Nevirapine

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEVIRAPINE (Nevirapine)

Composition:

Active substance: nevirapine;

1 tablet contains 200 mg of nevirapine;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: oval-shaped tablets, with a score line on both sides, white or almost white in color.

Pharmacotherapeutic group.

Direct-acting antiviral agents. Non-nucleoside reverse transcriptase inhibitors. Nevirapine. ATC code J05AG01.

Pharmacological properties.

Pharmacodynamics. Nevirapine is a non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI). Nevirapine binds directly to reverse transcriptase, blocking both RNA-dependent and DNA-dependent DNA polymerase activity, thereby disrupting the enzyme's catalytic site. The action of nevirapine does not compete with either template or nucleoside triphosphates. Nevirapine is not an inhibitor of HIV-2 reverse transcriptase or eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, and δ).

In clinical studies, nevirapine has been associated with increased levels of HDL cholesterol and an overall improvement in the ratio of total cholesterol to HDL cholesterol. This is generally considered to be associated with a lower risk of cardiovascular events in the general population. However, in the absence of specific studies on nevirapine regarding changes in cardiovascular risk in HIV-infected patients, the clinical significance of these observations remains uncertain. The selection of antiretroviral agents should be based primarily on their antiviral efficacy.

The antiviral activity of nevirapine in vitro has been measured in various cell lines, including peripheral blood mononuclear cells, macrophages, monocyte-derived cells, and lymphoblastoid cell lines. In recent studies using human peripheral blood lymphocytes and human embryonic kidney 293 cells, EC50 values (concentration for 50% inhibition) ranged from 14 to 302 nM against laboratory and clinical isolates of HIV-1.

Nevirapine demonstrated in vitro antiviral activity against group M HIV-1 isolates from monophyletic groups A, B, C, D, F, G, and H, as well as circulating recombinant forms (CRFs), including CRF01_AE, CRF02_AG, and CRF12_BF (mean EC50 value 63 nM). Nevirapine showed no in vitro antiviral activity against group O HIV-1 isolates or HIV-2.

Nevirapine in combination with efavirenz demonstrated strong antagonistic effects against HIV-1 in vitro and antagonized the effects of the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive or synergistic activity against HIV-1 when combined with protease inhibitors: amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir, as well as with NRTIs (nucleoside reverse transcriptase inhibitors): abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized in vitro by the anti-HBV (hepatitis B virus) agent adefovir and the anti-HCV (hepatitis C virus) agent ribavirin.

When selecting new antiretroviral agents for use in combination with nevirapine, the potential for cross-resistance should be considered. Upon discontinuation of antiretroviral therapy, including nevirapine, the long elimination half-life of nevirapine must be taken into account. When antiretroviral agents with shorter elimination half-lives are discontinued simultaneously with nevirapine, low plasma concentrations of nevirapine may persist for a week or longer, potentially leading to the development of resistance.

Pharmacokinetics.

Pharmacokinetics in adults. Nevirapine is readily absorbed (>90%) following oral administration in healthy volunteers and HIV-1-infected adult patients. Absolute bioavailability in healthy volunteers after a single 50 mg dose was 93% (mean value). Peak plasma concentration of nevirapine (2 µg/mL or 7.5 µM) is achieved within 4 hours after a single 200 mg dose. With repeated dosing, peak plasma concentrations of nevirapine increase linearly across the dose range of 200 to 400 mg/day. A steady-state plasma concentration of 4.5 µg/mL (17 µM) is achieved at a dose of 400 mg/day.

Neither food nor antacids or buffered medicinal products (e.g., didanosine) affect the absorption of nevirapine.

Nevirapine readily crosses the placenta and is excreted into breast milk. Nevirapine is approximately 60% protein-bound in plasma over a concentration range of 1 to 10 µg/mL. The concentration of nevirapine in human cerebrospinal fluid is about 45% of its plasma concentration. This ratio is approximately equal to the unbound fraction in plasma.

Nevirapine undergoes biotransformation via oxidative metabolism mediated by cytochrome P450 to several hydroxylated metabolites. In vitro studies using human liver microsomes suggest that the oxidative metabolism of nevirapine is primarily mediated by CYP3A isoenzymes, although other isoenzymes may play a secondary role. The drug is predominantly excreted in urine (81.3%), with a minor portion eliminated in feces (10.1%). Over 80% of the dose in urine consists of glucuronide conjugates of hydroxylated metabolites. Less than 3% of the total dose is excreted unchanged.

Nevirapine is an inducer of hepatic cytochrome P450 metabolic enzymes. With continued treatment at doses of 200–400 mg/day over 2–4 weeks, the pharmacokinetics show an approximately 1.5- to 2-fold increase in apparent clearance of nevirapine compared to single-dose administration. Autoinduction also results in a corresponding reduction in the elimination half-life of nevirapine in plasma from approximately 45 hours after a single dose to about 25–30 hours after multiple doses of 200–400 mg/day.

In the multinational 2NN study, a pharmacokinetic sub-study was conducted in a group of 1077 patients, including 391 women. Female patients showed 13.8% lower nevirapine clearance compared to males. This difference was not considered clinically significant.

Since neither body weight nor body mass index (BMI) influenced nevirapine clearance, the gender difference cannot be explained by differences in body weight between men and women.

The pharmacokinetics of nevirapine in HIV-1-infected adults are not altered by age (within 18–68 years) or race.

Renal impairment. Renal impairment (mild, moderate, or severe) does not result in any significant changes in the pharmacokinetics of nevirapine. However, in patients with end-stage renal disease requiring dialysis, a 43.5% reduction in nevirapine exposure (AUC) was observed over a weekly period. Accumulation of hydroxynevirapine metabolites in plasma also occurred. Therefore, to compensate for the effect of dialysis on nevirapine clearance, an additional 200 mg dose of nevirapine after each dialysis session may be considered. In other cases, patients with creatinine clearance ≥20 mL/min do not require dose adjustment of nevirapine.

Hepatic impairment. Patients with impaired liver function should be closely monitored for drug-induced toxicity. Patients with impaired liver function and ascites may be at risk of systemic accumulation of nevirapine.

Pharmacokinetics in children.

Plasma nevirapine concentrations in children are within the same range as in adults, but show greater variability, particularly in infants as young as two months.

Clinical characteristics.

Indications.

Treatment of HIV-1 infected patients, in combination with other antiretroviral agents.

Prevention of HIV-1 transmission from mother to child in pregnant women who are not receiving antiretroviral therapy during delivery, as well as administration of a single oral dose to the newborn after birth.

Contraindications.

Nevirapine is contraindicated in patients with clinically significant hypersensitivity to the active substance or to any of the excipients of this medicinal product.

Nevirapine should not be prescribed to patients with severe hepatic dysfunction (Child-Pugh class C) or to those who have previously received treatment aimed at stabilizing AST or ALT levels that were five times higher than the upper limit of normal (ULN).

The drug should not be re-administered to patients who previously discontinued this medicinal product due to severe rash, or rash accompanied by symptoms indicating systemic involvement or hypersensitivity reactions, including clinical signs of nevirapine-induced hepatitis.

The drug should not be re-administered to patients in whom AST or ALT levels exceeded five times the ULN during nevirapine therapy, or to those who previously experienced hepatic function abnormalities upon re-administration of nevirapine (see section "Special precautions for use").

Nevirapine is contraindicated in rare inherited conditions associated with intolerance to an excipient of the drug (see section "Special precautions for use").

Herbal preparations containing St. John's wort (Hypericum perforatum) must not be used during nevirapine treatment due to the risk of reduced plasma concentration and diminished clinical effects of nevirapine (also see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes (CYP3A, CYP2B) and may cause decreased plasma concentrations of other concomitantly administered medicinal products that are extensively metabolized by CYP3A or CYP2B (see subsection "Pharmacokinetics"). Therefore, dose adjustment may be necessary.

Absorption of nevirapine is not affected by food intake, or by the use of antacids or medicinal products based on alkaline buffer formulations.

Most of the interaction data are presented as percentage change (geometric mean) with a 95% prediction interval (95% PI).

§ – Cmin below the level of quantification

↑ – increase, ↓ – decrease, ↔ – no effect

a Data are presented as geometric means with a 90% prediction interval (90% PI).

Other information. The formation of nevirapine hydroxylated metabolites is not affected by the presence of dapsone, rifabutin, rifampin, or trimethoprim/sulfamethoxazole. Ketoconazole and erythromycin inhibit the formation of nevirapine hydroxylated metabolites.

Nevirapine may reduce plasma concentrations of methadone by enhancing its hepatic metabolism. In the presence of Nevirapine, steady-state methadone plasma levels decreased by 42% at Cmax and by 60% in methadone exposure (AUC). Cases of opioid withdrawal syndrome have been reported in patients receiving Nevirapine and methadone concurrently. Patients receiving methadone who start Nevirapine therapy should be monitored for signs of withdrawal, and methadone dosage should be adjusted accordingly.

Special precautions for use.

If nevirapine is administered as monotherapy, rapid and sustained resistance develops. Therefore, nevirapine should always be prescribed in combination with at least two other antiretroviral agents.

The first 18 weeks of nevirapine therapy are a critical period during which close monitoring of patients is essential to detect potentially serious or life-threatening skin reactions (including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis) or serious forms of hepatitis or hepatic failure. The greatest risk of liver-related adverse events and skin reactions occurs during the first 6 weeks of therapy. However, after this period, the risk of hepatic complications still persists, and patient status should continue to be monitored at regular intervals.

Women with elevated CD4 cell counts at the start of treatment have an increased risk of developing hepatic adverse reactions.

Due to serious and life-threatening cases of hepatotoxicity observed in controlled and uncontrolled trials, nevirapine should not be prescribed to women with CD4+ counts exceeding 250 cells/mm³ or to men with CD4+ counts exceeding 400 cells/mm³ unless the benefit of treatment clearly outweighs the associated risk.

In some cases, liver damage may progress despite discontinuation of treatment. Patients who develop symptoms of hepatitis, severe skin reactions, or hypersensitivity reactions must discontinue nevirapine immediately and seek prompt medical evaluation.

Reinitiation of nevirapine after severe hepatic, skin, or hypersensitivity reactions is not recommended. Dosing must be carefully managed, especially during the initial 14-day period (see section "Dosage and administration").

Skin reactions. Severe and life-threatening skin reactions, including fatal cases, have been observed in patients receiving nevirapine. Even isolated rashes require close monitoring. Nevirapine must be permanently discontinued if a patient develops a severe rash or a rash accompanied by systemic symptoms (such as fever, blistering, mucosal lesions, stomatitis, conjunctivitis, facial swelling, muscle or joint pain, or general malaise), including Stevens-Johnson syndrome or toxic epidermal necrolysis. Nevirapine must also be permanently discontinued in cases of hypersensitivity reactions characterized by rash with systemic symptoms and visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, renal dysfunction, or other signs of visceral organ involvement (see section "Adverse reactions").

Patients should be informed that the most common manifestation of nevirapine toxicity is rash. An initial lead-in dosing period is recommended, as it has been shown to reduce the incidence of rash (see section "Dosage and administration"). Most cases of nevirapine-associated rash occur within the first 6 weeks of therapy; therefore, close monitoring for rash is essential during this period. Patients should be advised that if a rash develops during the lead-in period, the dose should not be escalated until the rash resolves. The 200 mg once-daily regimen should not exceed 28 days, after which an alternative regimen should be considered.

Rare cases of rhabdomyolysis have been reported in patients experiencing skin and/or liver reactions associated with nevirapine use.

Concomitant administration of prednisolone (40 mg/day during the first 14 days of nevirapine therapy) does not reduce the incidence of nevirapine-associated rash and may even increase the frequency of rash during the first 6 weeks of therapy.

Risk factors for skin reactions include non-adherence to the recommended initial dosing regimen of 200 mg daily. Delay between onset of initial symptoms and seeking medical advice may increase the risk of more serious outcomes. Women have a higher risk of developing rash during HIV therapy compared to men, regardless of whether the regimen includes nevirapine.

Any patient who develops a serious rash accompanied by systemic symptoms such as fever, blistering, oral mucosal lesions, conjunctivitis, facial swelling, muscle or joint pain, or general malaise must discontinue nevirapine and seek immediate medical attention. Re-administration of nevirapine is contraindicated in such patients.

If a patient develops a rash that may be related to nevirapine, liver function tests should be performed. Patients with moderate or marked elevations in liver enzymes (AST or ALT >5 × ULN) should discontinue nevirapine.

In cases of hypersensitivity reactions characterized by rash with systemic symptoms such as fever, arthralgia, myalgia, and lymphadenopathy, as well as visceral involvement (e.g., hepatitis, eosinophilia, granulocytopenia, renal dysfunction), nevirapine must be permanently discontinued and immediate medical attention sought. Reinitiation of nevirapine is not recommended in these patients.

Hepatic reactions. Severe and life-threatening hepatotoxicity, including fatal fulminant hepatitis, has been observed in patients receiving nevirapine. The first 18 weeks of treatment are a critical period requiring close monitoring. The risk of hepatic reactions is highest during the first 6 weeks of therapy.

However, the risk persists beyond this period, and appropriate monitoring should continue throughout treatment. Patients should be informed that hepatic reactions are a major manifestation of nevirapine toxicity. Patients who develop symptoms of hepatitis must discontinue nevirapine and seek immediate medical attention, including liver function testing.

Serious hepatotoxicity, including liver failure requiring transplantation, has been reported in HIV-negative individuals who received multiple doses of nevirapine as post-exposure prophylaxis. Such prophylaxis is not an approved indication; therefore, nevirapine use in these cases is not recommended.

Elevated AST and ALT levels (>2.5 × ULN) and/or co-infection with hepatitis B and/or C at the initiation of antiretroviral therapy are associated with an increased risk of hepatic adverse reactions during antiretroviral therapy in general, including regimens containing nevirapine.

Women and patients with elevated CD4 counts are at increased risk of hepatic reactions.

Women have a threefold higher risk of hepatic reactions, often accompanied by rash (5.8% vs. 2.2%). Patients with elevated CD4 counts at the start of nevirapine therapy are at greater risk of nevirapine-associated hepatic reactions. According to retrospective analysis, women with CD4 counts >250 cells/mm³ have a 12-fold higher risk of hepatic adverse reactions compared to women with CD4 counts <250 cells/mm³ (11.0% vs. 0.9%). An increased risk has also been observed in men with CD4 counts >400 cells/mm³ (6.3% vs. 1.2% in men with CD4 counts <400 cells/mm³).

Liver monitoring. Abnormalities in liver function tests have been reported during nevirapine therapy, sometimes within the first weeks of treatment. Asymptomatic elevations in liver enzymes are frequently reported and do not necessarily contraindicate nevirapine use. Asymptomatic elevation of gamma-glutamyl transferase is not a contraindication to continuing therapy.

Frequent liver function testing is strongly recommended, according to clinical needs, especially during the first 18 weeks of therapy. Clinical and laboratory monitoring should continue throughout nevirapine treatment. Physicians and patients must closely monitor for prodromal signs or laboratory findings suggestive of hepatitis, such as anorexia, nausea, jaundice, bilirubinuria, acholic stools, or increased hepatic tenderness. Patients should be warned to seek medical attention if these signs occur.

If AST or ALT levels exceed 2.5 × ULN before or during treatment, liver function tests should be performed more frequently during routine clinical visits. Nevirapine should not be initiated in patients with pre-treatment AST or ALT levels >5 × ULN until levels stabilize to <5 × ULN.

If AST or ALT levels increase to >5 × ULN during treatment, nevirapine must be discontinued immediately. If AST or ALT return to baseline levels and the patient has no clinical signs or symptoms of hepatitis or systemic symptoms, and laboratory tests show no organ dysfunction, reinitiation of nevirapine may be considered based on clinical judgment and individual assessment. Reinitiation should begin with intensified clinical and laboratory monitoring, starting at a dose of 200 mg/day for 14 days, followed by escalation to 400 mg/day. If hepatic abnormalities recur, nevirapine must be permanently discontinued.

In cases of clinical hepatitis characterized by anorexia, nausea, vomiting, jaundice, and abnormal laboratory results (such as moderate or marked liver function test abnormalities, excluding gamma-glutamyl transferase), nevirapine must be permanently discontinued. Nevirapine should not be re-administered to patients who previously discontinued it due to nevirapine-induced clinical hepatitis.

Other warnings. Pancreatitis, peripheral neuropathy, and thrombocytopenia have been reported during use of nevirapine in combination with other antiretroviral drugs. These conditions are typical of other antiretroviral therapies. They may occur during nevirapine combination therapy; however, it is unlikely that these reactions are directly related to nevirapine treatment.

Opportunistic infections and other HIV-related complications may still develop in patients receiving nevirapine or other antiretroviral therapy. Therefore, patients must remain under close clinical supervision by physicians experienced in managing HIV-infected patients. Nevirapine therapy does not reduce the risk of horizontal transmission of HIV-1 to others.

Although the efficacy of nevirapine in preventing mother-to-child transmission of HIV-1 has been demonstrated in women not receiving other antiretroviral drugs, it is recommended, whenever possible, to treat women with a combination of antiretroviral drugs before delivery to minimize the risk of vertical transmission.

Comprehensive antiretroviral therapy has been associated with lipodystrophy in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy, and dorsocervical fat accumulation ("buffalo hump").

Combination antiretroviral therapy has been linked to metabolic abnormalities (hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia).

Cases of hepatorenal syndrome have been reported.

In HIV-infected patients with advanced immunodeficiency at the initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur.

Osteonecrosis has been reported in isolated cases, particularly in patients with known risk factors, progressive HIV disease, and/or long-term combination antiretroviral therapy.

In women and infants previously exposed only to single-dose nevirapine for prevention of mother-to-child transmission of HIV-1, the efficacy of nevirapine as part of combination therapy may be reduced.

Nevirapine is extensively metabolized by the liver, and its metabolites are primarily excreted by the kidneys. Pharmacokinetic data indicate that in patients with renal insufficiency undergoing dialysis, an additional 200 mg dose of nevirapine after each dialysis session may compensate for reduced nevirapine clearance due to dialysis. Dose adjustment of nevirapine is not required in patients with creatinine clearance ≥20 mL/min (see subsection "Pharmacokinetics").

Women taking nevirapine should not use hormonal contraceptives except DMPA as a sole method, as nevirapine may reduce plasma concentrations of these agents (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, when using hormonal therapy during menopause while taking nevirapine, therapeutic efficacy should be monitored.

Immune reconstitution syndrome.

In HIV-infected patients with advanced immune deficiency at the initiation of combination antiretroviral therapy, an inflammatory response to opportunistic pathogens may occur, leading to severe clinical conditions or symptom exacerbation. These reactions typically occur within the first few weeks or months after starting combination antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory reaction should be evaluated and treated if necessary.

Patients with rare hereditary conditions of galactose intolerance, such as galactosemia, Lapp lactase deficiency, or glucose-galactose malabsorption, should not take this medication.

Warnings regarding concomitant use with other medicinal products (for detailed information, see section "Interaction with other medicinal products and other forms of interaction"). Nevirapine may alter plasma exposure of other drugs, and other drugs may alter plasma exposure of nevirapine.

Concomitant use of nevirapine with efavirenz, rifampicin, ketoconazole, fosamprenavir, saquinavir, or atazanavir (unless co-administered with low-dose ritonavir) is not recommended.

Use during pregnancy or breastfeeding. A substantial amount of data in pregnant women does not indicate any malformations or fetoneonatal toxicity.

Nevirapine may be considered for use during pregnancy if necessary.

Adequate and well-controlled studies on the treatment of HIV-infected pregnant women have not been conducted.

There are no reports of congenital defects associated with nevirapine use.

Nevirapine should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

According to guidelines, HIV-infected women should not breastfeed their infants to avoid the risk of postnatal HIV transmission to the child, even if the mother is receiving nevirapine.

Ability to affect reaction speed when driving or operating machinery.

There are no data on the effect of nevirapine on the ability to drive or operate machinery.

Patients should be informed about possible adverse reactions during nevirapine use, such as headache, fever, and fatigue.

Method of Administration and Dosage

Adults. The recommended dose of nevirapine is 1 tablet of 200 mg once daily for the first 14 days (this initial dosing regimen must be followed, as it has been shown to reduce the frequency of rash occurrence). Thereafter, the dose is 1 tablet of 200 mg twice daily in combination with at least two other antiretroviral agents. When used concomitantly, the recommended dosage regimens of the companion drugs should be followed according to the manufacturer's instructions, with appropriate monitoring during treatment.

Children. The total daily dose for any patient should not exceed 400 mg. Tablets may be used in children only when the single dose of the drug is 200 mg; in all other cases, nevirapine should be administered to children in the form of a suspension. Pediatric nevirapine dosage can be calculated either based on body surface area (BSA) or body weight. When using BSA calculated by the Mosteller formula, the recommended oral dose for children of various ages is 150 mg/m² once daily for 2 weeks, followed by 150 mg/m² twice daily thereafter.

Formula Mosteller: BSA (m²) =

Recommended oral dose by weight for children under 8 years of age – 4 mg/kg body weight once daily for 2 weeks, followed by 7 mg/kg twice daily. For children aged 8 years and older, the recommended dose of Nevirapine tablets is 4 mg/kg once daily for 2 weeks, then 4 mg/kg twice daily.

General notes. Patients should be informed about the necessity of taking Nevirapine daily as prescribed by the physician. If a dose has been missed, the next dose should not be doubled, but should be taken as soon as possible.

Before initiating therapy with Nevirapine, and at appropriate intervals during therapy, biochemical tests, including liver function tests, should be performed (see section "Special precautions"). The dosing regimen of 200 mg once daily should not last longer than 28 days, after which an alternative regimen must be initiated.

Patients who develop a rash during the initial 14-day period of taking the daily dose of 200 mg should not increase the dose until the rash resolves (see section "Special precautions").

Patients who have discontinued taking Nevirapine for more than 7 days must restart the drug at the recommended doses with a two-week initial dosing period.

Prevention of mother-to-child HIV transmission. The following dosing regimen is recommended for pregnant women and their infants:

mother: single dose of 200 mg as early as possible during onset of labor;

newborn: the drug should be administered in the form of a suspension. Single oral dose of the oral suspension – 2 mg/kg within 72 hours after birth. If the mother received a dose of Nevirapine less than 2 hours before delivery, the newborn should receive a single dose of Nevirapine 2 mg/kg immediately after birth, followed by a second dose of 2 mg/kg within 24–72 hours after the first dose.

Children. The decision to use Nevirapine 200 mg tablets in children should be made by a physician.

Overdose.

There is no known antidote for Nevirapine overdose.

Cases of Nevirapine overdose ranging from 800 to 6,000 mg/day over 15 days of administration have been reported. Symptoms observed in patients included edema, nodular erythema, fatigue, malaise, headache, insomnia, nausea, pulmonary infiltrates, transient dizziness, vomiting, elevated transaminase levels, and weight loss. All symptoms resolved after discontinuation of the drug.

Adverse reactions.

Adults. In addition to rash and laboratory abnormalities in liver function, the most commonly reported adverse effects associated with NVP therapy observed across all clinical trials were nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain, and myalgia. Rarely, NVP therapy may cause anemia or neutropenia. Arthralgia has been reported in isolated cases as an independent condition in patients receiving regimens containing NVP.

The most serious adverse reactions were Stevens-Johnson syndrome, toxic epidermal necrolysis, severe hepatitis, or severe hepatic failure, and hypersensitivity syndrome characterized by rash and accompanied by systemic symptoms such as fever, arthralgia, myalgia, and lymphadenopathy, as well as visceral organ involvement including hepatitis, eosinophilia, granulocytopenia, and renal dysfunction. The first 18 weeks of treatment represent a critical period requiring close monitoring.

Adverse reactions possibly related to NVP use have been reported. Criteria for assessing frequency of adverse drug reactions:

over 10% – very common;

1–10% – common;

0.1–1% – uncommon;

0.01–0.1% – rare;

less than 0.01% – very rare.

Blood and lymphatic system disorders. Rare: granulocytopenia, anemia.

Immune system disorders. Common: allergic reactions; uncommon: hypersensitivity syndrome, anaphylaxis.

Nervous system disorders. Common: headache.

Gastrointestinal disorders. Common: nausea; uncommon: vomiting, abdominal pain; rare: diarrhea.

Hepatobiliary disorders. Common: hepatitis (1.2%), abnormalities in liver function tests; uncommon: jaundice; rare: hepatic failure/fulminant hepatitis.

Skin and subcutaneous tissue disorders. Common: rash (9%); uncommon: Stevens-Johnson syndrome (0.3%), urticaria; rare: toxic epidermal necrolysis, angioedema.

Musculoskeletal and connective tissue disorders. Uncommon: muscle pain (myalgia); rare: joint pain (arthralgia).

General disorders and administration site conditions. Uncommon: fatigue, fever.

Skin and subcutaneous tissues: The most common clinical manifestation of NVP toxicity is rash. Severe, life-threatening skin reactions occur with a frequency of approximately 2%, including Stevens-Johnson syndrome (about 0.3%) or, less frequently, toxic epidermal necrolysis, which typically develops within the first 6 weeks of therapy. Rashes may occur alone or as part of a hypersensitivity syndrome characterized by rash, systemic symptoms such as fever, arthralgia, myalgia, and lymphadenopathy, and visceral organ involvement such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction. Fatal outcomes have been reported with Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity syndrome.

Rashes typically appear on the trunk, face, and extremities and are usually mild or moderate, presenting as maculopapular erythematous lesions, with or without pruritus. Allergic reactions (including anaphylaxis, angioedema, and urticaria) have been reported. The vast majority of rash cases of any severity occur within the first 6 weeks of therapy.

Hepatobiliary events. The most common laboratory abnormalities observed are elevations in liver function tests, including ALT, AST, gamma-glutamyl transferase, total bilirubin, and alkaline phosphatase. Asymptomatic elevations in gamma-glutamyl transferase are most frequently observed. Cases of jaundice have been reported. Hepatitis, severe and life-threatening hepatotoxicity, and fatal fulminant hepatitis have been observed in patients receiving NVP. The risk of hepatitis during one year of NVP therapy was twice that observed in the placebo group. Elevated AST or ALT levels and/or positive serology for hepatitis B or C were associated with a higher risk of hepatic adverse events in both the NVP and control groups. The risk of hepatic adverse events during one year of NVP therapy was less than 2% among patients with negative tests for hepatitis B and/or C. The first 18 weeks represent a critical period requiring close patient monitoring. The risk of hepatic adverse events is highest during the first 6 weeks of therapy. However, the risk persists beyond this period; therefore, careful monitoring should continue throughout the entire treatment duration (see section "Special precautions for use"). Clinical manifestations of hepatitis may occur alone or in combination with rash and/or other systemic symptoms. For monitoring recommendations regarding liver function tests, see section "Special precautions for use."

Children. Adverse reactions associated with NVP most commonly observed in children are similar to those in adults, except for granulocytopenia, which is more frequently observed in children. Anemia has been observed to occur more frequently in children.

Prevention of vertical transmission. No serious cases of rash or hepatic adverse reactions related to NVP were observed in either mothers or infants.

Combined antiretroviral therapy has been associated with lipodystrophy in HIV-infected patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast enlargement, and dorsocervical fat accumulation ("buffalo hump").

Combined antiretroviral therapy may lead to metabolic disturbances (hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia).

Pancreatitis, peripheral neuropathy, and thrombocytopenia have also been reported with the use of NVP in combination with other antiretroviral agents.

Cases of hepatorenal syndrome have been described.

In HIV-infected patients with advanced immunodeficiency at the initiation of combination antiretroviral therapy, inflammatory reactions to asymptomatic or residual opportunistic infections may occur.

Osteonecrosis has been reported rarely, particularly in patients with well-known risk factors, advanced HIV disease, and/or prolonged combination antiretroviral therapy.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

60 tablets in a high-density polyethylene container with a plastic cap equipped with a first-opening control system.

1 container in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

STRAIDS PHARMA SCIENCE LIMITED.

Manufacturer's address and location.

No. 36/7, Suragadajakkannahalli, Indlavadi Cross, Anekal Taluk, Bangalore, Karnataka 562106, India.

Marketing authorization holder.

Strides CIL Limited.

Address of the marketing authorization holder.

Julia House, 3 Themistocles Dervis Street, CY-1066 Nicosia, Cyprus.