Nevirapine Capsules

Pharmacological Action Mechanism: Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus (HIV-1). Nevirapine binds directly to the reverse transcriptase of HIV-1 and blocks the activity of RNA-dependent and DNA-dependent DNA polymerases by destroying the catalytic site of the enzyme. Nevirapine does not compete with substrates or nucleoside triphosphates. Nevirapine has no inhibitory effect on the reverse transcriptase of HIV-2 virus and eukaryotic cell DNA polymerases (such as human DNA polymerase α, β, γ or δ). In vitro sensitivity: The correlation between the sensitivity of HIV-1 virus to nevirapine in vitro and the ability of nevirapine to inhibit HIV-1 virus replication in humans has not been established. The in vitro antiviral activity of nevirapine was determined by peripheral blood monocytes, macrophages, and lymphocytes, and its IC50 (half-maximal inhibitory concentration) ranged from 10-100nM for laboratory and clinically isolated HIV-1. Cell culture studies suggest that nevirapine has a synergistic effect against HIV-1 when combined with zidovudine, didanosine, stavudine, lamivudine, saquinavir, and indinavir. Resistance: HIV-1 strains with 100- to 250-fold reduced sensitivity to nevirapine have been isolated in vitro. Genetic analysis has shown that mutations occur at amino acid positions 181 and/or 106 on the HIV-1 reverse transcriptase gene. Cross-resistance: Rapidly emerging HIV strains with cross-resistance to non-nucleoside reverse transcriptase inhibitors have been found in vitro. Data on cross-resistance between the non-nucleoside reverse transcriptase inhibitor nevirapine and nucleoside reverse transcriptase inhibitors are limited. Zidovudine-resistant isolates were sensitive to nevirapine in vitro in four patients; nevirapine-resistant isolates were sensitive to zidovudine and didanosine in vitro in six patients. Due to the different acting enzymes, cross-resistance between nevirapine and HIV protease inhibitors is unlikely. Toxicological studies: Genetic toxicity: The results of the Ames test, mammalian chromosome aberration test (CHO/Hg PRT) and mouse micronucleus test for nevirapine were all negative. Reproductive toxicity: Fertility impairment was observed in female rats when the systemic exposure (measured in AUC) was equivalent to the human exposure at the clinically recommended dose. No obvious teratogenic effect was observed in reproductive toxicity studies in pregnant rats and rabbits. When the systemic exposure (measured in AUC) of rats was 50% higher than the human exposure at the clinically recommended dose, a significant decrease in fetal weight was observed. Carcinogenicity: Long-term carcinogenicity studies of nevirapine are still in progress. In carcinogenicity studies, nevirapine increased the incidence of liver tumors in mice (at doses of 750 mg/kg/day) and rats (at doses of 35 mg/kg/day). However, these findings may be related to the fact that nevirapine is a strong liver enzyme inducer and does not produce genotoxicity.

The main ingredient of this product is nevirapine, and its chemical name is: 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one. The chemical structure is: Molecular formula: C15H14N4O Molecular weight: 266.30

This product is a hard capsule, and the content is off-white powder.

This product is suitable for the treatment of HIV-1 (human immunodeficiency virus) infection. It is easy to develop drug resistance when used alone and should be used in combination with other anti-HIV-1 drugs.

This product should be used with one or more other anti-HIV-1 drugs. Adults: Oral, 200 mg once a day for 14 consecutive days (this introduction period can reduce the incidence of rash); then change to 200 mg twice a day. Children: The recommended oral dose for children aged 2 months to 8 years (excluding 8 years) is once a day for the first 14 days, 4 mg/kg each time; then change to twice a day, 7 mg/kg each time. The recommended dose for children aged 8 years and above is once a day for the first 14 days, 4 mg/kg each time; then change to twice a day, 4 mg/kg each time. The total daily dose for any patient should not exceed 400 mg. Patients should be informed of the need to take nevirapine daily according to the prescribed dose. If a dose is missed, the patient should take the next dose as soon as possible, but do not double it. If a patient stops taking nevirapine for more than seven days, they should restart according to the dosing principle, that is, 200 mg of the drug once a day for 14 consecutive days, followed by 200 mg twice a day; children should receive 4 or 7 mg/kg depending on age.

Adults: In addition to rash and abnormal liver function, the most common adverse reactions associated with nevirapine treatment in all clinical studies are nausea, fatigue, fever, headache, lethargy, vomiting, diarrhea, abdominal pain and myalgia. Experience from clinical studies and clinical practice show that the most serious adverse reactions are severe hepatitis/liver failure, including Stevens-Johnson syndrome, toxic epidermal necrolysis and allergic reactions. It is characterized by severe rash, accompanied by systemic symptoms such as fever, malaise, fatigue, myalgia or joint pain, and visceral damage such as hepatitis, eosinophilia, agranulocytosis, and renal impairment. Hepatitis, severe life-threatening hepatotoxicity and acute hepatitis have been reported in patients treated with nevirapine. In a large clinical trial, 1,121 patients received an average of more than one year of nevirapine treatment, and the risk of severe liver events was 1.2% (0.6% in the placebo group). The first 12 weeks of treatment is a critical period, but the above symptoms will also appear later. Patients with elevated alanine aminotransferase and aspartate aminotransferase indices or a history of hepatitis B or C infection prior to antiretroviral therapy have a higher incidence of hepatic events. The most common clinical toxicity of nevirapine is rash, which occurred in 16% of patients treated with the combination regimen in phase II/III controlled studies. In these clinical trials, 35% of patients taking nevirapine experienced rash, while 19% of patients taking zidovudine didanosine or zidovudine alone in the control group experienced rash. The incidence of severe, life-threatening skin reactions was 6.6% in the nevirapine group and 1.3% in the control group. The rash was usually mild to moderate, erythematous papules or papulomacules, with or without pruritus, distributed on the trunk, face, or extremities. Most rashes occurred within the first 6 weeks of medication. Severe rashes mostly occurred in the first 28 days of medication; 25% of patients with severe rashes required hospitalization, and one patient required surgical treatment. A total of 7% of patients discontinued nevirapine treatment due to rash. Pediatric patients: In addition to neutropenia being more common in pediatric patients, other common adverse reactions associated with nevirapine reported in pediatric patients were consistent with those observed in adults. The safety of nevirapine in infants less than one month old has not been established.

Patients who are allergic to nevirapine are contraindicated. Patients who have discontinued nevirapine treatment due to severe rash, rash with systemic symptoms, allergic reaction, and hepatitis caused by nevirapine should not take it again. Patients who have had AST or ALT>5 times the upper limit of normal value during the treatment of nevirapine and whose liver function abnormalities recur rapidly after taking nevirapine again should not take it again.

Precautions for children: The clearance rate in children is faster than that in adults, and the clearance rate decreases with age. Side effects are similar to those in adults. Precautions for pregnancy and lactation: Pregnant women: No obvious teratogenic effects were found in reproductive studies of pregnant rats and rabbits. When the systemic exposure (measured in AUC) produced by the dose administered to rats was 50% higher than the systemic exposure in humans at the clinically recommended dose, a significant decrease in fetal weight was observed, but there was no effect on maternal and fetal development. There is a lack of appropriate, controlled studies on the treatment of HIV-1 infection in pregnant women. The use of this product in pregnant women should only be considered when the potential benefits of the drug outweigh the possible fetal harm caused by the drug. Breastfeeding: From the preliminary results of an ongoing pharmacokinetic study (ACT grams 250), nevirapine can pass the placenta and exist in breast milk for 10 HIV-1 infected pregnant women who took a single dose of 100 mg or 200 mg of this product starting an average of 5.8 hours before delivery. HIV-infected mothers are advised not to breastfeed their infants to avoid postpartum transmission of HIV to their infants. Elderly precautions: The pharmacokinetics of nevirapine have not been evaluated in HIV-1 patients over 55 years of age.

Nevirapine is an inducer of hepatic cytochrome P450 metabolizing enzymes and can reduce the plasma concentrations of drugs that are mainly metabolized by CYP3A and CYP2B. Therefore, if a patient is receiving a stable dose of a drug metabolized by CYP3A or CYP2B, the dose of the former needs to be adjusted if this product is started in combination. Nucleoside reverse transcriptase inhibitors: There is no need to adjust the doses of these drugs when this product is used in combination with zidovudine, didanosine, and zalcitabine. A treatment study with zidovudine treatment as the background, in which patients were treated with nevirapine, didanosine or nevirapine zalcitabine, showed that nevirapine had no effect on the steady-state pharmacokinetics of zidovudine and zalcitabine. Ritonavir: No dose adjustment is required when this product is used in combination with ritonavir. A 49-day clinical trial (n=14) showed that HIV-1 infected patients treated with nevirapine and ritonavir (600 mg twice daily, using a dose-escalating regimen) did not significantly change the plasma concentrations of both. Indinavir: A 36-day clinical trial (n=19) showed that HIV-1 infected patients treated with nevirapine and indinavir (800 mg once every 8 hours) simultaneously had an average decrease in indinavir AUC of 28% (95%CI-39, -16) and an average decrease in Cmax of 11% (95%CI-49, 59). No definite clinical conclusions have been drawn on the potential effects of co-administration of nevirapine and indinavir. Comparison of the pharmacokinetic parameters of nevirapine in this study with those in the past showed that co-administration with indinavir had no effect on the pharmacokinetics of nevirapine. Saquinavir: A 42-day clinical trial (n=23) showed that HIV-1 infected patients were treated with nevirapine and saquinavir (hard capsule, 600 mg, three times a day). The results showed that the combination of the two led to an average decrease in saquinavir AUC of 24% (95%CI-42, -1) and an average decrease in Cmax of 8% (95%CI-47, -1). Due to the interaction, the decrease in saquinavir hard capsule AUC may further cause a decrease in saquinavir plasma concentration. The clinical significance of the interaction between the two is still unclear. Co-administration does not affect the pharmacokinetics of nevirapine. Ketoconazole: This product cannot be used simultaneously with ketoconazole. HIV-1 infected patients (n=22) took nevirapine for 2 weeks, once a day, 200 mg each time; then continued to take it twice a day for 2 weeks, 200 mg each time, and took ketoconazole 400 mg/day for 4 weeks. The study found that both the AUC and Cmax of ketoconazole decreased. Compared with previous data, the plasma concentration of nevirapine increased by 15-30% when used with ketoconazole. Therefore, nevirapine and ketoconazole should not be used together. In patients receiving long-term treatment with nevirapine, if they had taken cimetidine and macrolide drugs (CYP3A inhibitors), the steady-state plasma concentration of nevirapine increased by 21% (n=11) and 12% (n=24), respectively. The effect of nevirapine on CYP3A will reduce the plasma concentration of other drugs that are mainly metabolized by CYP3A. If patients are taking drugs that are metabolized by CYP3A at a fixed dose, pay attention to dose adjustment when starting nevirapine treatment. Rifampicin/Rifabutin: There is no sufficient data on whether dose adjustment is needed when treating nevirapine with rifampicin. Therefore, these drugs should only be used together with clear indications and careful monitoring. Rifabutin can significantly increase the systemic clearance of nevirapine (9%), which is not clinically significant. It is safe to take nevirapine and rifabutin at the same time, and no dose adjustment is required. Oral contraceptives: Clinical data on the effect of nevirapine on the pharmacokinetics of oral contraceptives are not yet complete. Nevirapine will reduce the plasma concentration of oral contraceptives (including some hormonal contraceptives); therefore, these drugs should not be used in combination with nevirapine. For women who may become pregnant and are taking nevirapine, it is recommended to use other methods of contraception. When patients take oral contraceptives to regulate hormone levels, if they take nevirapine in combination, the former should be monitored. Methadone: Nevirapine increases hepatic metabolism and reduces the plasma concentration of methadone. It has been reported that patients who use methadone and nevirapine at the same time have experienced withdrawal syndrome. Therefore, when patients on methadone maintenance medication take nevirapine in combination, it is recommended to carefully observe the signs of withdrawal syndrome and adjust the methadone dose accordingly. Others: In vitro studies using human hepatocyte microsomes have shown that the hydrolysis metabolism of nevirapine is not affected by dapsone, rifabutin, rifampicin, and trimethoprim/sulfamethoxazole. Ketoconazole and erythromycin can significantly inhibit the hydroxylation metabolism of nevirapine.

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0.2g

Tentative 18 months

Beijing Sunho Pharmaceutical Co., Ltd.

• Founded in:

  2000-10-27

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  No. 18, Zhonghe Street, Beijing Economic and Technological Development Zone, Beijing

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  91110302722616050J

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