VYRAMUN (Pills)
Active material: Nevirapine
When ATH: J05AG01
CCF: Viricide, active against HIV
When CSF: 09.01.04.01.02
Manufacturer: BOEHRINGER INGELHEIM PHARMA GmbH & Co. KG (Germany)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Pills Oval, lenticular, white, with the notation “54” and “193”, split line, on the one hand and labeled as a symbol of the company – the other side of the tablet.
| 1 tab. | |
| Nevirapine | 200 mg |
Excipients: microcrystalline cellulose, lactose, povidone K25, sodium starch glycolate (Type A), colloidal silicon dioxide, magnesium stearate.
10 PC. – blisters (6) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.
DESCRIPTION OF ACTIVE SUBSTANCES.
Pharmacological action
Antiviral agent. Nenukleotidnym is a reverse transcriptase inhibitor of HIV-1. Directly connects to the reverse transcriptase and blocks the activity of RNA-dependent DNA-dependent polymerase, causing the destruction of the catalytic plot enzyme.
The mechanism of nevirapine does not compete with matrix or nucleoside analog trifosfatami, not ingibiruet retroactive transkriptazu HIV-2 and DNK-polimerazu (a, b, или c d) man.
In combination with AZT/DDI reduces the amount of virus in serum and increases CD4+ cell.
Pharmacokinetics
After oral administration of nevirapine is rapidly absorbed (more 90%) in healthy volunteers and HIV-1 infected adult patients. After receiving a single dose 200 mg Cmax in plasma achieved through 4 h and was 2 ± 0.4 pg / ml (7.5 mmol). In kursovom observed linear increase (C)max nevirapine in plasma in the range of doses 200-400 mg / day.
Eating, antacids and other medications, containing an alkaline buffering component (eg, didanosine), It has no effect on the absorption of nevirapine.
Nevirapine is a lipophilic substance and substantially not ionized at physiological pH. After the on/in the introduction of healthy adults (V)d was 1.21 ± 0.09 l/kg., that confirms a good distribution of nevirapine in human tissues. Nevirapine concentrations in cerebrospinal fluid is 45%(±5%) of plasma concentration.
When plasma concentration 1-10 µg/ml binds to plasma proteins in 60%.
Cssmin achieved dose 400 mg / day was 4.5 ± 1.9 pg / ml.
Metabolized with the participation of mikrosomaionah liver enzymes system CYP, mostly CYP3A izofermentami with the formation of several gidroksilirovannyh metabolites.
Report the news (about 80%) as conjugated to glucuronic acid metabolites, in small quantities – in unchanged form.
Nevirapine is an inducer of microsomal enzymes system CYP.
The ingestion of 200 mg 2 times / day for 2-4 Sun. the apparent clearance of Nevirapine is increased 1.5-2 compared with a single admission to the same dose, T1/2 the Terminal phase is reduced c 45 h the one-time admission to 25-30 h when kursovom. Changing these settings is associated with pharmacokinetic samoindukciej.
Pharmacokinetic parameters of nevirapine does not vary depending on the age of the patients 19-68 years of age or ethnicity. Vd slightly higher in women, than men, but significant differences in the concentration of nevirapine, related to sex, not found.
Children, HIV-1, AUC и Cmax increased in proportion to the dose. After the end of the removals of nevirapine concentrations in blood plasma decreased linearly over time.
Clearance of nevirapine in terms of body mass reached maximum values in patients aged 1 to 2 years, then decreased in proportion to the age. Clearance of nevirapine in patients under the age of 8 years has been approximately 2 times lower, than in adults. T1/2 After reaching Css averaged 25.9 ± 9.6 h (for a group of HIV-1 infected patients with an average age of 11 Months).
With long-term use T1/2 the Terminal phase varies depending on the age and is in children aged 2 Months before 1 year – 32 no, 1-4 years – 21 no, 4-8 years – 18 no, senior 8 years – 28 no.
Testimony
Treatment of adults and children, HIV-1 (in combination with at least 2 antiretroviral drugs).
Prevention of transmission, caused by HIV-1, from mother to newborn (female, not receiving antiretroviral treatment during delivery).
Dosage regimen
When administered to adults – 200 mg 1 times / day daily for the first 14 days (introductory period), then increase the dose to 200 mg 2 times / day every day (in combination with at least 2 antiretroviral drugs).
The recommended dose for children aged 2 Months before 8 years – 4 mg / kg 1 time / day during the first 14 days, then 7 mg / kg / day 2 times / day; for children 8 and older – 4 mg / kg 1 time / day during the first 14 days, then 4 mg / kg 2 times / day.
The maximum dose for patients of any age is 400 mg / day.
Patients, which during the 14-day lead-in period use of nevirapine rash, There should be no increase in doses up to the complete disappearance of the rash.
To prevent transmission of HIV from mother to child is recommended a single dose during labor 200 mg followed by a single oral administration to newborn during 72 hours after birth in a dose of 2 mg / kg.
At moderate changes in indicators of functional status of the liver (except for GGT) dose nevirapine should be interrupted until the, While these figures do not return to the original level, then nevirapine is used in dose 200 mg / day. The subsequent increase in dose (by 200 mg 2 times / day) should be carried out with great caution, after a long period of observation of the patient. Rechecks when changes in liver treatment should stop definitively.
Patients, not treated with nevirapine more 7 days, resume treatment, starting dose 200 mg / day for 14 days, then increase the dose to 200 mg 2 times / day.
Side effect
Dermatological reactions: makulo-papular eritematosnaya rash, sometimes pruritic (localized on the trunk, the face or extremities). In most cases, the rash is observed during the first 28 days.
Allergic reactions: possible fever, arthralgia, myalgia, lymphadenopathy, accompanied by one or more of the following symptoms: hepatitis, eozinofilija, granulocytopenia, violation of the kidney and symptoms, indicating the defeat of other internal organs; anaphylactic reactions, angioedema, hives, Stevens-Johnson syndrome and toksičeskij épidermalʹnyj necrolysis (in rare cases leading to death).
From the digestive system: often – increased activity of GGT; possible – increased ALT, IS, AP and General level of bilirubin, nausea, vomiting, diarrhea, stomach ache; in a few cases – jaundice, heavy gepatotoksicskie reactions.
From the hematopoietic system: granulocytopenia (more children).
CNS: fatigue, headache, drowsiness.
Other: fever, myalgia.
Contraindications
Hypersensitivity to nevirapine.
Pregnancy and lactation
Adequate and well-controlled clinical studies safety of nevirapine during pregnancy did not take place. Established, that nevirapine readily crosses the placental barrier. Pregnancy may only, if the expected benefit to the mother outweighs the potential risk to the fetus.
Nevirapine is secreted in breast milk. If necessary, use during lactation should decide the issue of termination of breastfeeding.
Shows the effectiveness and safety of nevirapine for the prevention of transmission of HIV-1 from mothers to children when administered a single dose during labor 200 mg single dose 2 mg/kg for a newborn during the 72 hours after birth.
During the treatment it is recommended to use barrier methods of contraception.
IN experimental studies have been detected tertogennogo of nevirapine. Shown to decrease fertility in females rats when administered in doses of nevirapine, to ensure receipt of the active substance in the blood system, defined based on AUC, which is approximately equivalent to such when applying the nevirapine in the recommended clinical dose.
Cautions
First 8 weeks of treatment requires special monitoring of the patient's condition with a view to rapidly detect potential severe and life-threatening skin reactions (incl. Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatitis or kidney failure.
Dose nevirapine should be interrupted, If the patients noted the emergence of pronounced rash or rash in combination with fever, formation of Vesicle, lesions of the oral cavity, conjunctivitis, swelling of the face, Myalgia or artralgiej, general malaise, and also when expressed changes liver samples, eozinofilii, granoulozitopenia, gepatite, renal failure or signs of other internal organs. In such cases, nevirapine did not apply again.
Violation of the dosage during the introductory period increases the incidence of skin reactions.
When the break reception more 7 days to reapply should begin with an introductory period.
To apply caution in patients with impaired liver or kidney. Patients with impaired renal function, dialysis, It is recommended to use nevirapine dose 200 mg after each dialysis procedure. This allows you to compensate for the effect of dialysis on clearance of nevirapine. In patients with KK ≥ 20 ml/min dose adjustment is not required.
During the period of treatment should be dynamic control of functional status of the liver, especially during the first 6 Months. If you increase the values of ALT and AST in 2 times should be more frequent control the liver.
If the value of the ALT and AST exceeds the upper bound of the norm in more than 5 time, nevirapine should immediately cancel. At lower values the enzymes may reapply, which begin with a 14-day lead-in period mode 200 mg/day, followed by an increase to 400 mg / day. In repeated fast negative changes in the liver nevirapine should be abolished.
Asymptomatic increase in GGT is not an indication for nevirapine cancellation.
With the appearance of clinical and laboratory signs of hepatitis (moderate or expressed by changes in liver except GGT) Nevirapine is completely overturned and then do not apply.
Long-term effects of nevirapine, currently unknown.
Dose nevirapine does not reduce the risk of transmission of HIV-1 sexual contact.
Together with the use of nevirapine and hormonal contraceptives should monitor the effectiveness of the past.
Effects on ability to drive vehicles and management mechanisms
In case of sleepiness during treatment, It is recommended that you avoid potentially hazardous activities.
Drug Interactions
Together with the use of nevirapine may decrease plasma concentration of hormonal contraceptives for oral administration, What causes a decrease in the effectiveness.
While the application of ketoconazole and nevirapine, there was a reduction in AUC and Cmax ketoconazole. Ketokonazol increases the concentration of nevirapine in plasma 15-28% (concurrent use is not recommended).
Together with the use of cimetidine minimum Css nevirapine in plasma was higher, than without zimetidina.
Ketoconazole and erythromycin result in a significant reduction in the formation of nevirapine hydroxylated metabolites.
Nevirapine does not affect the farmakokinetiku rifampicin. However, a significant decrease in the AUC called rifampin and nevirapine-minimum. If you are applying and rifabutin dose, there was a reduction in the concentration of nevirapine. Currently, there are insufficient data to determine whether it is necessary to change the dose, while applying the nevirapine and rifampicin or rifabutin.
Since nevirapine causes induction of isoenzymes by CYP2B6 and CYP3A, together with the use of drugs, those actively, with the participation of these enzymes, may reduce plasma concentrations of these drugs.
Together with the use of nevirapine and preparations, containing St. John's wort, may reduce the concentration below the therapeutic levels of nevirapine, that can lead to loss of virologic effectiveness and sustainability development of the virus to nevirapine (concurrent use is not recommended).
Due to the nature of metabolism of methadone, nevirapine can lower concentrations of methadone in plasma by enhancing the metabolism of methadone in the liver. Patients, at the same time receiving methadone and nevirapine, there were cases of drug withdrawal (when using such a combination should monitor the patient's condition and to adjust the dose of methadone).
