Вирамун®

General characteristics. Structure:

Active ingredient: 10,35 mg of not Virapinum of hemihydrate that corresponds to 10 mg of not Virapinum in 1 ml of suspension.

Excipients: carbomer, polysorbate 80, sorbitol 70, sucrose, methylparahydroxybenzoate, пропилпарагидроксибензоат, sodium hydroxide, the water purified.

Pharmacological properties:

Pharmacodynamics. Not Virapinum is nenukleozidny inhibitor (NNIOT) VICh-1 return transcriptase. Not Virapinum directly contacts the return transcriptase and blocks activity of a RNA-dependent and DNA-dependent DNA polymerase, causing destruction of the catalytic website of this enzyme. Activity  of not Virapinum    does not compete  with  triphosphates  of a matrix  or  nucleosides. Not Virapinum does not inhibit the return VICh-2 transcriptase and DNA polymerases of cells an eukaryote (such as DNA polymerases of the person and, in, at or 8).

Sensitivity of HIV of in vitro. The interrelation between sensitivity of VICh-1 to ВИРАМУНУ® in vitro and inhibition of replication of VICh-1 at the person is not established. Antiviral activity of not Virapinum of in vitro was estimated on mononuclear cells of peripheral blood, macrophages of a monocytic origin and lymphoblastoid cellular lines. IC50 values concerning laboratory and clinical VICh-1 isolates varied from 10 to 100 nmol. On cellular culture it is shown that activity concerning HIV of 1 not Virapinum applied in a combination with ZDV, ddl, d4T, 3TC, sakvinaviry and indinaviry was the additive or synergistic.

Stability. In vitro is established a possibility of emergence of HIV isolates with reduced sensitivity (by 100 - 250 times) to not Virapinum. The genotypic analysis revealed mutations in a gene of RT of HIV in the 181 and/or 106 amino-acid position, depending on a virus strain and the used cellular line. When using not Virapinum in a combination with several others NNIOT time of emergence of resistance to in vitro not Virapinum, did not change. In researches of phases during 1 to> 12 weeks monitorirovatsya phenotypical and genotypic changes of the VICh-1 isolates emitted at the patients receiving ВИРАМУН® (n = 24) or ВИРАМУН® in a combination with ZDV (n = 14). After monotherapy ВИРАМУНОМ® within 1 week reduced sensitivity to not Virapinum of in vitro is noted at the isolates emitted at 3/3 patients. At some patients, most earlier in 2 weeks after the beginning of therapy, it was found one or bigger number of mutations in RT gene, in 103, 106, 108, 181, 188 and 190 amino-acid positions. By eighth week of monotherapy the drug VIRAMUN® at all inspected patients (n = 24) emitted HIV isolates which sensitivity to not Virapinum of in vitro was reduced more than by 100 times in comparison with initial and one or bigger number of mutations of a gene of RT associated with resistance to not Virapinum are revealed. At 80% of patients isolates with a mutation in a position 181, irrespective of a dose were emitted. The combination therapy the drug VIRAMUN® + ZDV did not change the frequency of developing of the viruses steady against not Virapinum, or degree of resistance to in vitro not Virapinum. However in these cases other type of mutations which is preferential arising in 103, 106, 188 and 190 amino-acid positions was observed. At patients (at 6 of 14) with the initial isolates which had a gene of RT of natural type an impression was made that combination therapy ВИРАМУН® + ZDV did not detain emergence of ZDV steady mutations of a gene of RT. In the research INCAS genotypic and phenotypical stability was estimated at the patients receiving ВИРАМУН® as a part of a triple and double combination therapy and at the patients of control group who were not receiving ВИРАМУН®. At the patients who were earlier not receiving anti-retrovirus therapy (the number CD4 of cells at them made 200-600/mm3), treatment ВИРАМУН® + ZDV (N = 46), ZDV + by ddl (N = 51) or ВИРАМУН® + ZDV + ddl was carried out (N = 51); observation was carried out for 52 weeks of treatment or more. Virologic examination was conducted initially, in 6 and 12 months. The used method of assessment of phenotypical stability demanded for implementation of amplification of a virus of presence of, at least, 1000 copies/ml of HIV RNA. In 3 studied groups of patients the initial isolates available to a research were emitted. These patients received treatment within, at least, 24 weeks. Five cases of phenotypical resistance to not Virapinum were initially noted; IC50 values at three of them increased by 5-6,5 times, and at two - more than by 100 times. In 24 weeks the patients receiving ВИРАМУН® had all isolates which managed to be emitted rezistentna to this drug. In 30-60 weeks similar isolates were available for 86% of patients.

Suppression of a virus is lower than a limit of its detection was reached at 16 patients (<20 copies/ml - at 14, <400 copies/ml - at 2). When using an assumption that suppression is lower <20 copies/ml indicate sensitivity of a virus to the drug VIRAMUN®, was established (by direct or indirect assessment) that sensitivity to this drug remained at 45% of patients. All patients receiving ВИРАМУН® + ZDV and tested for existence of phenotypical resistance in six months were steady to ВИРАМУНУ®. For the entire period of observation one case of resistance to a didanozin is established. Resistance to a zidovudine arose more often in 30-60 weeks, especially at the patients receiving a double combination therapy. Based on IC50 given about increase, it was established that resistance to ZDV arises, apparently, less often at the patients receiving ВИРАМУН® + ZDV + ddl than at patients of other medical groups. Concerning stability to ВИРАМУНУ® it was shown that all received isolates had, at least, one mutation connected with resistance. To the most often single changes were exposed to K103N and Y181C. Thus, use of the highly active modes of medicinal therapy is followed by delay of development of resistance to anti-retrovirus means. The genotypes correlating with phenotypical stability to ВИРАМУНУ® are identified at 12 isolates emitted from plasma of the patients receiving triple therapy. The mutations associated with the stability to ВИРАМУНУ® developing in the course of treatment are given in the table:

Mutation	Frequency
K101E	2
K103N	8
V106A	2
Y181C	5
G190A	6

These data obtained in the research INCAS show that use of the highly active modes of medicinal therapy is followed by delay of development of resistance to anti-retrovirus drugs. The clinical importance of the phenotypical and genotypic changes connected with therapy by not Virapinum is not established yet.

Resistance in perinatal transmission. The mutations causing resistance to not Virapinum were found in 19% of women within 6-8 weeks after single use of drug (research HIVNET 012). Among the mutations associated with resistance to not Virapinum K103N mutation (57%), further a mutation in the mix K103N and Y181C (19%) most often was found in these women. At repeated inspection in 12-24 months after the delivery the mutations associated with resistance to not Virapinum were not revealed at 11 women (were found in all these patients of a mutation in 6-8 weeks). Resistance to not Virapinum is revealed at 46% of the infected newborns (research HIVNET 012). Most often Y181C mutation was found. Among all those newborns (n = 7) in whom mutations were found at the age of 6-8 weeks, at repeated inspection at the age of 12 months of a mutation, associated with resistance to not Virapinum, were not revealed. The clinical importance of these results and their influence on the subsequent treatment using NNIOT are not clear.

Cross stability. In the researches in vitro bystry emergence of strains of the HIV having cross resistance to NNIOT is established.
 
Data on cross stability between the representative of NNIOT not Virapinum and nukleozidny inhibitors of the return transcriptase are very limited. In the researches in vitro it is shown that steady to the ZDV isolates received at four patients kept sensitivity to not Virapinum and that the isolates, steady against not Virapinum, received at six patients were sensitive to ZDV and ddl. Cross stability between not Virapinum and inhibitors of HIV protease is improbable owing to distinctions of the involved enzymes - "targets".

Cross resistance among registered so far NNIOT is eurysynusic. A number of genotypic researches demonstrates that in case of inefficiency of any NNIOT at most of these patients the strains of viruses which are characterized by cross other drug resistance from this group come to light. The data existing now indicate inexpediency of consecutive use various NNIOT.

Pharmacokinetics Adults. Not Virapinum well (> 90%) is soaked up after intake. Absolute bioavailability after use of a single dose of drug, made: for the tablet containing 50 mg, 93 ± 9% (average size ± SD), and for solution (intake) 91 ± 8%. The peak of concentration of not Virapinum in plasma after a single dose of drug in a dose of 200 mg was reached in 4 hours and made 2 + 0,4 mkg/ml (7,5 µmol). After multiple dose of drug in doses from 200 to 400 mg/day the peak of concentration of not Virapinum increased linearly depending on dose size. Basal level of concentration of not Virapinum in the period of a steady condition of pharmacokinetics at reception of 400 mg a day made 4,5 ± 1,9 mkg/ml (17 ± 7 µmol).

Meal, antacids or drugs which dosage form contains the alkaline buffer (for example, a didanozina) does not influence absorption of not Virapinum.

Not Virapinum has high lipophilicity and is practically not ionized at physiological PH value. Not Virapinum well gets through a placental barrier and is defined in breast milk. Linkng of not Virapinum with proteins of plasma makes about 60%, its concentration in plasma vary from 1 to 10 mkg/ml. Concentration of not Virapinum in cerebrospinal fluid at the person make 45% (± 5%) from concentration in plasma; this ratio approximately corresponds to the fraction of drug which is not connected with proteins of plasma.

Not Virapinum biotransformirutsya intensively by metabolism (oxidation reaction) with participation of P450 cytochrome to several hydroxylated metabolites. Oxidizing metabolism of not Virapinum is carried out, generally by means of P450 cytochrome isoenzymes from the CYP3A family, also other isoenzymes can play an additional role. By results of a pharmacokinetic research it was removed about 91,4 ± 10,5% marked by drug dose isotope, it is preferential (81,3 ± 11,1%) with urine and, to a lesser extent (10,1 ± 1,5%), with a stake. More than 80% of the radioactive label found in urine were connected with conjugates of hydroxylated metabolites with glucuronides. Thus, the main way of biotransformation and removal of not Virapinum at the person consists in metabolism with participation of P450 cytochrome, conjugation with glucuronides and excretion of the metabolites connected with glucuronides with urine. Only the small share (<5%) radioactivity in urine (corresponding <3 % of the general dose) was connected with not changed connection, that is, renal excretion plays a small role in removal of not Virapinum.

It is shown that not Virapinum is the inductor of metabolic enzymes of P450 cytochrome in a liver. If after reception of a single dose treatment continues during 2-4 weeks (reception of 200-400 mg/day), then indicators of pharmacokinetics are characterized by an autoinduktion: the seeming oral clearance of not Virapinum increases approximately by 1,5-2 times. Autoinduktion also leads to the corresponding reduction of a final phase of an elimination half-life of not Virapinum from plasma: approximately from 45 o'clock (single dose) till about 25-30 o'clock (after multiple dose of drug in doses of 200-400 mg/day).

Though at women the volume of distribution of not Virapinum (with correction concerning body weight) was a little higher, than at men, significant distinctions of concentration of not Virapinum in plasma (after single or multiple dose of drug) depending on a floor were not noted. Not Virapinum pharmacokinetics at the VICh-1-infitsirovannykh adult patients, apparently, does not change depending on age (range of 18-68 years) or race (Negroids, the Latin American or Caucasian race). This information is obtained as a result of assessment of the integrated data from several clinical trials.

Insufficiency of function of kidneys. Comparison of indicators of pharmacokinetics after a single dose of the drug VIRAMUN® at patients with small (50 <clearance of creatinine <80 ml/min.), moderated (30 <clearance of creatinine <50 ml/min.) or considerable dysfunction of kidneys is carried out (clearance of creatinine <30 ml/min.), noted at diseases of kidneys or at a final stage of the renal failure demanding carrying out dialysis and at patients with normal function of kidneys (clearance of creatinine> of 80 ml/min.). The renal failure (small, moderate or considerable) did not lead to reliable changes of pharmacokinetics of the drug VIRAMUN®. However at patients with a final stage of the renal failure demanding carrying out dialysis during the period of the influence making 1 week reduction of AUC of not Virapinum by 43,5% was noted. Also accumulation of hydroxylated metabolites of not Virapinum in plasma was noted. Auxiliary therapy by not Virapinum using later each session of dialysis of the additional dose making 200 mg could compensate influence of dialysis on clearance of drug. On the other hand, patients, the clearance of creatinine at whom makes> 20 ml/min., do not demand selection of doses ВИРАМУНА®.

Insufficiency of function of a liver. Comparison of indicators of pharmacokinetics after a single dose of the drug VIRAMUN® at patients with a liver failure and at patients with normal function of a liver is carried out. Individual selection of a dose of drug is not required from patients with easy or moderate insufficiency of function of a liver.

However results of studying of pharmacokinetics at one patient with the moderate expressed ascites indicate a possibility of accumulation of not Virapinum in system circulation at patients with considerable abnormal liver functions.

Pregnant women. In researches it is shown that at the time of delivery at the VICh-1-infitsirovannykh women the drug VIRAMUN® elimination half-life (after a single dose inside in a dose of 200 mg) is extended (till 60-70 o'clock), and the clearance substantially varies (2,1 ± 1,5 l/h) that depends on degree of a physiological stress at the time of delivery. Not Virapinum quickly gets through a placental barrier. Concentration of not Virapinum in blood of an umbilical cord after reception by mothers of the dose of drug making 200 mg exceeded 100 ng/ml, and the ratio of concentration in blood of an umbilical cord and in blood of mother made 0,84 ± 0,19 (n = 36; range 0,37-1,22).

Mothers nursing. In order to avoid risk of post-natal transfer of HIV it is recommended that HIV-positive mothers did not resort to feeding by a breast of newborn children. Results of two pharmacokinetic researches showed what ВИРАМУН® easily gets through a placenta and can be found in breast milk. In the research ACTG 250 studying of the tests of breast milk received at the VICh-1-infitsirovannykh pregnant women after a single dose by them in ВИРАМУНА® in a dose of 100 mg or 200 mg was carried out (the average time before childbirth made 5,8 hours). It is established that an average of a ratio of concentration ВИРАМУНА® in breast milk and in blood serum of mothers made 76% (54-104%). In the research HIVNET 006 it is shown that after a single dose in drug in a dose of 200 mg an average ratio of concentration in breast milk and in plasma of mothers made 60,5% (25-122%).

Pharmacokinetics at children. Newborns. At the newborns (who were born at the VICh-1-infitsirovannykh women who were once receiving not Virapinum in a dose of 200 mg at the time of delivery) who during 72 h after the delivery received VIRAMUN® suspension inside in a dose of 2 mg/kg the average geometrical size of an elimination half-life of not Virapinum made 47 hours. Levels in plasma within the first week of life made more than 100 ng/ml.

The pharmacokinetics of not Virapinum was studied in two open researches at children with VICh-1 an infection aged from 9 months up to 14 years which received single doses of suspension of not Virapinum (7,5 mg, 30 mg or 120 mg on sq.m) in the morning, on an empty stomach. The size AUC and peak concentration of not Virapinum increased in proportion to a dose. After absorption of not Virapinum of its concentration in plasma (expressed logarithmic) decreased linearly over time. The final phase of an elimination half-life of not Virapinum after a single dose made 30,6 ± 10,2 hours.

In a research with repeated use of not Virapinum (in the form of suspension or tablets in a dose of 240-400 mg/sq.m/day) this drug was used as monotherapy or in a combination with ZDV or ZDV and ddl at 37 VICh-1-infitsirovannykh children from 2 months to 15 years. These patients received not Virapinum in a dose of 120 mg/sq.m/day within about 4 weeks, and in the subsequent - in a dose of 120 mg/sq.m 2 times a day (patients are more senior than 9 years) or in a dose of 200 mg/sq.m 2 times a day (patients up to 9 years). The clearance of not Virapinum, in terms of body weight, reached the maximum values at children aged from 1 year up to 2 years, and then decreased with increase in age. The clearance of not Virapinum, in terms of body weight, at children up to 8 years was approximately twice higher, than at adults. Not Virapinum elimination half-life for all group of patients in general (after achievement of the period of a steady condition of pharmacokinetics) made 25,9 ± 9,6 hours. With increase in duration of use of drug average values of a final phase of an elimination half-life of not Virapinum changed with age as follows: from 2 months to 1 year - 32 hours, from 1 year to 4 years - 21 hour, from 4 to 8 years - 18 hours, are more senior than 8 years - 28 hours.

Indications to use:

Treatment of HIV infection in a combination with other anti-retrovirus drugs which are applied to treatment of VICh-1 of an infection. At monotherapy resistant strains of a virus arise drug VIRAMUN ® quickly and practically always. Therefore ВИРАМУН® it has to be applied always in a combination, at least, with two other anti-retrovirus drugs.

For the warning of a VICh-1 broadcast from mother to the child, at pregnant women who do not receive anti-retrovirus therapy during childbirth ВИРАМУН® it is shown and it can be applied at mother as monotherapy, in the form of the single dose accepted inside at the time of delivery and at the child, also in the form of the single dose entered inside after the birth. To minimize risk of transmission of VICh-1 to the child, carrying out a combination therapy at mother before childbirth is recommended when it is obviously possible.

Route of administration and doses:

Inside. Adults: The recommended dose ВИРАМУНА®: one tablet of 200 mg, daily, during the first 14 days (use of this initial stage is necessary as it is established that at the same time rash frequency decreases), and in the subsequent one tablet 200 mg, 2 times a day, in a combination not less than with two additional anti-retrovirus drugs. In case of use of a combination therapy it is necessary to conform to the rules of dosing and monitoring recommended by manufacturers.

Children: The recommended dose ВИРАМУНА® for intake at children aged from 2 months up to 8 years makes 4 mg/kg within two weeks once a day, and in the subsequent 7 mg/kg 2 times a day. For patients at the age of 8 years the recommended dose is also more senior makes 4 mg/kg within two weeks once a day, and in the subsequent 4 mg/kg 2 times a day. The total daily dose at any patient should not exceed 400 mg.

General recommendations. Patients need to report about need to accept ВИРАМУН® daily as it is offered to them. In case of the admission of administration of drug the patient should not double the following dose, it is necessary to accept the next dose as soon as possible.

Prior to reception ВИРАМУНА® and through the corresponding intervals during therapy biochemical researches, including researches of function of a liver have to be conducted.

Patients at whom during a 14-day initial stage of daily administration of drug in a dose of 200 mg a day rash is noted should not increase a dose until rash does not disappear. The patients who interrupted reception ВИРАМУНА® for the term of more than 7 days when resuming therapy have to use again recommended use mode, that is accept drug in a dose of 200 mg (children have 4 mg/kg/day) (initial stage), and then one tablet of 200 mg twice a day once a day (at children of 4 or 7 mg/kg 2 times a day depending on age).

Prevention of transmission of HIV from mother to the child. The following mode of dosing for pregnant women and their newborn children is recommended: dosing at mothers: a single dose of 200 mg as soon as possible after the beginning of childbirth. Dosing at the newborn: single introduction orally 2 mg/kg within 72 hours after the birth. If mother received ВИРАМУН® less than in two hours prior to childbirth, the newborn should enter the first dose ВИРАМУНА® (2 mg/kg) immediately after the birth, and the second dose (2 mg/kg) - within 24-72 hours after the first.

Features of use:

The first 18 weeks of therapy by not Virapinum have critical value. During this period careful observation of patients for identification of possible heavy and life-threatening skin reactions (including cases of a syndrome of Stephens-Johnson and a toxic epidermal necrolysis) or serious hepatitis / is required to a liver failure. The greatest risk of hepatological and dermatological reactions exists in the first 6 weeks of therapy. The risk of the undesirable phenomena from a liver is increased at women and at patients with higher number CD4 of cells. It is necessary to adhere to strictly recommended therapy mode, especially during the initial 14-day stage.

Reactions from skin. At the patients receiving ВИРАМУН® serious and life-threatening dermatological reactions, including from the death were noted. Cases of the Stephens-Johnson's syndrome (SJS), the toxic epidermal necrolysis (TEN) and a syndrome of hypersensitivity characterized by rash, the general reactions and damage of internals were observed. Careful observation of patients within the first 18 weeks of treatment is necessary. Careful observation is required also in case of development of the isolated rash. ВИРАМУН® it has to be cancelled at any patient in case of development of the expressed rash or the rash which is followed by the general symptoms (fever, formation of bubbles, changes in an oral cavity, conjunctivitis, a face edema, a joint pain or muscles, a febricula), at Stephens-Johnson's syndrome or a toxic epidermal necrolysis. ВИРАМУН® it has to be cancelled at any patient in case of development of the reactions of hypersensitivity which are characterized by rash and the general symptoms, and also changes of internals including at hepatitis, an eosinophilia, a granulocytopenia and dysfunction of kidneys, or other signs of damage of internals (see the section "Side effect").

Patients need to report that the main manifestation of toxicity ВИРАМУНА® is rash. The initial stage of treatment as it is established that it reduces rash frequency has to be used (see the section "Dosing and Use"). In most cases the rash connected with reception ВИРАМУНА® arises in the first six weeks of therapy. Therefore during this period careful observation of patients concerning dermatological reactions is necessary. Patients have to be informed that in case of development of any rash during an initial stage of treatment the dose of drug should not be raised until rash does not disappear.

It is shown that simultaneous use of Prednisonum (40 mg/day, during the first 14 days of reception ВИРАМУНА®) does not reduce the frequency of developing of rash, and, on the contrary, can speed up dermatological reactions within the first 6 weeks of therapy.

Disturbance of the recommendation of use of drug in a dose of 200 mg a day during the initial stage of therapy is among risk factors of development of serious skin reactions. The risk of development of more serious result of dermatological reactions increases in a delay case with the request for medical consultation after the beginning of symptoms. The risk of development of rash in women, apparently, is more, than at men, as in case of use ВИРАМУНА®, and the therapy which is not containing ВИРАМУН®.

The patient who has an expressed rash or the rash which is followed by the general symptoms (fever, formation of bubbles, changes in an oral cavity, conjunctivitis, a face edema, a joint pain or muscles, a febricula) has to stop administration of drug and consult with the doctor. Repeated use ВИРАМУНА® for these patients is not allowed. If at the patient rash is noted and there is a suspicion on communication with reception ВИРАМУНА®, the research of function of a liver has to be conducted. At patients with the moderated or expressed disturbances (the nuclear heating plant or ALT exceeds the upper bound of norm more than by 5 times), ВИРАМУН® has to быьб it is cancelled.

In case of the reactions of hypersensitivity which are characterized by rash which is followed by the general symptoms (fever, arthralgias, mialgiya and a lymphadenopathy) in combination with signs of damage of internals, for example hepatitis, an eosinophilia, a granulocytopenia and dysfunction of kidneys, not Virapinum has to be cancelled; repeated use of not Virapinum is not allowed.

Reactions from a liver. At the patients treated by not Virapinum were noted a serious or life-threatening hepatotoxic, including fatal fulminantny hepatitis. The first 18 weeks of treatment during which careful control is necessary have critical value. The highest risk of reactions from a liver is noted in the first 6 weeks of therapy. The increased risk of undesirable hepatological reactions is noted at women and patients with higher number CD4 of cells. This risk remains and further therefore frequent control has to continue throughout all treatment. It is necessary to inform patients that reactions from a liver are a main type of toxicity ВИРАМУНА® and that emergence of the signs indicating development of hepatitis has to be a reason for immediate consultation with the doctor.

About a serious hepatotoxic, including development of the liver failure demanding transplantation of a liver it was reported when using repeated doses ВИРАМУНА® for the purpose of post-contact prevention of persons who were not infected HIV that is not among the approved indications for use of this drug.

Higher risk of undesirable reactions from a liver during performing any anti-retrovirus therapy including during use of the modes including ВИРАМУН® it is noted at initial increase in levels of nuclear heating plant or ALT more than by 2,5 times in comparison with the upper bound of norm and/or in the presence of the hepatitis B and/or C. The risk of development of the hepatological reactions associated with rash at women, apparently, is three times higher, than at men (4,6% in comparison with 1,5%). The risk of development of the hepatological reactions associated with rash at treatment ВИРАМУНОМ® can be also higher at patients with higher number CD4 of cells. According to the retrospective analysis, women with number CD4 of cells have more than 250 cells/mm3, risk of the hepatological reactions associated with rash was 9 times higher, than women with number CD4 of cells have less than 250 cells/mm3 (8,4% in comparison with 0,9%). The increased risk was observed also at men with number CD4 of cells> 400 cells/mm3 in comparison with men with number CD4 of cells <400 cells/mm3 (4,5% in comparison with 0,7%).

Control of a condition of a liver. When using ВИРАМУНА® it was reported about changes of the indicators of function of a liver sometimes arising in the first weeks of therapy. Asymptomatic increase in level of enzymes of a liver is described often and is not an unconditional contraindication for use ВИРАМУНА®. Asymptomatic increase gamma глутамил transferases is not a contraindication to therapy continuation.

Strict control of indicators of function of a liver through short intervals of time, depending on a clinical condition of patients, especially within the first 18 weeks of treatment is recommended. Clinical and laboratory control has to continue throughout the entire period of treatment ВИРАМУНОМ®. Doctors and patients have to treat such antecedent signs or symptoms of hepatitis as anorexia, nausea, jaundice, a bilirubinemia, an akholichny chair, a hepatomegalia or morbidity of a liver watchfully. Patients have to be informed on need to address for medical consultation in such cases.

In case of increase in nuclear heating plant or ALT more than by 2,5 times in comparison with the upper bound of norm before the beginning or in the course of treatment, indicators of function of a liver have to be checked more often during the regular clinical visits. ВИРАМУН® it should not be appointed to patients who have an initial level of nuclear heating plant or ALT more than by 5 times exceeds the upper bound of norm (until it steadily does not decrease to level less than by 5 times of the exceeding VGN).

If nuclear heating plants or ALT raise more than 5 times above VGN during treatment, ВИРАМУН® has to be immediately cancelled. If the level of nuclear heating plant and ALT are returned to reference values and if the patient has no clinical signs or symptoms of hepatitis, the general symptoms or other phenomena indicating dysfunctions of internals, use ВИРАМУНА® can be resumed (if there is a clinical need). The decision on it has to be made in each separate case, proceeding from clinical reasons. Repeated appointment ВИРАМУНА® has to be carried out in the conditions of the increased clinical and laboratory vigilance, in an initial dose of 200 mg/day (within 14 days), with the subsequent its increase to 400 mg/day. If abnormal liver functions renew, not Virapinum has to be finally cancelled.

If there is a hepatitis which is followed by such clinical manifestations as anorexia, nausea, vomiting, jaundice, and laboratory disturbances (moderate or considerable changes of indicators of function of a liver, without GGT), not Virapinum has to be cancelled finally. ВИРАМУН® it should not be appointed repeatedly to those patients from whom its cancellation owing to development of clinically expressed hepatitis caused by not Virapinum was required.

Other cautions. In case of use ВИРАМУНА® in a combination with other anti-retrovirus drugs it was reported also about development of such undesirable reactions as pancreatitis, peripheral neuropathy and thrombocytopenia. These phenomena often are associated with other anti-retrovirus drugs. Their emergence can be expected when using ВИРАМУНА® in a combination with other drugs; the probability of communication of these reactions using not Virapinum is small.

At the patients receiving ВИРАМУН® or any other anti-retrovirus therapy, opportunistic infections and other complications of HIV infection can continue to develop. Therefore such patients have to remain under careful clinical observation of the doctors having experience of treatment of the diseases associated with HIV infection. Data on ability ВИРАМУНА® to reduce risk of horizontal transmission of HIV to 1 other persons are not available.

In spite of the fact that ability ВИРАМУНА® to prevent VICh-1 transmission from mother is established to the child (at the women who were not receiving other anti-retrovirus drugs), for minimization of a possibility of a VICh-1 broadcast to the child, more intensive treatment of mother before childbirth using combinations of anti-retrovirus drugs is recommended (when it is possible).

ВИРАМУН® it is intensively metabolized in a liver, and metabolites of not Virapinum are removed preferential by kidneys. Results of pharmacokinetic researches indicate the need of respect for care at appointment ВИРАМУНА® to patients with moderate dysfunction of a liver. ВИРАМУН® it should not be appointed to patients with considerable abnormal liver functions. The pharmacokinetic researches conducted at the patients with renal failures who were on a hemodialysis showed that auxiliary therapy ВИРАМУНОМ® with addition of the dose making 200 mg after each session of dialysis can help to compensate influence of dialysis on clearance ВИРАМУНА®. Thus, with clearance of creatinine more than 20 ml/min. of changes of dosing ВИРАМУНА® are not required from patients.

At the women accepting ВИРАМУН® it is not necessary to use as the main method of contraception oral contraceptives and other hormonal methods as not Virapinum can reduce concentration of these drugs in plasma. Besides, in case of use during therapy ВИРАМУНОМ® of oral contraceptive means for hormonal regulation, control of therapeutic effect of hormonal treatment is necessary.

The existing data of pharmacokinetic researches indicate inexpediency of simultaneous use of rifampicin and not Virapinum. In need of treatment of the accompanying tuberculosis at the patients receiving the therapy mode including not Virapinum the possibility of use of a rifabutin can be considered. Rifabutin and not Virapinum can be applied jointly without dosing changes.

Influence on ability to driving of motor transport and to control of mechanisms. Special researches concerning ability to driving of motor transport and control of mechanisms were not conducted.

Pregnancy and period of a lactation. Full-fledged controlled researches of treatment at VICh-1-infitsirovannykh pregnant were not conducted so far. ВИРАМУН® it has to be applied during pregnancy only when the possible advantage surpasses potential risk for a fruit.

Safety and efficiency ВИРАМУНА®, VICh-1 used for prevention of transmission from mother to the child, is established in case of use of drug as a part of the mode of therapy including a single dose in a dose of 200 mg by mother at the time of delivery and peroral introduction of a single dose of 2 mg/kg newborn during 72 h after the birth.

According to the recommendation that HIV-positive mothers should not nurse newborn children (in order to avoid risk of post-natal transfer of HIV), mothers who receive ВИРАМУН® have to stop breastfeeding.

Side effects:

At adults. Skin rash and changes of indicators of function of a liver. Nausea, fatigue, fever, a headache, vomiting, diarrhea, an abdominal pain and mialgiya were the undesirable phenomena which are the most often reported during all clinical trials connected with therapy. Seldom or never - anemia and a neutropenia. In rare instances at the patients receiving ВИРАМУН® as a part of the therapy modes it was reported about arthralgias as the only undesirable phenomenon.

Experience of use showed that the most serious side effects are Stephens-Johnson's syndrome, a toxic epidermal necrolysis, heavy hepatitis / a liver failure and the syndrome of hypersensitivity which is characterized by rash, the general symptoms (such as fever,
arthralgias, mialgiya and lymphadenopathy) and signs of damage of internals (such as hepatitis, eosinophilia, granulocytopenia and dysfunction of kidneys). A critical period during which careful control is required are the first 18 weeks of treatment. 

Skin and hypodermic fabrics. The most frequent clinical sign of toxicity ВИРАМУНА® is rash. Serious or life-threatening skin reactions meet approximately in 2% (see table 1). They include the Stephens-Johnson's syndrome (SJS) and, more rare, the toxic epidermal necrolysis (TEN) which arise most often within the first six weeks of therapy. Total frequency of SSD, according to the data obtained at 2861 patients accepting not Virapinum in clinical trials made 0,3% (9/2861).

Rash arises separately or within the syndrome of hypersensitivity which is characterized by the general symptoms (such as fever, arthralgias, mialgiya and lymphadenopathy) and signs of damage of internals (such as hepatitis, eosinophilia, granulocytopenia and dysfunction of kidneys). It was reported about deaths of SSD, TEN and syndrome of hypersensitivity.

Table 1. Risk of development of rash (%) in the adult patients participating in placebo - controlled issledovaniyakh1,2, for 52 weeks lecheniya3 (regardless of a causal relationship)

	ВИРАМУН®	Placebo
	n=1374 %	n=1331 %
Rash of all gradation 4	24,0	14,9
Gradation 3 or 4 4	1,7	0,2

1 Research 1090: background therapy included 3TC at all patients, and combinations of NIOT and SP

2 Researches 1037, 1038 and 1046: background therapy included ZDV and ZDV+ddl; at some patients as monotherapy Viramun® was applied
3 Percent were calculated on the basis of the probabilistic estimates received with
help of a method of Kaplana-Meyer
4 System of gradation of NCI

Rash usually poorly or is moderately expressed, is characterized by the makulopapulezny erythematic elements which are followed or not followed by an itch, localized on a trunk, a face and extremities. It was reported about allergic reactions (including an anaphylaxis, a Quincke's disease and a small tortoiseshell). Rash (any degree of manifestation) most often develops in the first 6 weeks of treatment.

Gepatobiliarny reactions. Among changes of laboratory indicators increase in indicators of function of a liver, including ALT, nuclear heating plant, GGT, the general bilirubin and an alkaline phosphatase is most often observed. Asymptomatic increase in GGT is most often noted. It was reported about jaundice cases. At the patients receiving not Virapinum it was reported about cases of hepatitis, a considerable and life-threatening hepatotoxic, and also fatal fulminantny hepatitis. According to clinical trials, the risk of clinical hepatological reactions at the patients accepting ВИРАМУН® by one year of treatment exceeded risk of use of placebo approximately twice. As in group where it was applied ВИРАМУН®, and in control group, increase in level of nuclear heating plant or ALT and/or a seropozitivnost concerning the hepatitis B and/or Page was associated with the greatest risk of hepatological undesirable reactions. The risk of hepatological reactions at patients without symptoms of the hepatitis B and/or S at treatment ВИРАМУНОМ® during 1 year made less than 2%. A critical period which demands careful control are the first 18 weeks of treatment. The greatest risk of hepatological disturbances is noted in the first 6 weeks of therapy. However this risk remains also in the subsequent therefore frequent control has to continue during the entire period of treatment.

The clinical expressed hepatitis can be isolated or be followed by rash and/or the general symptoms.

At children. Safety was estimated at the VICh-1-infitsirovannykh children aged from 3 days up to 19 years. Most of these patients received ВИРАМУН® in a combination with ZDV or ddl, or with ZDV + ddl (two researches). In the open research BI 882 (ACTG 180) patients were observed on average for 33,9 months (from 6,8 months to 5,3 years, including a long-term phase of observation in the research BI 892). In the research ACTG 245 (double blind placebo - a controlled research) patients whose average age made 7 years (from 10 months to 19 years) received a combination therapy, including ВИРАМУН®, within, at least, 48 weeks in a dose of 120 mg/sq.m for two weeks once a day, and in the subsequent 120 mg/sq.m 2 times a day.

The most often reported undesirable phenomena connected with ВИРАМУНОМ® were similar to the undesirable reactions observed at adults except for a granulocytopenia which was more often noted at children. At two patients receiving in these researches VIRAMUN® SSD or a syndrome, transitional between Stephens-Johnson's syndrome and a toxic epidermal necrolysis developed. After cancellation ВИРАМУНА® this complication at both patients abated.
 
Prevention of vertical transmission. Safety ВИРАМУНА®, applied once in a dose of 200 mg (two doses in one research) at HIV-positive pregnant women at the beginning of childbirth, and also the newborn within the first 72 hours of life [single administration of suspension in a dose of 2 mg/kg (6 mg in one research)], was estimated more than at 950 couples (mother child) in randomized, controlled clinical trials. Observation of newborns after use of a single dose continued from 6 weeks to 18 months. In these researches the similar low frequency of the undesirable phenomena in group where it was applied ВИРАМУН®, and in control groups is established. Serious dermatological or hepatological reactions which would be regarded as connected with ВИРАМУНОМ® were not observed neither at mothers, nor at newborns.

Thus, at treatment by the drug VIRAMUN® it is possible to expect the following side reactions:
• rash (including, serious and life-threatening skin reactions, including fatal cases of SSD/TEN)
• the hypersensitivity syndrome which is characterized by rash, the general symptoms (fever, arthralgias, mialgiya and a hyperadenosis), and also one or several following manifestations: hepatitis, an eosinophilia, a granulocytopenia, dysfunction of kidneys (it was reported also about other signs of damage of internals)
• changes of indicators of function of a liver (nuclear heating plant, ALT, GGT, general bilirubin, alkaline phosphatase)
• jaundice
• hepatitis, including serious and life-threatening hepatotoxic and fatal fulminantny hepatitis
• nausea
• fatigue
• fever
• headache
• vomiting
• diarrhea
• abdominal pain
• mialgiya
• arthralgias
• granulocytopenia
• allergic reactions (anaphylaxis, Quincke's disease, small tortoiseshell)
• anemia.

Interaction with other medicines:

It is shown what ВИРАМУН® is the inductor of metabolizing enzymes of system of P450 cytochrome of a liver (CYP3A, CYP2B) and can lead to decrease in concentration in plasma of other at the same time applied medicines which are intensively metabolized CYP3A or CYP2B (see the section "Pharmacokinetics"). Therefore if at the patient to whom the mode of dosing of any drug which is metabolized by means of CYP3A or CYB2B was picked up earlier treatment begins the drug VIRAMUN®, there can be a need for dose adjustment of this drug.

Nukleozidny analogs. In case of simultaneous use of not Virapinum with a zidovudine, didanoziny or zaltsitabiny dose adjustment of not Virapinum is not required. During the analysis of data on use of a zidovudine for VICh-1 of the infected patients (n = 11) receiving not Virapinum (400 mg/day) in a combination with a zidovudine (100-200 mg 3 times a day), it is established that not Virapinum led to doubtful decrease (for 28%) the areas under a curve "concentration time" (AUC) of a zidovudine and to doubtful decrease (for 30%) Cmax of a zidovudine, at the same time was noted considerable variability of both parameters. The method of pair comparison of data showed that the zidovudine did not exert any impact on not Virapinum pharmacokinetics. In one cross research it is established that not Virapinum did not exert impact on pharmacokinetics (in a phase of its steady state) a didanozina (n = 18) or a zaltsitabina (n = 6).

Results of a 28-day research at HIV-positive patients (n = 22) at whom it was applied ВИРАМУН®, нелфинавир (750 mg three times a day) and ставудин (30-40 mg twice a day) showed lack of statistically significant changes of AUC or Cmax of a stavudin. Besides, in a population pharmacokinetic research of 90 patients which ламивудин it was appointed together with ВИРАМУНОМ® or placebo, lack of changes of the seeming clearance and volume of distribution of a lamivudin was established that indicates lack of inductive action ВИРАМУНА® on clearance of a lamivudin.

Nenukleozidny analogs. Results of clinical trial (n = 23) showed that pharmacokinetics indicators (in a phase of its steady state) not Virapinum did not change at simultaneous use of ifavirenets. However concentration of ifavirenets in the presence of not Virapinum authentically decreased. AUC of ifavirenets decreased by 28%, and Cmin for 32%. At simultaneous use of not Virapinum and ifavirenets increase in a dose of the last up to 800 mg can be required (once a day).
Protease inhibitors. In the researches VIRAMUN® provided below it was applied in a dose of 200 mg within two weeks once a day, and during 14 or bigger number of the next days - in a dose of 200 mg 2 times a day.

Sakvinavir. Results of clinical trial at the HIV-positive patients (n = 23) receiving not Virapinum and саквинавир (solid gelatin capsules; 600 mg 3 times a day), showed that simultaneous use of these drugs led to reduction of the average size AUC of a sakvinavir by 38% and did not influence authentically not Virapinum levels in plasma. The clinical importance of this interaction is not known, but is not excluded that increase in a dose of a sakvinavir can be required. In other research (n = 20) estimated use of a sakvinavir (soft gelatin capsules, once a day) together with ritonaviry (100 mg). All patients at the same time received not Virapinum. This research showed that the combination of a sakvinavir (soft gelatin capsules) and a ritonavira in a dose of 100 mg did not exert significant impact   on      not Virapinum pharmacokinetics.   Influence   of not Virapinum   on pharmacokinetics of a sakvinavir (soft gelatin capsules) in the presence of a ritonavir in a dose of 100 mg is regarded as weak and clinically insignificant.

Ritonavir. In case of combined use ВИРАМУНА® with ritonaviry correction of the mode of dosing is not required. Results of clinical trial at the HIV-positive patients (n = 25) accepting not Virapinum and ритонавир (600 mg twice a day, with use of the mode of gradual building of a dose), showed lack of reliable changes of concentration of a ritonavir or not Virapinum in plasma.

Indinavir. Results of clinical trial at the HIV-positive patients (n = 19) receiving not Virapinum and индинавир (800 mg every 8 hours), showed that simultaneous use of these drugs leads to reduction of the average sizes AUC of an indinavir by 31%; concentration of not Virapinum in plasma authentically did not change. Any certain clinical conclusions concerning potential mutual influence of at the same time applied not Virapinum and an indinavir were not made. In case of use of an indinavir together with not Virapinum in a dose of 200 mg twice a day, it is necessary to consider increase in a dose of an indinavir up to 1000 mg (every 8 hours). However now there is no developed opinion on the fact that short-term or long-term anti-virus action of the indinavir in a dose of 1000 mg (each 8 hours) which is applied together with not Virapinum in a dose of 200 mg twice a day will differ from effect of an indinavir in a dose of 800 mg (each 8 hours) and not Virapinum in a dose of 200 mg twice a day.

Nelfinavir. Results of a 28-day research at the HIV-positive patients (n = 23) accepting ВИРАМУН® and нелфинавир (750 mg three times a day), showed lack of statistically reliable changes of pharmacokinetics of a nelfinavir after addition ВИРАМУНА®. Concentration ВИРАМУНА® , apparently, also  did not change.

However concerning the main metabolite of a nelfinavir, M8 which has comparable activity with the main connection reduction of the average sizes AUC by 62%, Cmax by 59% and Cmin by 66% is established. Adequate (concerning safety and efficiency) the dose of a nelfinavir for use in a combination with not Virapinum is not established yet.

Lopinavir/ritonavir. Not Virapinum used in a combination with lopinavirom/ritonaviry in doses of 400/100 mg (3 capsules) 2 times a day led to decrease in the average sizes AUC of a lopinavir by 27% and reduction of Cmax and Cmin by 22% and 55%, respectively. For use in a combination with not Virapinum increase in a dose of a lopinavira/ritonavir up to 533/133 mg 2 times a day (4 capsules), inclusion in food time is recommended. Results of a pharmacokinetic research at children showed that concentration of a lopinavir at its combined use with not Virapinum decrease. When using in a combination with not Virapinum (when there is a clinical suspicion based on results of the previous treatment or datas of laboratory) it is necessary to consider increase in a dose of a lopinavira/ritonavir (at children aged from 6 months up to 12 years) to 13/3,25 mg/kg at children with body weight from 7 to <15 kg, to 11/2,75 mg/kg at children with the body weight from 15 to 45 kg and to the maximum dose making 533/133 mg, children with body weight have more than 45 kg; reception 2 times a day.

When using not Virapinum with any inhibitors of protease of special fears concerning safety did not arise.

Ketokonazol. Use of not Virapinum (twice a day) together with ketokonazoly (400 mg once a day) led 200 mg to significant reduction of a median of AUC of a ketokonazol by 63% and decrease in a median of Cmax of a ketokonazol by 40%. In the same research it was established that кетоконазол led to increase by 15-28% of concentration of not Virapinum in plasma. Ketokonazol and not Virapinum it is not necessary to apply jointly. Impacts of not Virapinum on pharmacokinetics of an itrakonazol are unknown.

Flukonazol. Simultaneous use of a flukonazol and not Virapinum led to increase in influence of not Virapinum approximately for 100% (in comparison with earlier conducted research where not Virapinum was used as monotherapy). In case of the simultaneous use of these drugs which is followed by risk of the increased influence of not Virapinum it is necessary to be careful and to carefully observe patients. Clinically significant influence of not Virapinum on флуконазол was not noted.

Anticoagulants. The interaction between not Virapinum and anticoagulant observed by in vitro warfarin is complex. As a result of interaction, in case of combined use of these drugs, concentration of warfarin in plasma can change in such a way that there is a risk of both increase, and reduction of time of coagulation. The resulting influence of this interaction can change within the first weeks of simultaneous use of drugs or after cancellation of not Virapinum. In case of simultaneous use of warfarin and not Virapinum frequent control of a prothrombin time is necessary.

CYP isoenzyme inductors. Rifampicin. In an open research (n = 14) when studying influence ВИРАМУНА® on pharmacokinetics (in a phase of a steady state) rifampicin showed lack of significant changes of Cmax and AUC rifampicin. On the contrary, rifampicin significantly lowered AUC (-58%), Cmax (-50%) and Cmin (-68%) of not Virapinum in comparison with basic data. Therefore rifampicin and not Virapinum should not be applied at the same time. In need of treatment of mikobakterialny infections at the patients accepting not Virapinum it is necessary to consider use of a rifabutin instead of rifampicin.

Rifabutin. Use of not Virapinum (200 mg twice a day) together with rifabutiny (300 mg once a day; or, in case of simultaneous use of a zdovudin or inhibitors of protease, 150 mg once a day) led to doubtful changes of concentration of a rifabutin (increase in a median of AUC of a rifabutin by 12% and reduction of a median of Cminss of a rifabutin by 3%) and to significant increase in a median of Cmaxss by 20%. Essential changes of concentration of an active metabolite, 25-O-dezatsetil-rifabutina, it is not established. Considerable interindividual variability of results was noted. At some patients substantial increase of concentration of a rifabutin is revealed that can put at their higher risk of toxicity. In the same research it is shown that use of a rifabutin led to explicit and reliable increase in system clearance of not Virapinum (for 9% in comparison with control). Nevertheless, any of these changes of median sizes was not recognized as clinically essential.

Simultaneous use with ВИРАМУНОМ® St tinctures is not recommended. John (tincture of the St. John's Wort which is made a hole) or separate ingredients of St tincture. John that follows from data on St. John's Wort tincture interaction with other anti-retrovirus drugs. It is supposed that combined use of nenukleozidny inhibitors of the return transcriptase (NNIOT), including ВИРАМУНА®, with St tincture. John reduces concentration of NNIOT and, leading to the suboptimal VIRAMUNA® levels, can cause loss of virologic effect and stability to ВИРАМУНУ® or to all class NNIOT.

CYP isoenzyme inhibitors. Results of studying of interaction of not Virapinum and klaritromitsin (n = 18) showed that there is an essential decrease in AUC (for 30%), Cmax (-21%) and Cmin (-46%) of a klaritromitsin, but at the same time reliable increase in AUC (for 58%) and Cmax (for 62%) its active metabolite, 14-OH klaritromitsin. Reliable increase in Cmin (for 28%) not Virapinum and doubtful increase in its AUC (for 26%) and Cmax was noted (for 24%). These data allow to assume that at simultaneous use of these drugs any changes of their dosing are not required. However, at treatment of the patient with the infection caused by the Mycobacterium avium-intracellulare complex it is necessary to consider purpose of alternative drug as the active metabolite of a klaritromitsin in this case is inefficient.

During the subpopulation analysis which is carried out at the patients receiving ВИРАМУН® in clinical trials it is shown that basal concentration of not Virapinum in plasma (in the period of a steady condition of pharmacokinetics) were increased at the patients accepting Cimetidinum (+7%, n = 13).

Oral contraceptives. Not Virapinum (200 mg twice a day) was applied along with the contraceptive drug (Ortho-Novum® 1/35) containing ethinylestradiol (EEL; 0,035 mg) and норэтидрон (NEN; 1,0 mg), being accepted once inside. In comparison with the concentration in plasma established before use of not Virapinum, the median of AUC of 17alfa-ethinylestradiol in 28 days of use of not Virapinum considerably decreased (by 29%). Also reliable reduction of average sizes of time of circulation and an elimination half-life of ethinylestradiol was noted. Significant decrease (for 18%) AUC NEN medians is established (in the absence of changes of average sizes of time of circulation or an elimination half-life). Extent of these changes can indicate the need dose adjustments of an oral contraceptive in case of its use not for contraception, and according to other indications (for example, for treatment of endometriosis) if it is used together with not Virapinum. However when using the oral contraceptives containing estrogen/progesterone there is also a risk of inefficient contraception. At purpose of not Virapinum use of other methods of contraception is recommended to the women having ability to conceive (for example, barrier). In case of use at the patients receiving not Virapinum, oral contraceptives on other medical indications control of their therapeutic effect is necessary.

Other information. The researches in vitro with use of microsomes of a liver of the person showed that formation of hydroxylated metabolites of not Virapinum in the presence of dapsone, the rifabutin, Rifampinum and Trimethoprimum/sulfamethoxazole does not change. Ketokonazol and erythromycin significantly inhibited formation of hydroxylated metabolites of not Virapinum. Clinical trials in this respect are not conducted yet.

It is necessary to take into account that in case of simultaneous use with ВИРАМУНОМ® other connections which are substrates for CYP3A or CYP2B6 reduction of their concentration in plasma is possible.

Considering the known data on methadone metabolism, it is impossible to exclude that not Virapinum can reduce concentration of methadone in plasma, by means of strengthening of his metabolism in a liver. It was reported about development of a withdrawal of drugs in the patients receiving at the same time ВИРАМУН® and methadone. The patients receiving methadone for replacement of drugs when they begin use of not Virapinum, have to be under careful observation for early detection of a withdrawal and the corresponding dose adjustment of methadone.

Contraindications:

ВИРАМУН® it is contraindicated at patients with clinically significant hypersensitivity to active component or any component of drug.

ВИРАМУН® it should not be appointed to patients with serious dysfunction of a liver or in case of initial increase in level of nuclear heating plant or ALT, more than by 5 times exceeding the upper bound of norm until AST/ALT values do not decrease (steadily) to the level which does not exceed the upper bound of norm by 5 times.

ВИРАМУН® it is not necessary to apply repeatedly at patients who needed its cancellation owing to the expressed rash, to the rash which was followed by the general symptoms, reactions of hypersensitivity or development of clinically expressed hepatitis caused by not Virapinum.

ВИРАМУН® patients at whom earlier, during therapy not Virapinum noted the increase in level of nuclear heating plant or ALT exceeding the upper bound of norm more than by 5 times or to patients at whom after repeated use of not Virapinum resuming of abnormal liver functions was noted should not appoint repeatedly.

Overdose:

The antidote for elimination of overdose is not available. It was reported about cases of overdose ВИРАМУНА® (reception from 800 to 6000 mg a day during up to 15 days). At patients hypostases, a knotty erythema, fatigue, fever, a headache, sleeplessness, nausea, infiltrates in lungs, rash, dizziness, vomiting, increase in level of transaminases and decrease in body weight were noted. After drug withdrawal all specified phenomena stopped.

Storage conditions:

To store suspension at a temperature not above 30 °C. Drug has to be used within 2 months from the moment of opening of a bottle. Period of validity 3 years. Not to use after expiry date.

Issue conditions:

According to the recipe

Packaging:

Suspension for intake of 10 mg/ml. On 240 ml in a plastic bottle. Each bottle with the application instruction, the plastic measured syringe and an additional cover is placed in a cardboard pack.