourse.

There have been no special studies on the ability to drive and operate machinery. However, patients should be advised that adverse reactions such as fatigue and headache may occur during treatment with nevirapine and should be avoided when driving or operating machinery.

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 have had to stop therapy with nevirapine previously due to a severe rash, hypersensitivity reactions, or development of clinically significant hepatitis caused by taking the drug.

Severe hepatic impairment (Child-Pugh class C) or cases of baseline increases 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 reintroduced in patients who have previously had ACT or ALT elevations greater than 5 times the upper limit of normal, or in patients who have experienced a recurrence of liver dysfunction after reapplication of nevirapine.

When taking nevirapine, herbal products containing Hypericum perforatum extract should not be used due to the risk of decreased plasma concentrations of nevirapine and its clinical effects.

Nevirapine is not recommended for use with efavirenz, rifampicin, ketoconazole, delavirdine, etravirine, rilpivirine, elvitegravir (together with cobicistat), boceprevir, and fosamprenavir, saquinavir, atazanavir (unless used together with low-dose ritonavir).

Children under 16 years of age and weighing less than 50 kg or body surface area less than 1.25 square meter (for this dosage form).

Mild to moderate hepatic impairment (Child-Pugh grades A and B); concomitant use with telaprevir, rifabutin, warfarin, methadone, lopinavir/ritonavir, clarithromycin, fluconazole, itraconazole, ethinylestadiol, indinavir.

Side effects

The most commonly reported adverse reactions to nevirapine therapy in all clinical trials were rash, allergic reactions, hepatitis, altered liver function tests, nausea, vomiting, diarrhea, abdominal pain, fatigue, fever, headache, and myalgia.

According to post-registration follow-up, 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 rash with general symptoms such as fever, arthralgia, myalgia and lymphadenopathy as well as internal organ involvement, namely development of hepatitis, pancreatitis, eosinophilia, granulocytopenia and renal function impairment.

The first 18 weeks of therapy are critical and require close monitoring.

The following is the incidence of adverse events associated with nevirapine according to the WHO classification: very common (≥1/10), common (≥1/100 to <1/10), infrequent (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10 000).

Blood and lymphatic system disorders:
Often – granulocytopenia,
Infrequently – anemia.

Disorders of immune system:
Often – hypersensitivity (including anaphylactic reactions, angioedema, urticaria),
Infrequently – anaphylactic reaction,
Rarely – eosinophilia and systemic manifestations.

Nervous system disorders:
Often – headache.

Gastrointestinal tract disorders:
Often – nausea, vomiting, abdominal pain, diarrhea.

Hepatic and biliary tract disorders:
Often – hepatitis (including severe life-threatening hepatotoxicity) (1.9%),
Infrequently – jaundice,
Rarely – fulminant hepatitis (fatal outcome possible).

Skin and subcutaneous tissue disorders:
Very common – rash (12.5%),
Infrequent – Stevens-Johnson syndrome, toxic epidermal necrolysis (possible fatal outcome) (0.2%), angioedema, urticaria.

Musculoskeletal and connective tissue disorders:
Infrequent – arthralgia, myalgia.
Rarely – rhabdomyolysis (in patients who had skin and liver reactions while taking nevirapine).

General disorders and disorders at the site of administration
Often – fever, fatigue.
Laboratory and instrumental data
Often – increase of activity of liver function tests (alanine aminotransferase, aspartate aminotransferase, transaminase; gamma-glutamyltransferase, liver enzymes; hypertransaminemia).
Infrequent – hypophosphatemia, increased arterial pressure.

Description of individual adverse reactions

According to the clinical trial 1100.1090, from which most adverse reactions were reported (n=28), patients receiving placebo developed granulocytopenia more frequently (3.3%) than patients receiving nevirapine (2.5%).

Anaphylactic reactions have been observed in the post-registration period, but have not been reported in randomized controlled clinical trials. The frequency of their development was determined by statistical counting, based on the total number of patients who participated in randomized controlled clinical trials (n=2718).

Elevated blood pressure and decreased blood phosphorus levels were observed during clinical trials with concomitant use of tenofovir or emtricitabine.

Metabolic parameters:

Elevated weight, blood lipid, and glucose levels have been reported during antiretroviral therapy.

When nevirapine is used in combination with other antiretrovirals, adverse reactions such as pancreatitis, peripheral neuropathy and thrombocytopenia have been reported. These events are often associated with other antiretrovirals. Their occurrence can be expected when nevirapine is used in combination with other drugs; there is little chance that these reactions are associated with the use of nevirapine.

In HIV-infected patients with severe immunodeficiency at the time of initiation of antiretroviral therapy, inflammatory reactions to non-symptomatic or residual opportunistic pathogens may occur. The development of autoimmune diseases (such as Graves’ disease) have also been reported to appear on immune reactivation; however, the time to onset described is highly variable, and these phenomena may appear many months after initiation of therapy.

Skin and subcutaneous fat:

The most common clinical sign of nevirapine toxicity is rash. The rash is usually mild to moderate, characterized by erythematous maculopapular elements, with or without itching, localized on the trunk, face and extremities.

Overdose

Pregnancy use