Universal reference book for medicines
Name of the drug: NEVIRPINE

Active substance: nevirapine

Type: Antiviral drug active against HIV

Manufacturer: FARMASINTEZ (Russia)
Description of the active substance:
This information is a reference and it is not enough that the drug has been prescribed by a doctor ..

PHARMACHOLOGIC EFFECT
An antiviral agent.
It is a non-nucleotide inhibitor of HIV-1 reverse transcriptase. It directly combines with reverse transcriptase and blocks the activity of RNA-dependent and DNA-dependent polymerase, causing destruction of the catalytic site of the enzyme.
According to the mechanism of action, nevirapine does not compete with matrix or nucleoside triphosphates, does not inhibit the reverse transcriptase of HIV-2 and human DNA polymerase (?,?,? Or?).

In combination with zidovudine / Didanosine reduces the number of viruses in the serum and increases the number of CD4 + cells.

PHARMACOKINETICS
After oral administration, nevirapine is rapidly absorbed (more than 90%) in healthy volunteers and HIV-1 infected adult patients.
After a single dose of 200 mg C maxin blood plasma was achieved after 4 hours and was 2 ± 0.4 μg / ml (7.5 μmol). At the course of the course, there was a linear increase in C max of nevirapine in the plasma in the dose range of 200-400 mg / day.
Food intake, antacids and other medications containing an alkaline buffer component (eg, didanosine), does not affect the absorption of nevirapine.

Nevirapine is a lipophilic substance and practically does not ionize at a physiological pH.
After intravenous administration of a healthy adult, V d was 1.21 ± 0.09 L / kg, which confirms the good distribution of nevirapine in human tissues. The concentration of nevirapine in the cerebrospinal fluid is 45% (± 5%) of the plasma concentration.
At a plasma concentration of 1-10 μg / ml, it binds to plasma proteins by 60%.

C ss min was achieved at a dose of 400 mg / day and was 4.5 ± 1.9 μg / ml.

Metabolized with the participation of microsomal liver enzymes of the cytochrome P450 system, predominantly CYP3A isoenzymes with the formation of several hydroxylated metabolites.

It is excreted by the kidneys (about 80%) in the form of metabolites conjugated with glucuronic acid, in small amounts - in unchanged form.

Nevirapine is the inducer of the microsomal enzymes of the CYP system.

When ingestion of 200 mg 2 times / day for 2-4 weeks.
the apparent clearance of nevirapine increases by 1.5-2 times compared with a single dose at the same dose, T1/2 in the terminal phase decreases from 45 hours with a single dose of up to 25-30 hours for a course application. The change in these parameters is associated with pharmacokinetic self-induction.
The pharmacokinetic parameters of nevirapine do not change depending on the age of patients aged 19-68 years or of ethnicity.
V d in women is slightly higher than in men, but no significant differences in the concentration of nevirapine associated with sex have been identified.
In children infected with HIV-1, AUC and C max increased in proportion to the dose increase.
After the end of absorption, the concentration of nevirapine in the blood plasma decreased linearly with time.
The nevirapine's clearance in terms of body weight reached the maximum values ​​in patients aged 1 to 2 years, then decreased in proportion to age.
The nevirapine clearance in patients under the age of 8 years was approximately 2 times lower than in adult patients. T 1/2 after reaching C ss averaged 25.9 ± 9.6 hours (for the HIV-1 group of infected patients with an average age of 11 months).
With long-term use, T 1/2 in the terminal phase varies depending on age and is in children aged 2 months to 1 year - 32 hours, 1-4 years - 21 hours, 4-8 years - 18 hours, over 8 years - 28 hours

INDICATIONS
Treatment of adults and children infected with HIV-1 (in combination with at least 2 antiretroviral drugs).

Prevention of transmission of HIV-1 infection from mother to newborn (in women who have not received antiretroviral treatment during labor).

DOSING MODE
Admission to adults - 200 mg 1 time / day daily for the first 14 days (introductory period), then the dose is increased to 200 mg 2 times / day daily (in combination with at least 2 antiretroviral drugs).

Recommended dosages for children aged 2 months to 8 years - 4 mg / kg 1 time / day for the first 14 days, then 7 mg / kg / day 2 times / day;
children aged 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 of nevirapine use should not be increased until the rash disappears completely.

In order to prevent mother-to-child transmission of HIV, a single dose of 200 mg should be given at the time of delivery, followed by a single oral administration to the newborn within 72 hours after birth at a dose of 2 mg / kg.

With moderate changes in the functional status of the liver (with the exception of GGT), the use of nevirapine should be discontinued until these values ​​return to baseline, then nevirapine is used at a dose of 200 mg / day.
The subsequent increase in the dose (200 mg 2 times / day) should be carried out with great care after a long period of observation of the patient. If liver changes appear again, treatment should be discontinued.
In patients who have not received nevirapine for more than 7 days, treatment is resumed starting at a dose of 200 mg / day for 14 days, then increasing the dose to 200 mg 2 times / day.

SIDE EFFECT
Dermatological reactions: makulo-papular erythematous skin rash, sometimes accompanied by itching (localized on the trunk, face or limbs).
In most cases, the rash occurs within the first 28 days.
Allergic reactions: fever, arthralgia, myalgia, lymphadenopathy, accompanied by one or more of the following symptoms are possible: hepatitis, eosinophilia, granulocytopenia, impaired renal function, and symptoms indicative of involvement of other internal organs;
anaphylactic reactions, angioedema, hives, Stevens-Johnson syndrome and toxic epidermal necrolysis (in rare cases, resulting in death).
From the digestive system: often - increased GGT activity;
possible - increased activity of ALT, AST, APF and the level of total bilirubin, nausea, vomiting, diarrhea, abdominal pain; in isolated cases - jaundice, severe hepatotoxic reactions.
From the hemopoietic system: granulocytopenia (more often in children).

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

Other: fever, myalgia.

CONTRAINDICATIONS
Hypersensitivity to nevirapine.

PREGNANCY AND LACTATION
Adequate and strictly controlled clinical studies of the safety of nevirapine in pregnancy have not been conducted.
It was found that nevirapine easily penetrates the placental barrier. Use during pregnancy is possible only if the intended benefit to the mother exceeds the potential risk to the fetus.
Nevirapine is excreted in breast milk.
If it is necessary to use during the lactation period, the question of stopping breastfeeding should be solved.
The efficacy and safety of nevirapine for the prevention of mother-to-child transmission of HIV-1 during oral delivery of a single dose of 200 mg and a single dose of 2 mg / kg for a newborn within 72 hours after birth is shown.

During the period of treatment, the use of barrier methods of contraception is recommended.

In experimental studies, no teratogenic effects of nevirapine have been identified.
The decrease in fertility in female rats with nevirapine administered at doses that provide the active substance into the systemic blood flow, determined on the basis of AUC, is approximately equivalent to that of nevirapine in the recommended clinical doses.
APPLICATION FOR FUNCTIONS OF THE LIVER
Use with caution in patients with impaired renal function.
Patients with impaired renal function who are on dialysis are recommended to use nevirapine at a dose of 200 mg additionally after each dialysis procedure. This allows you to compensate for the effect of dialysis on the clearance of nevirapine. In patients with QC? 20 ml / min, dose adjustment is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Use with caution in patients with impaired hepatic function.
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 doubled, liver function 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 withdrawn.
In the case of a decrease in the enzyme values, it is possible to reuse, which starts with a 14-day introductory period in the 200 mg / day regime, followed by an increase to 400 mg / day. With repeated rapid negative changes in the liver function parameters, nevirapine should be discarded.
APPLICATION FOR CHILDREN
Recommended dosages for children aged 2 months to 8 years - 4 mg / kg 1 time / day for the first 14 days, then 7 mg / kg / day 2 times / day;
children aged 8 years and older - 4 mg / kg 1 time / day for the first 14 days, then 4 mg / kg 2 times / day.
In order to prevent mother-to-child transmission of HIV, a single dose of 200 mg should be given at the time of delivery, followed by a single oral administration to the newborn within 72 hours after birth at a dose of 2 mg / kg.

SPECIAL INSTRUCTIONS
In the first 8 weeks of treatment, special monitoring of the patient's condition is required to quickly identify possible severe and life-threatening skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatitis or renal insufficiency.

The use of nevirapine should be discontinued if patients develop a severe rash or rash in combination with fever, vesicle formation, oral cavity, conjunctivitis, facial swelling, myalgia or arthralgia, general malaise, and with marked changes in hepatic samples, eosinophilia, granulocytopenia, hepatitis, renal failure, or the appearance of signs of impaired function of other internal organs.
In such cases, nevirapine is not reapplied.
Disruption of the dosing regimen during the introductory period increases the incidence of skin reactions.

When taking a break for more than 7 days, re-use should begin with an introductory period.

Use with caution in patients with impaired hepatic or renal function.
Patients with impaired renal function who are on dialysis are recommended to use nevirapine at a dose of 200 mg additionally after each dialysis procedure. This allows you to compensate for the effect of dialysis on the clearance of nevirapine. In patients with QC? 20 ml / min, dose adjustment is not required.
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 doubled, liver function 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 withdrawn.
In the case of a decrease in the enzyme values, it is possible to reuse, which starts with a 14-day introductory period in the 200 mg / day regime, followed by an increase to 400 mg / day. With repeated rapid negative changes in the liver function parameters, nevirapine should be discarded.
The asymptomatic increase in GGT is not an indication for the withdrawal of nevirapine.

When clinical and laboratory signs of hepatitis appear (moderate or pronounced changes in liver function parameters except GGT), nevirapine is completely abolished and not reapplied.

The long-term effects of nevirapine are currently unknown.

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

With the simultaneous use of nevirapine and hormonal contraceptives should monitor the effectiveness of the latter.

Impact on the ability to drive vehicles and manage mechanisms

In case of occurrence of drowsiness on the background of treatment, it is recommended to avoid potentially dangerous activities.

DRUG INTERACTION
With simultaneous application with nevirapine, a decrease in plasma concentration of hormonal contraceptives for oral administration is possible, which causes a decrease in efficacy.

With the simultaneous use of ketoconazole and nevirapine, AUC and C max ketoconazole decreased.
Ketoconazole increases the concentration of nevirapine in plasma by 15-28% (simultaneous use is not recommended).
With simultaneous use with cimetidine, the minimum C ss of nevirapine in plasma was higher than without cimetidine.

Ketoconazole and erythromycin lead to a significant reduction in the formation of hydroxylated nevirapine metabolites.

Nevirapine has no effect on the pharmacokinetics of rifampicin.
However, rifampicin caused a significant decrease in AUC and minimal concentration of nevirapine.With simultaneous use of nevirapine and rifabutin, there is a decrease in the concentration of nevirapine. At present, there is insufficient data to determine the need for dose changes with the simultaneous use of nevirapine and rifampicin or rifabutin.
Since nevirapine induces the induction of isoenzymes CYP3A and CYP2B6, while simultaneous use with drugs actively metabolized with the participation of these enzymes, a decrease in the plasma concentration of these drugs is possible.

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

Due to the peculiarities of methadone metabolism, nevirapine can reduce the concentration of methadone in the blood plasma by enhancing the metabolism of methadone in the liver.
In patients who received concomitant methadone and nevirapine, cases of drug withdrawal syndrome were noted (when using this combination, the patient's condition should be monitored and the dose of methadone adjusted).
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