Дизаверокс

General characteristics. Structure:

Active ingredient: 150 mg of a lamivudin, 300 mg of a zidovudine.

The combined antiviral means applied to treatment of HIV infections (VICh-1 and VICh-2).

Pharmacological properties:

Pharmacodynamics. The antiviral combined means. Lamivudin and zidovudiya are highly effective selective VICh-1 and VICh-2 inhibitors. Lamivudin is synergist of a zidovudine concerning oppression of replication of HIV. Both components of drug are consistently metabolized by intracellular kinases to trifosfatny derivatives. Lamivudina triphosphate and a zidovudine triphosphate are substrates for the HIV return transcriptase and competitive inhibitors of this enzyme. However antiviral activity of a lamivudin and zidovudine is caused preferential by inclusion of their monophosphatic form in a chain of virus DNA, it is resulted by a rupture of a chain. Triphosphates of a lamivudin and zidovudine have considerably smaller affinity to DNA polymerases of human cells.

The combination therapy lamivudiny and a zidovudine slows down development of resistance to a zidovudine at patients who did not receive anti-retrovirus therapy earlier.

Lamivudin in a combination with a zidovudine reduces virus loading and increases number of cells of CD4+. The combination therapy lamivudnny and a zidovudine reduces risk of progressing of a disease and a lethal outcome.

Pharmacokinetics. It is well soaked up from a GIT (adults have a bioavailability of a lamivudin - 80-85%, a zidovudine - 60-70%). Both components of drug poorly contact proteins of plasma. Get into TsNS and cerebrospinal fluid. Lamivudin is brought from an organism preferential by kidneys in not changed look. T1/2 makes 5-7 h. The zidovudine is metabolized in a liver where there is a conjugation to glucuronic acid. It is removed by kidneys generally in the form of a glucuronide. T1/2 of a zidovudine makes about 1 h.

Special groups of patients. Patients of advanced age: the pharmacokinetics was not investigated at patients 65 years are more senior.

Children: at children 5-6 months are aged more senior pharmacokinetic indicators of a zidovudine are similar to indicators at adults. The zidovudine is well soaked up from intestines after reception in all studied dosages at adults and children; its bioavailability makes 64-70%, on average - 65%. The maximum concentration in an equilibrium state makes 4,45 microns (1,19 mkg/ml) after reception of 120 mg/sq.m of a zidovudine in the form of solution and 7,7 microns (2,06 mkg/ml) after reception of a dose of 180 mg/sq.m. The dose of 180 mg/sq.m 4 times a day leads to the same system exposure at children ("concentration time" from 0 to 24 h after administration of drug (AUC24) makes the area under a curve 10,7×мкг/мл), as well as reception of 200 mg of 6 times a day at adult (AUC24 10,9×mkg/ml).

In general, the pharmacokinetics of a lamivudin at children is similar to pharmacokinetics at adult patients. However absolute bioavailability (about 55-56%) was reduced at children aged 12 years are younger. The system clearance at children is higher, than at adults, and is inclined to decrease in process of a growing, reaching indicators, as at adults, by 12 years. In view of these distinctions, the recommended dose of a lamivudin at children (aged from 3 months up to 12 years with body weight from 6 kg to 40 kg) makes 8 mg/kg/day. After reception of this dose of AUC0-12 reaches 3800-5300 нг×ч/мл. The latest data demonstrate that exposure at children aged from 2 up to 6 years can be reduced by 30% in comparison with other age groups.

Patients with a renal failure: owing to decrease in renal clearance removal of a lamivudin is broken at a renal failure. The dose decline of a lamivudin is recommended at patients with clearance of creatine 50 ml/min. Concentration of a zidovudine in plasma also increases at patients with a heavy renal failure.

Abnormal liver function: Decrease in a glyukuronization at patients with an abnormal liver function owing to cirrhosis can cause cumulation of a zidovudine. Correction of doses is required from patients with a heavy renal failure.

Pregnancy: pregnancy does not influence pharmacokinetics of a lamivudin and zidovudine. Lamivudin and a zidovudine are found in the child's serum at the birth in the same concentration, as in serum of mother and umbilical blood at childbirth that confirms the theory of passive penetration through a gematoplatsentarny barrier.

Indications to use:

— HIV infection at children is more senior than 12 years and adults with the progressing immunodeficiency (CD4+ cells number less 500/mkl).

Route of administration and doses:

Inside, irrespective of meal of the adult and to children 12 years and with body weight not less than 30 kg, on 1 tablet 2 times a day are more senior.

At a chronic renal failure (at KK less than 50 ml/min.), a liver failure, at concentration of hemoglobin less than 9 g/dl or 5,59 mmol/l, neutropenias are lower 1 000/mkl it is necessary to apply ламивудин and a zidovudine in the form of separate drugs individually to select a dose of a lamivudin and a zidovudine.

Children with body weight less than 30 kg: it is necessary to use separate drugs of a lamivudin and zidovudine.

Patients of advanced age: there are no specific data on use of drug of Dizaveroks for elderly people. However at treatment of elderly patients it is recommended to observe extra care, considering age changes, for example changes of hematologic indicators and a renal failure.

Features of use:

Use at pregnancy and feeding by a breast. Дизаверокс pregnant women can appoint only when the expected advantage for mother exceeds possible risk for a fruit. Women who accept drug are not recommended to nurse the child.

Use at abnormal liver functions. At a liver failure it is necessary to apply ламивудин and a zidovudine in the form of separate drugs individually to select a dose of a lamivudin and a zidovudine.

Use at renal failures. At a chronic renal failure (at KK less than 50 ml/min.) it is necessary to apply ламивудин and a zidovudine in the form of separate drugs individually to select a dose of a lamivudin and a zidovudine.

Use for children. Drug is contraindicated to children aged up to 12 years and with body weight less than 30 kg.

Use for elderly patients. There are no specific data on use of drug of Dizaveroks for elderly people. However at treatment of elderly patients it is recommended to observe extra care, considering age changes, for example changes of hematologic indicators and a renal failure.

In need of individual selection of a dose it is recommended to accept separate drugs of a lamivudin and zidovudine. Doctors should be guided by information on use of these drugs.

Despite administration of drug of Dizaveroks or any other aitiretrovirusiy drug, at patients opportunistic infections and other complications of HIV infection can develop. Therefore, patients have to be under constant observation of the doctors having experience of treatment of HIV infection.

Patients should be informed that treatment by anti-retrovirus drugs, such as, Dizaveroks, prevents risk of transfer of HIV to other people at sexual contacts or transfusion of the infected blood, plety patients have to observe the appropriate measures of precaution.

It is necessary to warn patients about possible interaction of drug of Dizaveroks with other drugs at their accompanying reception.

Hematologic disturbances. Development of anemia, a neutropenia and leukopenia (the last usually is secondary in relation to a neutropenia) in the patients receiving zidovudiya is possible. These phenomena are more often observed at purpose of high doses of a zidovudine (1200-1500 mg/days) at patients with late stages of HIV infection at a reduced marrowy reserve prior to treatment. Therefore at the patients receiving Dizaveroks it is necessary to carry out careful control of hematologic indicators. The specified hematologic changes usually appear not earlier, than in 4-6 weeks about the beginnings of therapy. At patients with a late stage clinically expressed HIV infection blood tests are recommended to control at least once in 2 weeks within the first three months of therapy, and then - at least once a month.

At patients with early stage VICh-iifektsii side effects from system of blood are noted seldom. Blood tests can be done more rare, being guided by the general condition of patients, for example once in 1-3 months. Special selection of a zidovudine in case of development of heavy anemia or a miyelosupressiya in time a lechneiya by Dizaveroks, and also at patients with the previous oppression of marrow can be required, for example at concentration of hemoglobin less than 9 g/dl (5,59 mmol/l) or quantity of neutrophils less than 1,0 × 10%. As individually it is impossible to pick up Dizavsroks's dose, it is recommended to use separate drugs of a lamivudin and zidovudine.

Pancreatitis. At the patients accepting ламивудин and a zidovudine, cases of development of pancreatitis are described. However whether this complication by medicines or a basic disease - HIV infection is established, caused. Treatment by drug of Dizaveroks needs to be stopped immediately at emergence of the clinical symptoms or datas of laboratory testimonial of development of pancreatitis (an abdominal pain, nausea, vomiting or increase in values of biochemical markers).

Osteonecrosis. Though the etiology of an osteonecrosis is considered multifactor (for example, reception of glucocorticosteroids, alcohol intake, acute immunosuppression, the raised index of body weight play an important role in development of this complication), report about such cases, in particular, at patients with the progressing HIV infection / or for a long time receiving anti-retrovirus therapy. Patients have to see behind consultation the attending physician at emergence of such symptoms as slackness, constraint, joint pains or at emergence of difficulties at the movement.

Lactoacidosis / the expressed hepatomegalia with a steatosis. At the patients accepting anti-retrovirus drugs - analogs of nucleosides, in the form of monotherapy or in a combination, including, ламивудин and a zidovudine, are described rare, but with a possible lethal outcome, cases of lactoacidosis and the expressed hepatomegalia with fatty dystrophy of a liver. The majority of cases were registered at women.

Clinical symptoms of lactoacidosis include the general weakness, loss of appetite and sudden inexplicable loss of weight, gastrointestinal and respiratory disturbances (an asthma and increase of breath).

Дизаверокс it is necessary to apply with care at the patients having risk factors of damage of a liver. Administration of drug should be suspended at patients with clinical and laboratory symptoms of lactoacidosis or a hepatotoxic (including a hepatomegalia and a steatosis even in lack of increase in activity траисаминаз).

Redistribution of hypodermic and world cellulose. Some patients receiving a kominirovanny anti-retrovirus terpaiya have a redistribution/accumulation of fatty tissue, including the central obesity, a dorsovistseralyyua an adiposity ("a buffalo hump"), weight loss of extremities and the person, increase in mammary glands, increase in concentration of lipids and glucose in blood serum. The listed symptoms at patients can be observed together or separately.

Though one or several of the listed above side effects connected with the general syndrome which is often carried to a lipodystrophy can cause all drugs of classes of the protease inhibitors (PI) and the nukleozidny ingbitor of the return transcriptase (NIRT), data confirm existence of distinctions between certain representatives of the specified classes of drugs in ability to cause side effects.

It should be noted also that the syndrome of a lipodystrophy has a multifactorial etiology; for example, the HIV infection stage, advanced age, duration of anti-retrovirus therapy plays important, perhaps synergistic role.

The remote effects of the specified side effects are not known now.

Clinical inspection of patients has to include assessment of physical signs of redistribution of fatty tissue. It is necessary to define concentration of lipids and glucose in blood serum. Disturbances of lipidic exchange it is necessary to treat, being guided by their clinical manifestations.

Mitochondrial dysfunction. In the conditions of in vitro and in vivo of a vyyalen ability of nucleotide and nukleozidny analogs to cause damage of mitochondrions of various degree. There are messages about митохондриалыюй dysfunctions at the HIV-negative children submitted influence of nukleozidny analogs vnutriutrobno or right after the birth. The main displays of mitochondrial dysfunction, anemia, a neutropenia, a giperlaktatemiya and increase in activity of a lipase in a blood plasma were often passing. Also later manifestations of this disturbance were noted: hyper tone of muscles, spasm, anomaly of behavior.

Immunity recovery syndrome. In an initiation of treatment anti-retrovirus means of HIV-positive patients with a heavy immunodeficiency the aggravation of inflammatory process on fone of an asimptomagichesky or residual opportunistic infection is possible that can become the reason of a serious aggravation of symptoms or aggravation of symptomatology. Usually such reactions are observed within the first weeks or months after the beginning of performing anti-retrovirus therapy. The most significant examples are a Cytomegaloviral retinitis, a generalized and/or focal mikobakterialny infection and pneumocystic pneumonia. Any symptoms of an inflammation need to be revealed immediately and if necessary to begin treatment. Autoimmune diseases (such as Greyvs's disease, a polymiositis and a syndrome to Giyena-Barra) were observed against the background of immunity recovery, however time of primary manifestations varied, and the disease could arise in many months after the beginning of therapy and have an atypical current.

Patients with liver diseases. At patients with earlier revealed liver diseases (including chronic hepatitis), at use of the combined anti-retrovirus therapy the frequency of abnormal liver functions increases. Drug of Dizaveroks should be used with care at this category of patients. It is necessary to conduct careful observation of patients; at emergence of signs of deterioration in function of a liver it is necessary to consider a question of a possibility of cancellation of therapy.

Patients with chronic hepatitis B or C. Risk of a hepatotoxic action of anti-retrovirus drugs at patients with the combined infection of HIV and a virus of hepatitis B or C above, than in the presence of only HIV infection. Therefore patients with chronic hepatitis B or C who at the same time accept anti-retrovirus drugs are in group of the increased risk of adverse influence on a liver with a possible lethal outcome. For such patients careful observation, both clinical, and laboratory has to be conducted.

The accompanying viral hepatitis V. Preparat Dizaveroks should be used with care at patients. the HIV infected at the same time and a virus of hepatitis B as after the therapy termination lamivudnny emergence of clinical or laboratory signs of an exacerbation of hepatitis is possible that can have serious consequences at a decompensation of function of a liver. After the end of therapy by drug of Dizaveroks at the patients infected with HIV and virus of hepatitis B. it is necessary to watch biochemical indicators of function of a liver and markers of replication of a virus of hepatitis B.

The accompanying viral hepatitis of Page. Aggravation of anemia was observed at the combined reception of a ribavirin and zidovudine though the mechanism of development of this phenomenon remains not clear. Thus, simultaneous use of a ribavirnn and zidovudine, especially at patients about a zidovudine - the induced anemia in the anamnesis is not recommended. In it is dashing cases it is recommended to consider the possibility of change of the mode of antnretrovirusny therapy for the purpose of cancellation of a zidovudine.

Influence on ability to manage vehicles and mechanisms. It was not carried out special studying of influence of a lamivudin and a zidovudine on ability to drive the car and to work with the equipment. Pharmacological properties of these drugs demonstrate low probability of such influence. It is necessary to take a clinical condition of the patient, and also the nature of side effects of a lamivudin and zidovudine into account.

Side effects:

The undesirable reactions described below were noted at treatment of HIV infection lamivudiny and a zidovudine in the form of monotherapy or in the form of a combination of these drugs. Concerning many undesirable reactions not clearly whether they are called lamivudiny, a zidovudine, a wide range of other drugs used for treatment of HIV - infections, or are complications actually of HIV infection. Are a part of drug of Dizaveroks ламивудин and a zidovudine and therefore it can cause the side effects characteristic of each of these components. There are no data that the combination of a lamivudin and a zidovudine has the additive toxicity now.

The following classification of undesirable reactions depending on occurrence frequency is used: very often ≥1/10), it is frequent (≥1/100 or <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10 000 and <1/1 000), is very rare (<1/10000, including separate cases).

Lamivudin. From hemopoietic and lymphatic system: infrequently - a neutropenia, anemia, thrombocytopenia; seldom - a true erythrocyte aplasia.

From a metabolism and food: often - a giperlaktatemiya; seldom - lactoacidosis.

From a nervous system: often - a headache; seldom - paresthesias, peripheral neuropathy.

From a GIT: often - nausea, vomiting, pain in epigastriums, diarrhea; seldom - pancreatitis, increase in activity of amylase in blood serum.

From a liver and biliary tract: infrequently - tranzitarny increase in activity of liver enzymes (ALT, ACT); seldom - hepatitis.

From skin and a hypodermic fatty tissue: rash, alopecia.

From a musculoskeletal system and connecting fabric: often - an arthralgia, muscular disturbances; seldom - рабдомиолиз.

Others: fatigue, fever, febricula, redistribution/accumulation of a hypodermic fatty tissue.

Zidovudine. From hemopoietic and lymphatic system: often - anemia (hemotransfusion can be required), a neutropenia and a leukopenia; infrequently - thrombocytopenia and a pancytopenia (with a marrow hypoplasia); seldom - a true erythrocyte aplasia; very seldom - aplastic anemia.

From a metabolism and food: often - a giperlaktatemiya; seldom - lactoacidosis, anorexia.

From mentality: seldom: - alarm, depression.

From a nervous system: very often - a headache; often - dizziness; seldom - sleeplessness, paresthesias, drowsiness, decrease in intellectual activity, a spasm, confusion of consciousness.

From cardiovascular system: seldom - a cardiomyopathy.

From respiratory system, bodies of a thorax and a mediastinum: infrequently - an asthma; seldom - rhinitis, sinusitis, cough.

From a GIT: often - nausea, vomiting, a stomach ache, diarrhea; infrequently - a meteorism; seldom - pigmentation of a mucous membrane of an oral cavity, a food faddism, dyspepsia, pancreatitis.

From a liver and biliary tract: often - increase in activity of liver enzymes and concentration of bilirubin; seldom - damage of a liver, such as the expressed hepatomegalia with a stenosis.

From skin and a hypodermic fatty tissue: infrequently - rash and an itch; seldom - pigmentation of nails and skin, a small tortoiseshell and the increased perspiration.

From a musculoskeletal system and connecting fabric: often - a mialgiya; infrequently - a myopathy.

From kidneys and urinary tract: seldom - the speeded-up urination.

From reproductive system and mammary glands: seldom - a gynecomastia.

Others: febricula, fever, generalized pain syndrome and adynamy, fever, stethalgia and grippopodobny syndrome, redistribution/accumulation of a hypodermic fatty tissue.

Interaction with other medicines:

As drug of Dizaveroks contains ламивудин and a zidovudine, he can enter any interactions characteristic of each of components. The probability of metabolic interactions with lamivudnny is small as only a small part of the administered drug is exposed to metabolism and contacts proteins of plasma, and drug is almost completely removed by kidneys in an invariable look.

The zidovudine too in small degree contacts proteins of plasma, but eliminirutsya preferential by means of hepatic metabolism to an inactive glucuronide.

Drugs with preferential hepatic metabolism, especially by means of a glyukuronization, can potentially oppress metabolism of a zidovudine. Some medicines representing classes of drugs which need to be applied with care against the background of therapy by drug of Dizaveroks are listed below.

Interactions with participation of a lamivudin. Lamivudin is preferential brought by means of cationic transport system, respectively, it is necessary to remember a possibility of interaction of drug of Dizaveroks with the medicines having the same way of removal.

Trimethoprimum/sulfamethoxazole: the concomitant use of a lamivudin and a combination of Trimethoprimum and sulfamethoxazole (160 mg +800 mg, co-trimoxazole) leads to increase in a kontsetration of a lamivudin in plasma for 40% at reception of this drug in therapeutic doses. However dose adjustment of a lamivudin is not required to patients with normal function of kidneys. Lamivudin does not influence pharmacokinetics of Trimethoprimum or sulfamethoxazole. It is necessary to be careful at simultaneous use of co-trimoxazole and drug of Dizaveroks for patients with a renal failure. The effect of joint purpose of a lamivudin and high doses of co-trimoxazole for treatment of ppevmotsistny pneumonia and a toxoplasmosis was not studied. Zaltsitabin: ламивудин intracellular phosphorylation of a zaltsitabin at a concomitant use can oppress. Thus, it is not recommended to use drug of Dizaveroks in a combination with zaltsitabiny.

Interactions with participation of a zidovudine. Atovakhon: the zidovudine does not exert impact on pharmacokinetics of an atovakhon. However, pharmacokinetic data confirm that. what атовахон reduces extent of metabolism of a zidovudine to its glucuronide (in an equilibrium condition of AUC of a zidovudine increases by 33%, the maximum concentration in plasma of a glucuronide decreases by 19%). At purpose of a zidovudine in doses from 500-600 mg/days and the accompanying 3 weeks course of treatment of an acute pneumocystic ppevoniya atovakhony increase in frequency of the side reactions connected with the raised zidovudine kontsetration in plasma is improbable. In need of longer combination of use of these drugs careful observation of a kliiinchesky condition of the patient is recommended.

Klaritromitsin: absorption of a zidovudine decreases at odnovrmenny reception of tablets of a klaritromitsin. The interval between receptions of a zidovudine and a klaritromitsin has to make not less than 2 hours.

Lamivudin: the concomitant use of a zidovudine and a lamivudin leads to increase for 13% of time of influence of a zidovudine and to increase by 28% of its maximum concentration in plasma. However, at the same time the general exposure of a zidovudine (AUC) considerably does not change. The zidovudine does not influence pharmacokinetics of a lamivudin.

Phenytoinum: at some patients receiving a zidovudine in combination with Phenytoinum decrease in concentration of Phenytoinum in blood was revealed, and in one case increase in concentration of Phenytoinum was noted. These observations testify to need to control concentration of Phenytoinum in blood at patients who at the same time accept drug Dizaveroks and Phenytoinum.

Probenetsid: according to some information, пробенецид increases an average elimination half-life of a zidovudine and AUC as a result of oppression of formation of a glucuronide. In the presence of a probenentsid the renal ekskrektion of a glucuronide and, perhaps, the zidovudine decreases.

Rifampicin: limited data show that at a combination of a zidovudine and rifampicin AUC of a zidovudine on 48 ± 34% decreases. However, clinical value of this observation is unknown.

Stavudin: the zidovudine can inhibit process intracellular a fosforilirovapiya of a stavudin at their concomitant use. Thus, combined use of a stavudin and drug of Dizaveroks is not recommended.

Other drugs: acetylsalicylic acid, codeine, morphine, indometacin, ketoprofen, папроксеп, oxazepam, lorazepam, Cimetidinum, Clofibratum, dapsone, изоприназин can change metabolism of a zidovudine as a result of competitive oppression of formation of its glucuronide. Before purpose of these drugs in combination with drug of Dizaveroks. especially for prolonged treatment, it is necessary to estimate possible medicinal interactions.

The combination with nefrotoksichny and myelosuppressive medicines (пеитамидин, dapsone, Pyrimethaminum, co-trimoxazole, Amphotericinum, флуцитазин, ганцикловир, interferon, Vincristinum, vinblastine, doxorubicine) increases probability of manifestation of side effects of a zidovudine. At co-administration of drug of Dizaveroks and any of these drugs it is necessary to control carefully function of kidneys and hematologic indicators and if necessary to reduce a dose of one or several drugs.

Ribavirin blocks antiviral activity of a zidovudine.

Apply co-trimoxazole, pentamidine in the form of an aerosol to prevention of opportunistic infections, Pyrimethaminum and an acyclovir. Limited data of clinical tests confirm lack of the expressed increase in frequency of side effects of a zidovudine at its use along with these drugs.

Contraindications:

— hypersensitivity to a zidovudine and a lamivudin and to other components of drug;

— number of neutrophils (less 750/mkl);

— anemia (hemoglobin less than 7,5 g/dl or 4.65 mmol/l);

— the children's age up to 12 years and body weight is less than 30 kg;

— lactation period.

With care. A hepatomegalia, hepatitis, cirrhosis, obesity, the risk factors contributing to damage of a liver.

Overdose:

Symptoms: any specific dozozavisimy symptoms it is not revealed at acute overdose of a lamivudin or zidovudine except those which are listed in the section Side effect.

Treatment: control of a condition of the patient and a standard maintenance therapy, a continuous hemodialysis is recommended.

Storage conditions:

To store in original packaging of the producer at a temperature not above 25 °C, in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

10 pieces - planimetric strip packagings (2) - packs cardboard.
10 pieces - planimetric strip packagings (3) - packs cardboard.
10 pieces - planimetric strip packagings (6) - packs cardboard.
60 pieces - banks (1) - packs cardboard.
10 pieces - planimetric strip packagings (10) - packs cardboard.
100 pieces - banks (1) - packs cardboard.