Viramune^® (Suspension) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

West-Ward Columbus, Inc. (USA)

ATC Code

J05AG01 (Nevirapine)

Active Substance

Nevirapine (Rec.INN registered by WHO)

Dosage Form

Viramune®

Oral suspension 50 mg/5 ml: 240 ml bottle

Dosage Form, Packaging, and Composition

Oral suspension white or almost white, homogeneous.

Excipients: carbomer – 2.1 mg, polysorbate 80 – 0.5 mg, sorbitol-70 – 231.3 mg, sucrose – 150 mg, methylparaben – 1.8 mg, propylparaben – 0.24 mg, sodium hydroxide – 0.35 mg, purified water – up to 1 ml.

240 ml – plastic bottles (1) with plastic screw cap with child-resistant opening – cardboard boxes^×.

^× a plastic measuring syringe and an additional cap may be included.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; non-nucleoside reverse transcriptase inhibitors

Pharmacological Action

Antiviral drug. Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase and blocks the activity of RNA-dependent and DNA-dependent DNA polymerase, causing destruction of the catalytic site of this enzyme. The activity of nevirapine does not compete with template or nucleoside triphosphates. Nevirapine does not inhibit HIV-2 reverse transcriptase and eukaryotic cell DNA polymerases (such as DNA polymerases α, β, γ or δ).

HIV sensitivity in vitro

The relationship between the in vitro sensitivity of HIV-1 to Viramune^® and the inhibition of HIV-1 replication in humans has not been established.

The antiviral activity of nevirapine in vitro was evaluated in peripheral blood mononuclear cells, monocyte-derived macrophages, and lymphoblast cell lines. IC₅₀ values (inhibitory concentration) against laboratory and clinical isolates of HIV-1 ranged from 10 to 100 nmol. In cell culture, the activity of nevirapine against HIV-1, when used in combination with zidovudine, didanosine, lamivudine, stavudine, saquinavir, and indinavir, was additive or synergistic.

Resistance

In vitro, the possibility of the emergence of HIV isolates with reduced sensitivity (100-250 times) to nevirapine has been established. Genotypic analysis revealed mutations in the HIV RT gene at amino acid positions 181 and/or 106, depending on the virus strain and the cell line used. When nevirapine was used in combination with several other NNRTIs, the time to development of resistance to nevirapine in vitro did not change.

In phase I/II studies, phenotypic and genotypic changes in HIV-1 isolates from patients receiving Viramune^® (n=24) or Viramune^® in combination with zidovudine (n=14) were monitored for periods ranging from 1 to ≥12 weeks.

After Viramune^® monotherapy for 1 week, reduced sensitivity to nevirapine in vitro was noted in isolates from 3/3 patients. In some patients (as early as 2 weeks after the start of therapy), one or more mutations in the RT gene were detected at amino acid positions 103, 106, 108, 181, 188, and 190. By the eighth week of monotherapy with Viramune^®, all examined patients (n=24) had HIV isolates whose sensitivity to nevirapine in vitro was reduced by more than 100 times compared to baseline, and one or more mutations in the RT gene associated with resistance to nevirapine were identified. In 80% of patients, isolates with a mutation at position 181 were isolated, regardless of dose.

Combination therapy Viramune^® + zidovudine did not change the frequency of emergence of viruses resistant to nevirapine or the degree of resistance to nevirapine in vitro. However, in these cases, a different pattern of mutations was observed, predominantly occurring at amino acid positions 103, 106, 188, and 190. In patients (6 out of 14) with baseline isolates having a wild-type RT gene, combination therapy Viramune^® + zidovudine did not delay the appearance of zidovudine-resistant mutations in the RT gene.

In the INCAS study, genotypic and phenotypic resistance was assessed in patients receiving Viramune^® as part of triple and double combination therapy, and in control group patients not receiving Viramune^®. In previously antiretroviral-naive patients (CD4 cell count 200-600/mm³), treatment was conducted with Viramune^® + zidovudine (n=46), zidovudine + didanosine (n=51), or Viramune^® + zidovudine + didanosine (n=51); follow-up was carried out for 52 weeks of treatment or more. Virological examination was performed at baseline, 6 and 12 months. The phenotypic resistance assessment method used required the presence of at least 1000 copies/ml of HIV RNA for virus amplification. Baseline isolates available for study were isolated in the 3 patient groups studied. These patients received treatment for at least 24 weeks. Initially, five cases of phenotypic resistance to nevirapine were noted; IC₅₀ values in three of them increased by 5-6.5 times, and in two – by more than 100 times. At 24 weeks, all isolates that could be isolated from patients receiving Viramune^® were resistant to this drug. At 30-60 weeks, such isolates were present in 86% of patients. Virus suppression below the limit of detection was achieved in 16 patients (less than 20 copies/ml – in 14, less than 400 copies/ml – in 2). Using the assumption that suppression below 20 copies/ml indicates virus sensitivity to Viramune^®, it was established (by direct or indirect assessment) that sensitivity to this drug was maintained in 45% of patients. All patients receiving Viramune^® + zidovudine who were tested for phenotypic resistance were resistant to Viramune^® at 6 months. Throughout the observation period, one case of resistance to didanosine was established. Resistance to zidovudine occurred more frequently at 30-60 weeks, especially in patients receiving double combination therapy. Based on data on the increase in IC₅₀, it was found that resistance to zidovudine appears to occur less frequently in patients receiving Viramune^® + zidovudine + didanosine than in patients in other treatment groups. Regarding resistance to Viramune^®, it was shown that all obtained isolates had at least one mutation associated with resistance. The most frequent single changes were K103N and Y181C. Thus, the use of highly active drug therapy regimens is accompanied by a slowdown in the development of resistance to antiretroviral drugs. Genotypes correlating with phenotypic resistance to Viramune^® were identified in 12 isolates isolated from the plasma of patients receiving triple therapy. Mutations associated with the development of resistance to Viramune^® during treatment are shown in the table:

These data from the INCAS study show that the use of highly active drug therapy regimens is accompanied by a slowdown in the development of resistance to antiretroviral drugs.

The clinical significance of phenotypic and genotypic changes associated with nevirapine therapy has not yet been established.

Resistance in perinatal transmission

Mutations conferring resistance to nevirapine were detected in 19% of women within 6-8 weeks after a single dose of the drug (HIVNET 012 study). Among the mutations associated with nevirapine resistance, the K103N mutation was most frequently detected in these women (57%), followed by a mixture of K103N and Y181C mutations (19%). Upon re-examination 12-24 months after delivery, mutations associated with nevirapine resistance were not detected in 11 women (in all these patients, mutations were detected at 6-8 weeks). Resistance to nevirapine was detected in 46% of infected newborns (HIVNET 012 study). The Y181C mutation was most frequently detected. Among all those newborns (n=7) in whom mutations were detected at 6-8 weeks of age, upon re-examination at 12 months of age, mutations associated with nevirapine resistance were not detected. The clinical significance of these results and their impact on subsequent treatment with NNRTIs is unclear.

Cross-resistance

In vitro studies have established the rapid emergence of HIV strains with cross-resistance to NNRTIs. Data on cross-resistance between the NNRTI nevirapine and nucleoside reverse transcriptase inhibitors are very limited. In vitro studies have shown that zidovudine-resistant isolates obtained from four patients remained sensitive to nevirapine, and that nevirapine-resistant isolates obtained from six patients were sensitive to zidovudine and didanosine. Cross-resistance between nevirapine and HIV protease inhibitors is unlikely due to differences in the enzyme targets involved.

Cross-resistance

Cross-resistance among currently registered NNRTIs is widespread. A number of genotypic studies indicate that in case of failure of any NNRTI, most of these patients have virus strains characterized by cross-resistance to another drug from this group. Current data indicate the inappropriateness of sequential use of different NNRTIs.

Pharmacokinetics

Adults

Absorption

Nevirapine is well absorbed (> 90%) after oral administration. C_max of nevirapine in plasma after a single dose of 200 mg was reached in 4 h and was 2±0.4 µg/ml (7.5 µmol). After multiple doses of 200 to 400 mg/day, the C_max of nevirapine increased linearly depending on the dose. The baseline concentration of nevirapine at steady-state pharmacokinetics when taking 400 mg/day was 4.5±1.9 µg/ml (17±7 µmol).

Food intake, antacids, or drugs whose dosage form contains an alkaline buffer (e.g., didanosine) do not affect the absorption of nevirapine.

Distribution

Nevirapine is highly lipophilic and practically non-ionized at physiological pH. Nevirapine penetrates the placental barrier well and is detected in breast milk. The binding of nevirapine to plasma proteins is about 60%, its plasma concentrations range from 1 to 10 µg/ml. Nevirapine concentrations in human cerebrospinal fluid were 45% (5%) of plasma concentrations; this ratio approximately corresponds to the fraction of the drug not bound to plasma proteins.

Metabolism and excretion

Nevirapine is extensively biotransformed by metabolism (oxidation reaction) involving cytochrome P450 to several hydroxylated metabolites. The oxidative metabolism of nevirapine is carried out mainly by cytochrome P450 isoenzymes from the CYP3A family; other isoenzymes may also play an additional role.

According to pharmacokinetic study results, approximately 91.4±10.5% of the isotopically labeled dose of the drug was excreted, mainly (81.3±11.1%) in the urine and, to a lesser extent (10.1±1.5%), in the feces. More than 80% of the radioactive label found in the urine was associated with conjugates of hydroxylated metabolites with glucuronides. Thus, the main pathway of biotransformation and excretion of nevirapine in humans is metabolism involving cytochrome P450, conjugation with glucuronides, and excretion of glucuronide-bound metabolites in the urine. Only a small fraction (<5%) of the radioactivity in the urine (corresponding to <3% of the total dose) was associated with the unchanged compound, i.e., renal excretion plays a minor role in the excretion of nevirapine.

Nevirapine has been shown to be an inducer of cytochrome P450 metabolic enzymes in the liver. If, after a single dose, treatment is continued for 2-4 weeks (taking 200-400 mg/day), the pharmacokinetic parameters are characterized by autoinduction: the apparent oral clearance of nevirapine increases by approximately 1.5-2 times. Autoinduction also leads to a corresponding shortening of the terminal phase T_1/2 of nevirapine from plasma: from approximately 45 h (single dose) to 25-30 h (after multiple doses of 200-400 mg/day).

Pharmacokinetics in special clinical cases

Although the V_d of nevirapine (corrected for body weight) was slightly higher in women than in men, no significant differences in nevirapine plasma concentrations (after single or multiple doses) depending on gender were noted.

The pharmacokinetics of nevirapine in HIV-1-infected adult patients does not appear to change depending on age (range 18-68 years) or race (Black, Hispanic, or Caucasian). This information was obtained from an evaluation of pooled data from several clinical studies.

A comparison of pharmacokinetic parameters after a single dose of Viramune^® was performed in patients with mild renal impairment (CrCl 50-80 ml/min), moderate renal impairment (CrCl 30-50 ml/min) and severe renal impairment (CrCl less than 30 ml/min), noted in kidney disease or end-stage renal failure requiring dialysis, and in patients with normal renal function (CrCl greater than 80 ml/min). In renal failure of varying severity, no significant changes in the pharmacokinetics of Viramune^® were noted. However, in patients with end-stage renal failure requiring dialysis, over a 1-week exposure period, a 43.5% decrease in the AUC of nevirapine was noted. Accumulation of hydroxylated metabolites of nevirapine in plasma was also noted. Adjunctive therapy with nevirapine using an additional dose of 200 mg after each dialysis session could compensate for the effect of dialysis on drug clearance. On the other hand, patients with a CrCl greater than 20 ml/min do not require dose adjustment of Viramune^®.

A comparison of pharmacokinetic parameters after a single dose of Viramune^® was performed in patients with hepatic impairment and in patients with normal liver function. In patients with mild or moderate hepatic impairment, individual dose adjustment of the drug is not required. However, the results of a pharmacokinetic study in one patient with moderate/severe ascites indicate the possibility of accumulation of nevirapine in the systemic circulation in patients with significant hepatic impairment.

Studies have shown that during labor in HIV-1-infected women, the T_1/2 of Viramune^® (after a single oral dose of 200 mg) is prolonged (to 60-70 h), and clearance varies significantly (2.1±1.5 L/h), depending on the degree of physiological stress during labor. Nevirapine rapidly crosses the placental barrier. Nevirapine concentrations in umbilical cord blood after mothers took a 200 mg dose of the drug exceeded 100 ng/ml, and the ratio of concentrations in umbilical cord blood to maternal blood was 0.84±0.19 (n = 36; range 0.37-1.22).

To avoid the risk of postnatal HIV transmission, it is recommended that HIV-infected mothers do not breastfeed their newborns. The results of two pharmacokinetic studies showed that Viramune^® easily crosses the placenta and can be detected in breast milk. In the ACTG 250 study, breast milk samples from HIV-1-infected pregnant women after a single oral dose of Viramune^® 100 mg or 200 mg (mean time to delivery was 5.8 h) were studied. It was found that the mean ratio of Viramune^® concentrations in breast milk to maternal serum was 76% (54-104%). In the HIVNET 006 study, it was shown that after a single oral dose of 200 mg, the mean ratio of concentrations in breast milk to maternal plasma was 60.5% (25-122%).

Children

In newborns (born to HIV-1-infected women who received a single dose of Nevirapine 200 mg during labor) who received Viramune^® oral suspension at a dose of 2 mg/kg within 72 hours after birth, the mean T_1/2 of nevirapine was 47 h. Plasma concentrations during the first week of life were greater than 100 ng/ml.

The pharmacokinetics of nevirapine were studied in two open-label studies in children aged 9 months to 14 years with HIV-1 infection who received single doses of nevirapine suspension (7.5 mg, 30 mg, or 120 mg/m²) in the morning, on an empty stomach. The AUC and C_max of nevirapine increased proportionally to the dose. After absorption of nevirapine, its plasma concentrations (expressed logarithmically) decreased linearly over time. The terminal phase T_1/2 of nevirapine after a single dose was 30.6±10.2 h.

In a study with multiple use of nevirapine (as a suspension or tablets at a dose of 240-400 mg/m²/day), the drug was used as monotherapy or in combination with zidovudine or zidovudine + didanosine in 37 HIV-1-infected children aged 2 months to 15 years. These patients received Nevirapine at a dose of 120 mg/m²/day for approximately 4 weeks, and subsequently at a dose of 120 mg/m² twice daily (patients over 9 years) or at a dose of 200 mg/m² twice daily (patients under 9 years). The body weight-adjusted clearance of nevirapine reached maximum values in children aged 1 to 2 years, and then decreased with increasing age. The body weight-adjusted clearance of nevirapine in children under 8 years was approximately 2 times greater than in adults. The T_1/2 of nevirapine for the entire patient group as a whole (after reaching steady-state pharmacokinetics) was 25.9±9.6 h. With increasing duration of drug use, the mean values of the terminal phase T_1/2 of nevirapine changed with age as follows: from 2 months to 1 year – 32 h, from 1 year to 4 years – 21 h, from 4 to 8 years – 18 h, over 8 years – 28 h.

Indications

• Treatment of HIV infection in combination with other antiretroviral drugs used for the treatment of HIV-1 infection (with Viramune^® monotherapy, resistant virus strains arise rapidly and almost always, therefore Viramune^® should always be used in combination with at least two other antiretroviral drugs);
• For the prevention of HIV-1 transmission from mother to child in pregnant women who are not receiving antiretroviral therapy during labor. Viramune^® is indicated and can be used in the mother as monotherapy in the form of a single oral dose taken during labor, and in the child, also as a single oral dose administered after birth. To minimize the risk of HIV-1 transmission to the child, combination therapy for the mother before delivery is recommended whenever possible.

ICD codes

Dosage Regimen

Adults in the initial period, the drug is prescribed at a dose of 200 mg once daily for the first 14 days (it has been established that this dosing regimen reduces the frequency of rash development), then the dose is increased to 200 mg twice daily (in combination with at least two additional antiretroviral drugs). When using combination therapy, it is necessary to follow the dosing and monitoring rules recommended by the manufacturers.

Children aged from 2 months to 8 years the drug is prescribed at a dose of 4 mg/kg of body weight once daily for the first 14 days, then 7 mg/kg of body weight twice daily. The recommended dose for children aged 8 years and older is 4 mg/kg once daily for the first 14 days, then 4 mg/kg twice daily.

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

Patients should be informed about the need to take Viramune^® daily as prescribed. If a dose is missed, the patient should not double the next dose; the next dose should be taken as soon as possible.

Biochemical tests, including liver function tests, should be performed before starting Viramune^® and at appropriate intervals during therapy.

Patients who develop a rash during the 14-day initial period of daily drug intake at a dose of 200 mg/day should not increase the dose until the rash resolves.

Patients who have interrupted Viramune^® intake for more than 7 days, upon resuming therapy, should again use the recommended dosing regimen: take the drug at a dose of 200 mg (in children – 4 mg/kg/day) once daily (initial period), and then 200 mg twice daily (in children – 4 mg/kg or 7 mg/kg twice daily, depending on age).

For preventing HIV transmission from mother to child, a single dose of Viramune^® is recommended for the pregnant woman during labor (as early as possible after the onset of labor) at a dose of 200 mg, followed by a single oral administration to the newborn within 72 hours after birth at a dose of 2 mg/kg of body weight. If the mother took Viramune^® less than 2 hours before delivery, the newborn should be given the first dose (2 mg/kg) immediately after birth, and the second dose (2 mg/kg) within 24-72 hours after the first.

Adverse Reactions

In adults

Skin rash and changes in liver function test results are possible.

The most frequent adverse events associated with Viramune^® therapy in all clinical studies were nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain, and myalgia; very rarely – anemia and neutropenia.

In rare cases, arthralgias have been reported as the sole adverse event in patients receiving Viramune^® as part of treatment regimens.

Experience has shown that the most serious side effects are Stevens-Johnson syndrome, toxic epidermal necrolysis, severe hepatitis/liver failure, and a hypersensitivity syndrome characterized by rash, constitutional symptoms (fever, arthralgia, myalgia, and lymphadenopathy) and visceral involvement symptoms (hepatitis, eosinophilia, granulocytopenia, and renal dysfunction). The critical period requiring careful monitoring is the first 18 weeks of treatment.

Dermatological reactions

The most common clinical sign of Viramune^® toxicity is rash.

Serious or life-threatening skin reactions occur in approximately 2%. These include Stevens-Johnson syndrome and, less commonly, toxic epidermal necrolysis, which occur most frequently within the first 6 weeks of therapy. The cumulative incidence of Stevens-Johnson syndrome, based on data from 2861 patients who received Nevirapine in clinical studies, was 0.3% (9/2861).

Rash occurs in isolation or as part of a hypersensitivity syndrome characterized by constitutional symptoms (fever, arthralgia, myalgia, and lymphadenopathy) and signs of visceral involvement (hepatitis, eosinophilia, granulocytopenia, and renal dysfunction). Fatal cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity syndrome have been reported.

Table 1. Risk of rash (%) in adult patients participating in placebo-controlled studies^1,2, over 52 weeks of treatment³ (regardless of causality)

¹Study 1090: background therapy included lamivudine in all patients, and combinations of NRTIs and PIs

²Studies 1037, 1038 and 1046: background therapy included zidovudine and zidovudine+didanosine; some patients received Viramune^® as monotherapy

³Percentages were calculated based on probability estimates obtained using the Kaplan-Meier method

⁴NCI grading system

The rash is usually mild to moderate, characterized by maculopapular erythematous elements, with or without itching, located on the trunk, face, and extremities. Allergic reactions (including anaphylaxis, angioedema, and urticaria) have been reported. Rash (of any severity) most often develops within the first 6 weeks of treatment.

Hepatic adverse reactions

Among laboratory changes, elevated liver function tests are most commonly observed, including ALT, AST, GGT, total bilirubin, and ALP. Asymptomatic elevation of GGT is most frequently noted. Cases of jaundice have been reported. Cases of hepatitis, significant and life-threatening hepatotoxicity, and fatal fulminant hepatitis have been reported in patients receiving Nevirapine. According to clinical studies, the risk of clinical hepatic reactions in patients taking Viramune^® by 1 year of treatment was approximately twice that of placebo. In both the Viramune^® group and the control group, the highest risk of hepatic reactions was associated with elevated AST or ALT levels and/or seropositivity for hepatitis B and/or C. The risk of hepatic reactions in patients without evidence of hepatitis B and/or C when treated with Viramune^® for 1 year was less than 2%.

The critical period requiring careful monitoring is the first 18 weeks of treatment. The highest risk of hepatic reactions is noted in the first 6 weeks of therapy. However, this risk persists thereafter, so frequent monitoring should continue throughout the treatment period.

Clinically apparent hepatitis may be isolated or accompanied by rash and/or constitutional symptoms.

In children

Safety was assessed in HIV-1-infected children aged from 3 days to 19 years. Most of these patients received Viramune^® in combination with zidovudine or didanosine, or with zidovudine + didanosine (2 studies). In the open-label study BI 882 (ACTG 180), patients were observed for an average of 33.9 months (from 6.8 months to 5.3 years, including a long-term follow-up phase in study BI 892). In study ACTG 245 (a double-blind, placebo-controlled study), patients with a mean age of 7 years (from 10 months to 19 years) received combination therapy, including Viramune^®, for at least 48 weeks at a dose of 120 mg/m² once daily for two weeks, and subsequently 120 mg/m² twice daily.

The most frequently reported adverse events associated with Viramune^® were similar to the adverse reactions observed in adults, except for granulocytopenia, which was more common in children. Two patients receiving Viramune^® in these studies developed Stevens-Johnson syndrome or a syndrome transitional between Stevens-Johnson syndrome and toxic epidermal necrolysis. After discontinuation of Viramune^®, this complication resolved in both patients.

Prevention of vertical transmission

The safety of Viramune^®, used as a single dose of 200 mg (two doses in one study) in HIV-infected pregnant women at the onset of labor, and in newborns within the first 72 hours of life (single administration of suspension at a dose of 2 mg/kg /6 mg in one study/), was assessed in more than 950 pairs (mother-child) in randomized, controlled clinical studies. Follow-up of newborns after a single dose ranged from 6 weeks to 18 months. These studies established a similarly low frequency of adverse events in the Viramune^® group and the control groups. No serious dermatological reactions or hepatic reactions considered related to Viramune^® were observed in either mothers or newborns. Thus, when treating with Viramune^®, the following adverse reactions can be expected

• Rash (including serious and life-threatening skin reactions, including fatal cases of Stevens-Johnson syndrome and toxic epidermal necrolysis);
• Hypersensitivity syndrome characterized by rash, constitutional symptoms (fever, arthralgia, myalgia, and lymphadenopathy), as well as one or more of the following manifestations (hepatitis, eosinophilia, granulocytopenia, renal dysfunction, other signs of visceral involvement have also been reported);
• Changes in liver function tests (AST, ALT, GGT, total bilirubin, ALP);
• Jaundice, hepatitis (including serious and life-threatening hepatotoxicity and fatal fulminant hepatitis);
• Nausea, vomiting, diarrhea, abdominal pain;
• Headache, fatigue;
• Fever, myalgia, arthralgia;
• Granulocytopenia, anemia;
• Allergic reactions (anaphylaxis, angioedema, urticaria).

Contraindications

• Clinically significant hypersensitivity to nevirapine or any other component of the drug.

The drug is not prescribed for severe liver dysfunction or in case of baseline increase in AST or ALT levels more than 5 times the upper limit of normal (ULN), until AST/ALT values decrease (sustainably) to a level not exceeding 5 times the ULN.

Viramune^® should not be re-administered to patients who previously experienced an increase in AST or ALT levels exceeding the ULN by more than 5 times during nevirapine therapy, or to patients who experienced recurrence of liver function abnormalities after re-administration of nevirapine.

The drug should not be re-administered to patients who required its discontinuation due to the development of severe rash (including that accompanied by constitutional symptoms), hypersensitivity reactions, or clinically apparent hepatitis caused by nevirapine.

Use in Pregnancy and Lactation

Adequate controlled studies of the use of Viramune^® in HIV-1-infected pregnant women have not been conducted to date. Viramune^® should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

The safety and efficacy of Viramune^® used to prevent HIV-1 transmission from mother to child has been established when the drug is used as part of a treatment regimen that included a single oral dose of 200 mg for the mother during labor, and oral administration of a single dose of 2 mg/kg of body weight to the newborn within 72 hours after birth.

In accordance with the recommendation that HIV-infected mothers should not breastfeed their newborn infants to avoid the risk of postnatal HIV transmission, mothers receiving Viramune^® therapy should discontinue breastfeeding.

Use in Hepatic Impairment

The drug is not prescribed for severe liver dysfunction or in case of baseline increase in AST or ALT levels more than 5 times the upper limit of normal, until AST/ALT values decrease (sustainably) to a level not exceeding 5 times the upper limit of normal. Viramune^® should not be re-administered to patients who previously experienced an increase in AST or ALT levels exceeding the upper limit of normal by more than 5 times during nevirapine therapy, or to patients who experienced recurrence of liver function abnormalities after re-administration of nevirapine.

Use in Renal Impairment

Pharmacokinetic studies conducted in patients with renal impairment on hemodialysis showed that adjunctive therapy with Viramune^® with an additional dose of 200 mg after each dialysis session may help compensate for the effect of dialysis on the clearance of Viramune^®. Thus, in patients with creatinine clearance greater than 20 ml/min, no changes in Viramune^® dosing are required.

Pediatric Use

Can be used according to indications.

Special Precautions

It should be considered that the first 18 weeks of treatment with Viramune^® are an important period requiring careful monitoring of patients for the timely detection of possible severe and life-threatening skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis), severe hepatitis, or liver failure. The highest risk of hepatotoxic and dermatological reactions exists in the first 6 weeks of therapy. The risk of hepatic adverse events is increased in women and in patients with higher CD4 cell counts. During the initial 14-day period, special attention should be paid to strict adherence to the dosing regimen.

Dermatological reactions

Serious and life-threatening dermatological reactions, including fatal ones, have been observed in patients receiving Viramune^®. Cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity syndrome characterized by rash, constitutional reactions, and visceral involvement have been observed. Careful monitoring of patients during the first 18 weeks of treatment is necessary. Monitoring is also required if an isolated rash develops. Viramune^® should be discontinued in any patient who develops a severe rash or a rash accompanied by constitutional symptoms (fever, blistering, oral lesions, conjunctivitis, facial edema, joint or muscle pain, general malaise), in Stevens-Johnson syndrome or toxic epidermal necrolysis. Viramune^® should be discontinued in any patient who develops hypersensitivity reactions characterized by rash and constitutional symptoms, as well as visceral organ changes (including hepatitis, eosinophilia, granulocytopenia, and renal dysfunction) or other signs of visceral involvement.

Patients should be informed that the main manifestation of Viramune^® toxicity is rash. When prescribing the drug, the dosing regimen recommended for the initial treatment period should be used, as it has been established that this reduces the frequency of rash occurrence. In most cases, rash associated with Viramune^® intake occurs within the first 6 weeks of therapy. Therefore, it is during this period that careful monitoring of patients for dermatological reactions is necessary. Patients should be informed that if any rash develops during the initial treatment period, the drug dose should not be increased until the rash resolves.

Concomitant use of prednisone (40 mg/day for the first 14 days of Viramune^® intake) has been shown not to reduce the frequency of rash occurrence and, conversely, may increase dermatological reactions during the first 6 weeks of therapy.

Risk factors for the development of serious skin reactions include non-compliance with the recommendation to use the drug at a dose of 200 mg/day during the initial period of therapy. The risk of more serious outcomes of dermatological reactions increases if there is a delay in seeking medical consultation after the onset of symptoms. The risk of developing rash in women appears to be greater than in men, both when using Viramune^® and therapy not containing Viramune^®.

A patient who develops a severe rash or a rash accompanied by constitutional symptoms (fever, blistering, oral lesions, conjunctivitis, facial edema, joint or muscle pain, general malaise) should discontinue the drug and consult a doctor. Re-administration of Viramune^® in these patients is not permitted.

If a patient has a rash and a connection with Viramune^® intake is suspected, liver function tests should be performed. In patients with moderate or severe abnormalities (AST or ALT exceeding the ULN by more than 5 times), Viramune^® should be discontinued.

If hypersensitivity reactions occur, characterized by rash accompanied by constitutional symptoms (fever, arthralgia, myalgia, and lymphadenopathy) in combination with signs of visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction, Nevirapine should be discontinued; re-administration of nevirapine is not permitted.

Hepatotoxic reactions

Serious or life-threatening hepatotoxic reactions, including fatal fulminant hepatitis, have been observed in patients treated with nevirapine. The first 18 weeks of treatment are critical, during which careful monitoring is necessary. The highest risk of hepatic reactions is noted in the first 6 weeks of therapy. An increased risk of adverse hepatic reactions is noted in women and patients with higher CD4 cell counts. This risk persists further, so frequent monitoring should continue throughout the treatment. Patients should be informed that hepatic reactions are a major type of Viramune^® toxicity and the appearance of signs indicating the development of hepatitis should be a reason for immediate consultation with a doctor.

Cases of serious hepatotoxicity, including the development of liver failure requiring liver transplantation, have been reported with the use of multiple doses of Viramune^® for post-exposure prophylaxis in individuals who were not infected with HIV, which is not among the approved indications for this drug.

A higher risk of hepatic adverse reactions during any antiretroviral therapy, including during regimens containing Viramune^®, is observed with baseline increases in AST or ALT levels more than 2.5 times the upper limit of normal (ULN) and/or in the presence of hepatitis B and/or C. The risk of developing hepatotoxic reactions associated with rash appears to be three times higher in women than in men (4.6% compared to 1.5%). The risk of developing hepatotoxic reactions associated with rash during treatment with Viramune^® may also be higher in patients with a higher CD4 cell count. According to a retrospective analysis, in women with a CD4 cell count greater than 250 cells/mm³, the risk of hepatotoxic reactions associated with rash was nine times higher than in women with a CD4 cell count less than 250 cells/mm³ (8.4% compared to 0.9%). An increased risk was also observed in men with a CD4 cell count greater than 400 cells/mm³ compared to men with a CD4 cell count less than 400 cells/mm³ (4.5% compared to 0.7%).

Liver Function Monitoring

Changes in liver function tests have been reported with the use of Viramune^®, sometimes occurring as early as the first weeks of therapy. Asymptomatic elevation of liver enzyme levels is frequently described and is not an absolute contraindication for the use of Viramune^®. Asymptomatic elevation of GGT is not a contraindication to continuing therapy.

Strict monitoring of liver function tests at short intervals depending on the patient’s clinical condition is recommended, especially during the first 18 weeks of treatment. Clinical and laboratory monitoring should continue throughout the entire period of treatment with Viramune^®. Physicians and patients should be alert to such prodromal symptoms of hepatitis as anorexia, nausea, jaundice, bilirubinemia, acholic stools, hepatomegaly, or liver tenderness. Patients should be informed of the need to seek medical advice in such cases.

If AST or ALT increases to more than 2.5 times the ULN before starting or during treatment, liver function tests should be monitored more frequently during regular clinical visits. Viramune^® should not be administered to patients whose baseline AST or ALT level is more than 5 times the ULN (until it has stably decreased to a level less than 5 times the ULN).

If AST or ALT exceeds more than 5 times the ULN during treatment, Viramune^® should be discontinued immediately. If AST and ALT levels return to baseline and if the patient does not develop any clinical signs or symptoms of hepatitis, general symptoms, or other phenomena indicating organ dysfunction, the use of Viramune^® may be resumed (if there is a clinical need). This decision should be made on a case-by-case basis, depending on the clinical situation. Re-administration of Viramune^® should be carried out with increased clinical and laboratory vigilance, at an initial dose of 200 mg/day (for 14 days), followed by an increase to 400 mg/day. If liver function abnormalities recur, Nevirapine should be permanently discontinued.

If hepatitis occurs, accompanied by clinical manifestations such as anorexia, nausea, vomiting, jaundice, and laboratory abnormalities (moderate or significant changes in liver function tests, excluding GGT), Nevirapine should be permanently discontinued. Viramune^® should not be re-administered to patients who required its discontinuation due to the development of clinically apparent hepatitis caused by nevirapine.

Other Precautions

When Viramune^® is used in combination with other antiretroviral drugs, adverse reactions such as pancreatitis, peripheral neuropathy, and thrombocytopenia have also been reported. These phenomena are often associated with other antiretroviral drugs. Their occurrence can be expected when using Viramune^® in combination with other drugs; the likelihood of a causal relationship of these reactions with nevirapine use is low.

Patients receiving Viramune^® or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore, such patients should remain under close clinical supervision by physicians experienced in the treatment of HIV-associated diseases. There is no information on the ability of Viramune^® to reduce the risk of horizontal transmission of HIV-1 to others.

Although the ability of Viramune^® to prevent mother-to-child transmission of HIV-1 has been established (in women not receiving other antiretroviral drugs), to minimize the possibility of HIV-1 transmission to the child, more intensive treatment of the mother before delivery using combinations of antiretroviral drugs (when possible) is recommended.

Viramune^® is extensively metabolized in the liver, and nevirapine metabolites are primarily excreted by the kidneys. Results of pharmacokinetic studies indicate the need for caution when prescribing Viramune^® to patients with moderate hepatic dysfunction. Viramune^® should not be administered to patients with significant liver function impairment.

Pharmacokinetic studies conducted in patients with renal impairment undergoing hemodialysis showed that adjunctive therapy with Viramune^® with an additional dose of 200 mg after each dialysis session may help compensate for the effect of dialysis on the clearance of Viramune^®. Thus, in patients with CrCl greater than 20 ml/min, no changes in the dosing of Viramune^® are required.

Women taking Viramune^® should not use oral contraceptives and other hormonal methods as the primary method of contraception, as Nevirapine may reduce the plasma concentrations of these drugs. Furthermore, if oral contraceptive agents are used during therapy with Viramune^® for hormonal regulation, monitoring of the therapeutic effect of the hormonal treatment is necessary.

Available data from pharmacokinetic studies indicate the inappropriateness of simultaneous use of rifampicin and nevirapine. If treatment for concomitant tuberculosis is necessary in patients receiving nevirapine therapy, the possibility of using rifabutin may be considered. Rifabutin and Nevirapine can be used together without dosage adjustments.

Effect on Ability to Drive and Operate Machinery

No specific studies on the effect of the drug on the ability to drive a car and operate machinery have been conducted.

Overdose

Symptoms There are reports of cases of overdose with Viramune^® at daily doses of 800-6000 mg with a treatment duration of up to 15 days. Patients experienced edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, dizziness, vomiting, increased transaminase levels, and weight loss. After drug discontinuation, all symptoms resolved.

Treatment Drug discontinuation. No antidote is known.

Drug Interactions

Viramune^® has been shown to induce CYP3A and CYP2B isoenzymes, which may result in decreased plasma concentrations of drugs used in combination therapy that are actively metabolized by them. Therefore, when drugs metabolized by CYP3A and CYP2B are co-administered with Viramune^®, dose adjustment of these drugs may be required.

Nucleoside Analogues

No dose adjustment of nevirapine is required when co-administered with zidovudine, didanosine, or zalcitabine. Analysis of data on the use of zidovudine in HIV-1 infected patients (n=11) receiving Nevirapine (400 mg/day) in combination with zidovudine (100-200 mg three times/day) established that Nevirapine led to a non-significant decrease (by 28%) in the AUC of zidovudine and a non-significant decrease (by 30%) in the C_max of zidovudine, with significant variability in both parameters noted. A paired comparison of the data showed that zidovudine did not have any effect on the pharmacokinetics of nevirapine. One crossover study found that Nevirapine did not affect the (steady-state) pharmacokinetics of didanosine (n=18) or zalcitabine (n=6).

Results of a 28-day study in HIV-infected patients (n=22) using Viramune^®, nelfinavir (750 mg three times/day), and stavudine (30-40 mg twice/day) showed no statistically significant changes in the AUC or C_max of stavudine. Furthermore, in a population pharmacokinetic study of 90 patients who received lamivudine concomitantly with Viramune^® or placebo, no changes in the apparent clearance and volume of distribution of lamivudine were found, indicating no inductive effect of Viramune^® on lamivudine clearance.

Non-Nucleoside Analogues

Results of a clinical study (n=23) showed that the (steady-state) pharmacokinetic parameters of nevirapine were not changed with the concomitant use of efavirenz. However, the concentration of efavirenz in the presence of nevirapine was significantly reduced. The AUC of efavirenz decreased by 28%, and the C_min by 32%. When nevirapine and efavirenz are used concomitantly, an increase in the dose of the latter to 800 mg (once daily) may be required.

Protease Inhibitors

In the studies mentioned below, Viramune^® was used at a dose of 200 mg once daily for two weeks, and at a dose of 200 mg twice daily for 14 or more subsequent days.

Results of a clinical study in HIV-infected patients (n=23) receiving Nevirapine and saquinavir (600 mg three times/day) showed that concomitant use of these drugs led to a 38% decrease in the mean AUC of saquinavir and did not significantly affect nevirapine plasma levels. The clinical significance of this interaction is unknown, but it cannot be excluded that an increase in the dose of saquinavir may be required. In another study (n=20), the use of saquinavir in combination with ritonavir (100 mg) was evaluated. All patients were also receiving Nevirapine. This study showed that the combination of saquinavir and ritonavir at a dose of 100 mg did not have a significant effect on the pharmacokinetics of nevirapine. The effect of nevirapine on the pharmacokinetics of saquinavir in the presence of ritonavir at a dose of 100 mg was considered weak and clinically insignificant.

No dosage adjustment is required when Viramune^® is co-administered with ritonavir. Results of a clinical study in HIV-infected patients (n=25) taking Nevirapine and ritonavir (600 mg twice daily using a dose-escalation regimen) showed no significant changes in the plasma concentrations of ritonavir or nevirapine.

In clinical trials where HIV-infected patients received Viramune^® and indinavir (800 mg every 8 hours), a mean decrease in the AUC of indinavir by 31% was shown; the plasma concentration of nevirapine did not change significantly. No specific clinical conclusions were made regarding the potential mutual influence of concurrently used nevirapine and indinavir. When using indinavir concomitantly with nevirapine at a dose of 200 mg twice daily, increasing the indinavir dose to 1000 mg (every 8 hours) should be considered. However, there is currently no established opinion that the short-term or long-term antiviral effect of indinavir at a dose of 1000 mg (every 8 hours) used together with nevirapine at a dose of 200 mg twice daily will differ from the effect of indinavir at a dose of 800 mg (every 8 hours) and nevirapine at a dose of 200 mg twice daily.

Results of a 28-day study in HIV-infected patients (n=23) taking Viramune^® and nelfinavir (750 mg three times/day) showed no statistically significant changes in the pharmacokinetics of nelfinavir after the addition of Viramune^®. The concentration of Viramune^® also appeared unchanged. However, for the main metabolite of nelfinavir (M8), which has comparable activity to the parent compound, a decrease in mean AUC by 62%, C_max by 59%, and C_min by 66% was found. An adequate (in terms of safety and efficacy) dose of nelfinavir for use in combination with nevirapine has not yet been established.

Nevirapine, used in combination with lopinavir/ritonavir at doses of 400/100 mg twice daily, led to a mean decrease in the AUC of lopinavir by 27% and a decrease in C_max and C_min by 22% and 55%, respectively. For use in combination with nevirapine, an increase in the dose of lopinavir/ritonavir to 533/133 mg twice daily (taken with food) is recommended. Results of a pharmacokinetic study in children showed that lopinavir concentrations decrease when co-administered with nevirapine. When used in combination with nevirapine (in cases where there is clinical suspicion based on prior treatment outcomes or laboratory data), increasing the dose of lopinavir/ritonavir (in children aged 6 months to 12 years) to 13/3.25 mg/kg in children weighing 7 to 15 kg, to 11/2.75 mg/kg in children weighing 15 to 45 kg, and to a maximum dose of 533/133 mg in children weighing more than 45 kg; taken twice daily, should be considered. No specific safety concerns have arisen regarding the use of nevirapine with any protease inhibitors.

Antifungal Drugs

Use of nevirapine (200 mg twice daily) concomitantly with ketoconazole (400 mg once daily) led to a significant decrease in the median AUC of ketoconazole by 63% and a decrease in the median C_max of ketoconazole by 40%. In the same study, it was found that ketoconazole led to a 15-28% increase in the plasma concentration of nevirapine. Ketoconazole and Nevirapine should not be used concomitantly.

The effect of nevirapine on the pharmacokinetics of itraconazole is unknown.

Concomitant use of fluconazole and nevirapine led to an increase in nevirapine exposure by approximately 100% (compared to a previous study where Nevirapine was used as monotherapy). In case of concomitant use of these drugs, accompanied by a risk of increased nevirapine exposure, caution is necessary and patients should be carefully monitored. No clinically significant effect of nevirapine on fluconazole was noted.

Anticoagulants

The in vitro interaction observed between nevirapine and warfarin is complex. As a result of the interaction when these drugs are used concomitantly, the plasma concentration of warfarin may change in such a way that there is a risk of both increased and decreased clotting time. The resulting effect of this interaction may change during the first weeks of concomitant use of the drugs or after discontinuation of nevirapine. In case of concomitant use of warfarin and nevirapine, frequent monitoring of prothrombin time is necessary.

Inducers of CYP Isoenzymes

In an open study (n=14) investigating the effect of Viramune^® on the (steady-state) pharmacokinetics of rifampicin, no significant changes in the C_max and AUC of rifampicin were shown. In contrast, rifampicin significantly decreased the AUC (by 58%), C_max (by 50%), and C_min (by 68%) of nevirapine compared to baseline data. Therefore, rifampicin and Nevirapine should not be used simultaneously. If treatment for mycobacterial infections is necessary in patients taking Nevirapine, the use of rifabutin instead of rifampicin should be considered.

When Viramune^® was co-administered at a dose of 200 mg twice daily and rifabutin at a dose of 300 mg once daily (or 150 mg once daily together with zidovudine or protease inhibitors), a non-significant change in rifabutin concentrations was noted (an increase in the median AUC of rifabutin by 12% and a decrease in the median C_ss^min of rifabutin by 3%) and a significant increase in the median C_ss^max by 20%. No significant changes in the concentrations of the active metabolite, 25-O-desacetyl-rifabutin, were found. Significant interindividual variability in results was noted. In some patients, a significant increase in rifabutin concentrations was detected, which may expose them to a higher risk of toxicity. The same study showed that the use of rifabutin led to a clear and significant increase in the systemic clearance of nevirapine (by 9% compared to control). Nevertheless, none of these changes in median values were considered clinically significant.

When Viramune^® and preparations containing St. John’s wort are co-administered, a decrease in the concentration of nevirapine below the therapeutic level is possible, which may lead to loss of virological efficacy and development of virus resistance to Viramune^®. Therefore, simultaneous administration of this combination is not recommended.

Inhibitors of CYP Isoenzymes

Results of an interaction study of nevirapine and clarithromycin (n=18) showed that there is a significant decrease in the AUC (by 30%), C_max (by 21%), and C_min (by 46%) of clarithromycin, but simultaneously a significant increase in the AUC (by 58%) and C_max (by 62%) of its active metabolite, 14-OH clarithromycin. A significant increase in the C_min (by 28%) of nevirapine and a non-significant increase in its AUC (by 26%) and C_max (by 24%) were noted. These data suggest that no dosage adjustments of either drug are required when used concomitantly. However, when treating a patient with an infection caused by the Mycobacterium avium-intracellulare complex, the prescription of an alternative drug should be considered, as the active metabolite of clarithromycin is ineffective in this case.

In a subpopulation analysis conducted in patients receiving Viramune^® in clinical studies, it was shown that the baseline (steady-state) plasma concentrations of nevirapine were elevated in patients taking cimetidine (+7%, n=13).

Oral Contraceptives

Nevirapine (200 mg twice daily) was used concomitantly with a single oral dose of a contraceptive containing ethinyl estradiol (35 mcg) and norethindrone (1 mg). Compared to plasma concentrations established before nevirapine use, the median AUC of 17α-ethinyl estradiol after 28 days of nevirapine use significantly decreased (by 29%). A significant decrease in the mean circulation time and T_1/2 of ethinyl estradiol was also noted. A significant decrease (by 18%) in the median AUC of norethindrone was found (with no changes in mean circulation time or T_1/2). The extent of these changes may indicate the need for dose adjustment of the oral contraceptive if it is used not for contraception but for other indications (e.g., for the treatment of endometriosis) when used concomitantly with nevirapine. However, when using oral contraceptives containing estrogen/progestogen, there is also a risk of ineffective contraception. Therefore, the use of other methods of contraception (e.g., barrier methods) is recommended. If oral contraceptives are used in patients receiving Nevirapine for other medical reasons, monitoring of their therapeutic effect is necessary.

Other Interactions

An in vitro study with human liver microsomes showed that the formation of hydroxylated metabolites of nevirapine is not impaired in the presence of dapsone, rifabutin, rifampicin, and trimethoprim/sulfamethoxazole.

Ketoconazole and erythromycin lead to a significant decrease in the formation of hydroxylated metabolites of nevirapine. Clinical studies have not been conducted.

It should be noted that the concentration of some other substances that are substrates of CYP3A and CYP2B, when prescribed concomitantly with Viramune^®, may be decreased.

Due to the specific metabolism of methadone, Nevirapine may reduce its plasma concentration by enhancing the metabolism of methadone in the liver.

In patients receiving methadone and Viramune^® concomitantly, cases of narcotic withdrawal syndrome have been observed (when using such a combination, the patient’s condition should be monitored and the dose of methadone adjusted).

Storage Conditions

The drug should be stored at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. The drug must be used within 2 months of opening the bottle.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.