Nevirapine - instructions for use, dose, side effects, contraindications

Non-nucleoside inhibitor of HIV-1 reverse transcriptase. By noncompetitive binding to HIV-1 reverse transcriptase, it blocks the activity of RNA and DNA-dependent polymerase, inactivates the catalytic site of the enzyme and disrupts synthesis of the viral DNA. Does not compete with matrix or nucleoside triphosphates. Does not inhibit the inverse HIV-2 transcriptase and human DNA polymerase (α, β, γ or δ).

With monotherapy with nevirapine, resistant strains of the virus quickly appear. In combination with zidovudine / Didanosine reduces the number of viruses in the serum and increases the number of CD4⁺cells.

Pharmacokinetics:

Ingestion nevirapine quickly absorbed.Absolute bioavailability when taking a single dose is 91-93%. C_max in blood plasma is achieved after 4 hours. The intake of food, antacids and other drugs containing an alkaline buffer component (eg, didanosine), does not affect the absorption of nevirapine.

After iv introduction to healthy adults, the apparent volume of distribution is 1.21 ± 0.09 L / kg. About 60% of nevirapine binds to plasma proteins. Concentration ratio in CSF / blood plasma is 0.45. Nevirapine penetrates the placenta, and is also found in breast milk.

Metabolised in the liver with the participation of cytochrome P-450 isoenzymes (predominantly of the CYP3A family) to form several hydroxylated metabolites. Nevirapine is the inducer of the microsomal enzymes of the CYP system. Autoinduction leads to a decrease in T_1/2 from 45 hours (after a single dose) to 25-30 hours (after repeated administration of the drug).

It is excreted mainly (up to 90%, less than 3% - unchanged) by kidneys in the form of glucuronic acid-metabolized metabolites, 10% is excreted with feces.

The pharmacokinetic parameters of nevirapine in HIV-1-infected do not depend on age (in the age range of 19-68 years) or ethnicity.Significant differences related to sex in the concentration of nevirapine in the plasma after a single and multiple admission is not revealed.

In children 9 months to 14 years old, infected with HIV-1, after a single dose of nevirapine AUC and C_max increased in proportion to the dose increase. After complete absorption of nevirapine, its concentration in the blood plasma decreased linearly, T_1/2 was 30,6 ± 10,2 hours. With multiple admission, the clearance of nevirapine in terms of body weight reached the maximum values in children aged 1 to 2 years, then decreased in proportion to age. The clearance of nevirapine in patients under the age of 8 years was approximately 2 times higher than in adult patients. The values of T_1/2 with age changed in the following way: from 2 months to 1 year - 32 hours, from 1 to 4 years - 21 hours, from 4 to 8 years - 18 hours, over 8 years - 28 hours.

Indications:

Treatment of HIV infection caused by HIV-1 in adults and children (as part of combined antiretroviral therapy).

ICD-10

I.B20-B24.B24 Disease caused by human immunodeficiency virus [HIV], unspecified

Contraindications:

Hypersensitivity.

Carefully:Moderate and severe liver dysfunction (grade B and C on a scale Childe-I drink).

Pregnancy and lactation:

Adequate and strictly controlled clinical studies of the safety of nevirapine in pregnancy have not been conducted. Determined that nevirapine quickly penetrates the placental barrier. Use in pregnancy is possible when the intended benefit to the mother exceeds the potential risk to the fetus. To prevent the transmission of HIV-1 from mother to child nevirapine is administered orally once: the mother - during labor at a dose of 200 mg, the newborn - at a dose of 2 mg / kg for 72 hours after birth.

Nevirapine penetrates into the mother's milk. HIV-infected women are advised to avoid breastfeeding because of the risk of infection. Given these recommendations, patients receiving nevirapine, breastfeeding should be prohibited.

Action category for the fetus by FDA - B / C

Dosing and Administration:

Adults and children over 16 years of age (or with a body weight of more than 50 kg or a body surface area of more than 1.25 m²): inside, regardless of food intake at 200 mg / day for the first 14 days (introductory period), then 200 mg 2 times / day in combination with not less than two antiretroviral drugs.

Children: at the age of 2 months to 8 years - 4 mg / kg 1 time / day for the first 14 days, then 7 mg / kg / day 2 times / day; at the age of 8 years and older - 4 mg / kg 1 time / day for the first 14 days, then 4 mg / kg 2 times / day.

The maximum daily dose for patients of any age is 400 mg.

Patients who developed a rash during the 14-day introductory period for the use of nevirapine should not increase the dose of the drug until it completely disappears.

Patients who did not receive nevirapine more than 7 days, resume treatment, starting at a dose of 200 mg / day for 14 days, then increase the dose to 200 mg 2 times / day.

Side effects:

From the side of the central nervous system: often - increased fatigue, headache, drowsiness

From the skin: very often - maculopapular erythematous rash, sometimes accompanied by itching, infrequently - hives, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Allergic reactions: hypersensitivity, anaphylaxis, angioedema.

From the side of the musculoskeletal system: often - myalgia, infrequently - arthralgia.

From the digestive system: often - nausea, vomiting,diarrhea, abdominal pain, hepatitis, increased activity of ALT, AST, APF and the level of total bilirubin; infrequently - jaundice in isolated cases - severe hepatotoxic reactions.

On the part of the hematopoiesis system: often - granulocytopenia, infrequently - anemia

Other: fever, myalgia.

Post-marketing experience: severe hepatitis, hepatic insufficiency, kidney damage.

Overdose:

There is no specific antidote. In patients noted weakness, headache, fever, insomnia, rash, erythema nodosum, pulmonary infiltrates, vomiting, swelling, weight loss. All symptoms go away after the drug is discontinued.

Interaction:

Nevirapine as an inducer of isoenzymes CYP3A and CYP2B6 can reduce the concentration of drugs that undergo metabolism involving these isoenzymes.

Non-nucleoside analogues - simultaneous administration of nevirapine with efavirenz is not recommended (toxicity cumulation, lack of additive effect, decrease in AUC, C_min and C_max efavirenz, an increase in its dose is required),

Nucleoside analogues - with simultaneous administration with didanosine, lamivudine, stavudine, tenofovir, ziduovudine, dose adjustment for nevirapine is not required.

Inhibitors of HIV proteases - simultaneous administration with any of these drugs does not require correction of the dose of nevirapine.

Oral hormonal contraceptives - nevirapine accelerates their metabolism, contraceptive effect decreases, additional methods of contraception should be used.

Ketoconazole - simultaneous use is not recommended (AUC and C decrease_max ketoconazole and increases the concentration of nevirapine).

Fluconazole - with simultaneous use increases the risk of increasing the effects of nevirapine, you must be careful and watch the patient.

Itraconazole - it may be necessary to increase its dose with simultaneous use with nevirapine.

Clarithromycin - bioavailability reduced nevirapine, increased AUC and C_max less active metabolite, it is necessary to consider the possibility of prescribing an alternative drug, since the active metabolite of clarithromycin is ineffective in this case.

Anticoagulants - in the case of simultaneous use of warfarin and nevirapine, frequent monitoring of prothrombin time is necessary.

Rifampicin - simultaneous use is not recommended (significant decrease in AUC, C_min and C_maxnevirapine), should be replaced by rifabutin.

Drugs containing St. John's wort - simultaneous application is not recommended (it is possible to reduce the concentration of nevirapine below the therapeutic level, which can lead to a loss of virologic efficacy and the development of virus resistance to nevirapine).

Methadone - nevirapine can reduce its concentration in the blood plasma by increasing metabolism in the liver. In patients receiving both methadone and nevirapine, cases of development of withdrawal syndrome have been noted (when using this combination, it is necessary to monitor the patient's condition and adjust the dose of methadone).

Special instructions:

Nevirapine should not be used as a monotherapy for the treatment of HIV infection or added as a single drug to a regimen of therapy that is ineffective (rapid development of resistance). In the event of the cancellation of antiretroviral therapy, which included nevirapine, one should keep in mind its long T_1/2. If the use of antiretroviral drugs with a shorter duration than nevirapine T_1/2, then due to the persistence of low concentrations of nevirapine, the resistance of HIV can develop.

The first 18 weeks of treatment require special monitoring of the patient's condition in order to quickly identify possible severe and life-threatening skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis). The use of nevirapine should be discontinued, with a marked isolated rash or rash accompanied by fever, vesicle formation, oral cavity, conjunctivitis, facial swelling, myalgia or arthralgia, general malaise. It was shown that during the first 14 days of taking nevirapine, simultaneous prescribing of prednisone (40 mg / day) does not reduce the incidence of rash, but, on the contrary, may increase the frequency of reaction from the skin during the first 6 weeks of therapy. Disruption of the dosing regimen during the introductory period increases the incidence of skin reactions.

The use of nevirapine should also be interrupted if there is a marked change in liver function, eosinophilia, granulocytopenia, hepatitis, renal insufficiency, or signs of impaired function of other internal organs. In such cases, repeated use of nevirapine is not allowed.

Patients treated with nevirapine experienced serious or life-threatening hepatotoxicity, including fatal fulminant hepatitis. The maximum risk of reactions from the liver is noted in the first 6 weeks of therapy. An increased risk of unwanted hepatological reactions is observed in women and patients with a relatively high CD4 count⁺lymphocytes. If the benefit does not exceed the risk, then nevirapine should not be administered to adult women with CD4 counts⁺lymphocytes more than 250 / mm3 and adult men with CD4 counts⁺lymphocytes more than 400 / μl. In some cases, liver damage may continue after discontinuing therapy with nevirapine. Doctors and patients should be wary of such prodromal signs or symptoms of hepatitis, as anorexia, nausea, jaundice, bilirubinemia, achalemic stool, hepatomegaly or liver tenderness. During the period of treatment, a dynamic control of the functional state of the liver should be carried out, especially during the first 6 months. When the ALT and AST values are increased by a factor of 2, these parameters should be monitored more often. If the ALT and AST values exceed the upper limit of the norm by more than 5 times, nevirapine should be immediately canceled.

Patients with impaired renal function on dialysis are advised to use nevirapine 200 mg after each dialysis treatment. This allows you to compensate for the effect of dialysis on the clearance of nevirapine. Patients with QC≥20 ml / min dose adjustment is not required.

In patients receiving nevirapine or any other antiretroviral therapy, opportunistic infections and other complications of HIV infection can continue to develop,

The use of nevirapine does not reduce the risk of HIV-1 transmission during sexual intercourse.

Instructions

Nevirapine (Nevirapinum)