Зилакомб®

General characteristics. Structure:

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

Excipients: cellulose microcrystallic, gipromelloza, carboxymethylstarch of sodium, silicon dioxide colloid, magnesium stearate.

Cover: film covering: gipromelloza-2910, titanium dioxide (Е 171), macrogoal, polysorbate-80.

Pharmacological properties:

Pharmacodynamics. The combined antiviral drug which part are ламивудин and a zidovudine, being highly effective selective inhibitors of the return VICh-1 and VICh-2 transcriptase. Lamivudin is synergist of a zidovudine concerning oppression of replication of HIV in culture of cells. Both drugs are consistently metabolized by intracellular kinases to 5 triphosphates (TF). Lamivudina-TF and zidovudina-TF are substrates for the HIV return transcriptase and competitive inhibitors of this enzyme. However antiviral activity of drugs is caused preferential by inclusion of their monophosphatic form in a chain of virus DNA therefore there is a rupture of a chain. Triphosphates of a lamivudin and zidovudine have considerably smaller affinity to DNA polymerases of human cells. In vitro is shown low cytotoxicity of a lamivudin concerning lymphocytic and monocytic and macrophagic colonies and a number of cells - predecessors of red marrow. Thus, ламивудин possesses a wide therapeutic index.

Resistance. Resistance of VICh-1 to a lamivudin is caused by a mutation in M184V codon near an active center of the HIV return transcriptase. This strain is allocated as in vitro, and at the VICh-1-infitsirovannykh patients receiving the anti-retrovirus modes of therapy including ламивудин. Strains of viruses with M184V a mutation show considerable decrease in sensitivity to a lamivudin and show smaller replikativny activity of in vitro. The researches conducted by in vitro showed that at a zidovudine - resistant isolates of viruses development of sensitivity to a zidovudine is possible if they gain resistance to a lamivudin. Clinical value of this phenomenon is not clear.

Cross resistance. The cross sensitivity caused by M184V a mutation in the HIV return transcriptase limits use of all drugs of a class of the nukleozidny inhibitors of the return transcriptase (NIRT). A zidovudine and ставудин keep the anti-retrovirus activity in the relation lamivudin-resistant strains of VICh-1. Abakavir shows anti-retrovirus properties concerning lamivudin-resistant VICh-1 which resistance is caused only M184V by a mutation. M184V mutant strains show the sensitivity reduced by 4 times to a didanozin and a zaltsitabin; clinical value of this phenomenon is still not clear.

Resistance to thymidine analogs (such as zidovudine) is well described and corresponds to consecutive accumulation up to 6 specific mutations of the HIV return transcriptase in codons 41, 67, 70, 210, 215 and 219. Viruses gain phenotypical resistance to thymidine analogs by means of a combination of mutations in codons 41 and 215 or accumulation, at least, of four of six mutations. These mutations against the background of use of analogs of thymidine in itself are not the reason of high cross resistance to other nucleosides that allows to apply other approved NIOT afterwards. Distinguish two types of development of the mutations leading to multiresistance, the first type - mutations of virus return transcriptase in codons the 62, 75, 77, 116 and 151, second type - mutation T69S with an insert in the provision of 6 base pairs in this position that is followed by emergence of phenotypical resistance to a zidovudine and other NIOT. Any of these types of the mutations leading to multiresistance development significantly limits possibilities of treatment.

In clinical trials use of a combination of a lamivudin and zidovudine led to decrease in VICh-1 of loading and increase in CD4+ of cells. Clinical data demonstrate that use of a combination of a lamivudin and zidovudine or combination of a lamivudin and a zidovudine - the containing modes of therapy leads to essential decrease in risk of progressing of a disease and mortality. Separately monotherapy lamivudiny or a zidovudine led to emergence of HIV isolates with reduced sensitivity to these drugs in vitro. Clinical data demonstrate that the combination therapy lamivudiny and a zidovudine detains emergence a zidovudine - resistant strains at the patients who were earlier not receiving anti-retrovirus therapy (APT). Clinical value of the revealed in vitro of virus sensitivity to a zidovudine and a lamivudin is investigated. The combination therapy lamivudiny and a zidovudine is widely used as the APT component together with other anti-retrovirus drugs from other classes (HIV protease inhibitors, nenukleozidny inhibitors of the return transcriptase [NNIOT]). The combined modes of anti-retrovirus therapy including ламивудин are effective in treatment of the patients who earlier were not receiving anti-retrovirus drugs, and patients at whom HIV strains with M184V a mutation are allocated.

Pharmacokinetics. Absorption: ламивудин and a zidovudine are well soaked up from intestines. At adults after intake bioavailability of a lamivudin makes 80-85%, and a zidovudine - 60 - 70%.

The research of bioequivalence was conducted for the purpose of comparison of drug of the fixed combination ламивудин / a zidovudine with reception of a lamivudin (150 mg) and a zidovudine (300 mg) separately, accepted inside at the same time, at the same time extent of absorption and influence of food were investigated. Reception of the combined drug ламивудин / a zidovudine is equivalent to reception on an empty stomach of a lamivudin and a zidovudine separately.

After reception of a combination ламивудин / a zidovudine inside the maximum concentration (Smakh) of a lamivudin and zidovudine were noted in 0,75 (0,5-2) h and 0,5 (0,25-2) h and made 1,5 (1,3-1,8) mg/ml and 1,8 (1,5-2,2) mg/ml respectively.

Extent of absorption of a lamivudin and zidovudine (based on value of the area under a curve "concentration time" of AUC) and an elimination half-life (T1/2) after reception with food were similar to indicators after reception on an empty stomach though the speed of absorption was a little slowed down.

Reception of the crushed tablets together with a small amount of semisolid food or liquid does not influence pharmacological properties of drug and, therefore, clinical action. This conclusion is drawn on the basis of physical and chemical and pharmacokinetic characteristics of active ingredients provided that the patient immediately takes 100% of the crushed pill.

Distribution: the average seeming volume of distribution (Vd) for a lamivudin and a zidovudine makes 1,3 and 1,6 l/kg respectively. Lamivudin has linear pharmacokinetics when using in therapeutic doses and restrictedly contacts blood plasma albumine (less than 36% of in vitro seralbumin). The zidovudine contacts proteins of a blood plasma for 34-36%. Thus, interaction of a lamivudin and zidovudine with other medicines by means of substitution of proteinaceous bonds is improbable.

It is established that ламивудин and a zidovudine get into the central nervous system and cerebrospinal fluid. In 2-4 h after oral administration of the relation between concentration of a lamivudin and a zidovudine in liquor and in blood serum average 0,12 and 0,5 respectively.

Metabolism: ламивудин it is brought out of an organism preferential by kidneys in not changed look. Metabolic interactions of a lamivudin are improbable in view of insignificant metabolism in a liver (from 5 to 10%) and low linkng with proteins of a blood plasma.

5 glucuronide of a zidovudine are the main metabolite in plasma and urine, at the same time about 50-80% of the entered dose of a zidovudine are removed by renal excretion. 3-amino-3-dezoksitimidin is defined in urine after intravenous administration.

Removal: the elimination half-life (T1/2) of a lamivudin makes 5-7 h. The system clearance of a lamivudin makes about 0,32 l/h/kg, at the same time the renal clearance makes more than 70% with participation of organic cations of transport system.

At intravenous administration of a zidovudine average T1/2 made 1,1 h, and average system clearance - 1,6 l/h/kg. The renal clearance of a zidovudine makes 0,34 l/h/kg by means of glomerular filtering and active canalicular secretion in kidneys.

Pharmacokinetics in special groups. Advanced age. The pharmacokinetics of a lamivudin and zidovudine was not investigated at patients 65 years are more senior.

Children's age. 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 doses at adults and children; its bioavailability makes 60 - 74%, on average 65%. The maximum concentration in an equilibrium state (Css max) makes 4,45 µmol (1,19 mkg/ml) after reception of a zidovudine in a dose of 120 mg/sq.m of surface area of a body in the form of solution and 7,7 µmol (2,06 mkg/ml) after reception in a dose of 180 mg/sq.m of surface area of a body. The dose of 180 mg/sq.m of surface area of a body of 4 times/days leads to the same system exposure at children (AUC24 makes 10,7 h x mkg/ml), as well as a dose of 200 mg/sq.m of surface area of a body of 6 times/days at adults (AUC24 makes 10,9 h x mkg/ml).

In a research at 6 HIV-positive children aged from 2 up to 13 years the zidovudine pharmacokinetics after reception of 120 mg/sq.m of surface area of a body of 3 times/days and after transition to a dose of 180 mg/sq.m of surface area of a body of 2 times/days system exposure was estimated (AUC and Smakh) in plasma was similar at the double and triple mode of dosing (the same daily dose).

In general, the pharmacokinetics of a lamivudin at children is similar to pharmacokinetics at adult patients. However absolute bioavailability (about 55-65%) 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/days. After reception of this dose of AUC0-12 reaches 3800-5300 нг x h/ml. 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.

Renal failure. At a renal failure removal of a lamivudin is broken owing to reduced renal clearance. The dose decline of a lamivudin is recommended at patients with clearance of creatinine less than 50 ml/min. Concentration of a zidovudine in plasma also increases at patients with a renal failure of heavy degree.

Abnormal liver function. Decrease in a glyukuronirovaniye owing to cirrhosis can cause cumulation of a zidovudine. Correction of doses is required from patients with a heavy liver 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:

Treatment of HIV infection at adults and children with body weight not less than 30 kg.

Route of administration and doses:

Inside. By the drug Zilakomb® the doctors having experience of therapy of HIV - an infection have to carry out treatment.

Зилакомб® it is possible to accept irrespective of meal. For ensuring accuracy of dosing of a tablet it is necessary to swallow entirely. For those patients who have difficulties with a proglatyvaniye crushing of tablets with addition of a small amount of semisolid food or liquid is recommended. All amount of the received mix needs to be accepted inside immediately.

To adults and teenagers with body weight not less than 30 kg the recommended drug Zilakomb® dose - on 1 tablet 2 times a day.

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

When it is necessary to lower a drug Zilakomb® dose, to reduce a dose or to cancel one of its components (ламивудин or a zidovudine), it is possible to use separate drugs of a lamivudin and zidovudine in dosage forms of the tablet/capsule and solution for intake.

Use for special groups of patients. Use at abnormal liver functions. At a liver failure cumulation of a zidovudine as a result of delay of binding it with glucuronic acid can be noted. At patients with heavy degree of an abnormal liver function it is recommended to apply ламивудин and a zidovudine in the form of separate drugs to have an opportunity individually to select zidovudine doses.

Use at renal failures. Patients with a renal failure have concentration of a lamivudin and a zidovudine in blood are increased owing to delay of their elimination. As patients with a renal failure (clearance of creatinine less than 50 ml/min.) in some cases need to select individually a dose of a lamivudin and a zidovudine, it is recommended to appoint by it separate drugs of a lamivudin and zidovudine.

Use for patients of advanced age. There are no specific data on use of the drug Zilakomb® for patients of advanced age. 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.

Use for patients with hematologic side effects. At the expressed anemia (a hemoglobin content less than 90 g/l or 5,59 mmol/l) or neutropenias (number of neutrophils less than 1,0Õ109/l) dose adjustment of a zidovudine can be required. At use of the drug Zilakomb® it is impossible to pick up individually doses of a lamivudin and a zidovudine, it is recommended to use separate drugs of a lamivudin and zidovudine.

Features of use:

Pregnancy and lactation. It is not recommended to apply Zilakomb® in the first 3 months of pregnancy, except for cases when the expected advantage of therapy for mother exceeds probable risk for a fruit.

It is shown that treatment by a zidovudine of pregnant women and the subsequent administration of this drug by the newborn reduces transmission frequency of HIV from mother to a fruit. Concerning a lamivudin there are no such data. Therefore, pregnant women can appoint Zilakomb® only when the expected advantage for mother exceeds possible risk for a fruit.

VICh-infitsrovannym the refusal of breastfeeding of children is recommended to patients to avoid transfer of HIV infection.

At newborns and babies who at pregnancy or at the time of delivery were affected by NIOT, small temporary increase in blood of concentration of a lactate is noted. There are also rare messages on cases of an arrest of development and convulsive attacks. In general, for children whose mothers at pregnancy accepted NIOT the advantage of decrease in risk of infection of HIV, obviously, exceeds the danger connected with side effects of these drugs.

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

Despite administration of drug of Zilakomb® or any other anti-retrovirus 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 Zilakomb®, does not prevent risk of transfer of HIV to other people at sexual contacts or transfusion of the infected blood therefore patients have to observe the appropriate measures of precaution.

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

Hematologic disturbances. Against the background of therapy by the drug Zilakomb® development of hematologic disturbances is possible: anemias, neutropenias and leukopenias (the last usually is secondary in relation to a neutropenia). These phenomena are more often observed at purpose of a zidovudine in high doses (1200-1500 mg/days) at patients with late stages of HIV - infections at a reduced marrowy reserve prior to treatment. Therefore during treatment it is necessary to carry out by the drug Zilakomb® careful control of hematologic indicators. The specified hematologic changes usually appear not earlier than in 4-6 weeks from the beginning of therapy. At patients with a late stage of clinically expressed HIV infection blood tests are recommended to be carried out at least 1 time in 2 weeks within the first 3 months of therapy, and then - at least 1 time a month.

At patients with an early stage of HIV infection 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, 1 time in 1-3 months. Special selection of a dose of a zidovudine in case of development of heavy anemia or a miyelosupressiya can be required during treatment by the drug Zilakomb®, and also at patients with the previous oppression of marrow, for example, at concentration of hemoglobin of 90 g/l (5,59 mmol/l) or quantity of neutrophils less than 1,0Õ109/l. As individually it is impossible to pick up a drug Zilakomb® dose, it is recommended to use separate drugs of a lamivudin and zidovudine.

Pancreatitis. At the patients accepting ламивудин and a zidovudine, exceptional cases of development of pancreatitis are described. However whether this complication by medicines or a basic disease - HIV infection is established, caused. Treatment by the drug Zilakomb® 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 activity of biochemical markers).

Lactoacidosis / the expressed hepatomegalia with a steatosis. At the patients accepting analogs of nucleosides in the form of monotherapy or in a combination including, ламивудин and a zidovudine, cases of lactoacidosis and the expressed hepatomegalia with fatty dystrophy of a liver are described rare, but with a possible lethal outcome. The similar phenomena were noted, mainly, at women. Clinical symptoms of lactoacidosis include the general weakness, appetite loss, sudden, inexplicable loss of body weight, symptoms of a gastrointestinal tract disease (nausea, vomiting, an abdominal pain), respiratory disturbances (an asthma and increase of breath), neurologic symptoms (muscular weakness).

Analogs of nucleosides should be applied with care at all patients (especially corpulent women) with a hepatomegalia, hepatitis or other known risk factors of diseases of a liver and fatty dystrophy of a liver (including some medicines and alcohol). The patients with coinfection hepatitis C receiving therapy by interferon drugs an alpha and a ribavirina are exposed to the increased risk. Reception of analogs of nucleosides should be stopped at emergence of clinical or laboratory signs of lactoacidosis or a hepatotoxic (to which the hepatomegalia and a steatosis, even for lack of substantial increase of activity of aminotransferases belong).

Redistribution/accumulation of a hypodermic fatty tissue. Some patients receiving the combined anti-retrovirus therapy have a redistribution/accumulation of fatty tissue, including the central obesity, a dorsovistseralny adiposity ("a buffalo hump"), weight loss of extremities and faces, increase in mammary glands, increase in concentration of serumal lipids and glucose of blood. 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 relating to inhibitors of protease and NIOT, data confirm existence of distinctions between certain representatives of the specified classes of drugs concerning ability to cause these 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 and duration of anti-retrovirus therapy play important, perhaps, a synergistic role.

The remote effects of the specified side effects are unknown now. Clinical inspection of patients has to include assessment of physical signs of redistribution of fatty tissue. It is necessary to define concentration of serumal lipids and glucose of blood. Disturbances of lipidic exchange it is necessary to treat, being guided by their clinical manifestations.

Opportunistic infections. At administration of drug of Zilakomb® and other anti-retrovirus therapy the possibility of development of opportunistic infections remains. Therefore patients have to be under observation of the specialist in treatment of HIV infection.

Immunity recovery syndrome. In an initiation of treatment anti-retrovirus means of HIV-positive patients with a heavy immunodeficiency inflammatory reactions, and also residual opportunistic infections can develop that sometimes leads to serious clinical effects or strengthening of symptomatology. Usually such reactions are observed within the first weeks or months after the beginning of anti-retrovirus therapy. Typical examples are the Cytomegaloviral retinitis, the generalized or focal infection caused by Pneumocystis jiroveci (R. of Carinii). Emergence of any symptoms of an inflammation demands immediate inspection and, if necessary, treatment.

Against the background of a syndrome of immune recovery also formation of autoimmune diseases is possible (Greyvs's disease, a polymiositis, a syndrome to Giyena-Barra). Time of primary manifestations varied, and the disease could arise in many months after the beginning of therapy and have an atypical current. In case of muscular weakness, a shiver, a tremor, a hyperactivity patients are recommended to notify the attending physician immediately.

The patients who are at the same time infected with HIV and virus of the hepatitis B. Zilakomb® it is necessary to apply with care at patients with the dekompensirovanny cirrhosis caused by chronic hepatitis B as the exacerbation of hepatitis at cancellation of a lamivudin is in rare instances possible. It is necessary to carry out monitoring of function of a liver and markers of replication of a virus of hepatitis B within 4 months after drug withdrawal.

Patients with a slight or moderate liver failure or cirrhosis need decrease in a daily dose of a zidovudine. Зилакомб®, being the combined drug with the fixed dosage, it is not recommended for use at patients with a liver failure.

The patients who are at the same time infected with HIV and a virus of hepatitis C. 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 ribavirin and the drug Zilakomb®, especially at patients about a zidovudine - the induced anemia in the anamnesis is not recommended. In this case it is recommended to consider the possibility of change of the mode of anti-retrovirus therapy for the purpose of cancellation of a zidovudine.

Osteonecrosis. Development of an osteonecrosis is caused by action of a set of factors (including reception of glucocorticosteroids, an alcohol abuse, the expressed immunosuppression, a high index of body weight), in particular, cases of an osteonecrosis were registered at patients with late stages of HIV and/or the long combined anti-retrovirus therapy. This category of patients should recommend to address the specialist in case of joint pains, constraint and rigidity in joints.

Mitochondrial dysfunctions. Analogs of nucleotides and nucleosides show ability to cause mitochondrial damages of in vitro and in vivo. There are data on development of mitochondrial dysfunctions in the HIV-negative babies who were affected by analogs of nucleosides during pre-natal development and/or postnatalno. The following undesirable phenomena were registered: hematologic disturbances - anemia, a neutropenia; metabolic disturbances - increase in concentration of a lactate and lipase. These phenomena generally had tranzitorny character. The remote neurologic manifestations (a hyper tone, a convulsive syndrome, behavioural frustration) were noted. At the moment it is unknown whether neurologic disturbances are resistant or tranzitorny. The children who were affected by analogs of nucleotides and nucleosides during pre-natal development in cases of manifestation of the corresponding symptomatology need clinical observation and inspection for diagnosis of mitochondrial dysfunction.

Liver diseases. The risk serious, up to lethal, complications from a liver increases at patients with hepatitis B or C. Patients with the previous liver diseases, including chronic active hepatitises, have the increased risk of abnormal liver functions against the background of the combined anti-retrovirus therapy and need observation according to the accepted standards. At obvious deterioration in a course of a disease of a liver at this group of patients it is necessary to make the decision on a break or the termination of therapy.

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:

Treatment of HIV infection lamivudiny and a zidovudine in the form of monotherapy or in the form of a combination of these drugs can cause side effects. Concerning many side effects it is unknown whether they are caused lamivudiny, a zidovudine, a wide range of other drugs used for treatment of HIV infection or are a consequence of a basic disease. When performing the combined anti-retrovirus therapy metabolic disturbances, such as a gipertriglitseridemiya, a hypercholesterolemia, insulin resistance, a hyperglycemia are possible.

Are a part of the drug Zilakomb® ламивудин and a zidovudine and therefore it can cause the side effects characteristic of each of these ingredients. There are no data that the combination of a lamivudin and a zidovudine has the additive toxicity now.

Determination of frequency of side effects: very often (≥1/10); often (≥1/100 and <1/10); infrequently (≥1/1000 and <1/100); seldom (≥ 1/10 000 and <1/1000); very seldom (<1/10 000).

Lamivudin. Disturbances from blood and lymphatic system: infrequently - a neutropenia, anemia, thrombocytopenia; very seldom - a true erythrocyte aplasia.

Disturbances from immune system: seldom - a Quincke's disease.

Disturbances from a metabolism and food: often - a giperlaktatemiya; seldom - lactoacidosis; redistribution/accumulation of fatty tissue (frequency of this side effect depends on a set of factors, including on a specific combination of anti-retrovirus drugs).

Disturbances from a nervous system: often - a headache, sleeplessness; very seldom - paresthesias, there are messages on peripheral neuropathy, however its communication with therapy lamivudiny is not clear.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: often - cough, nasal symptoms.

Disturbances from digestive tract: often - nausea, vomiting, pain in epigastriums, diarrhea; seldom - pancreatitis (connection with treatment lamivudiny is not established), increase in activity of serumal amylase.

Disturbances from a liver and biliary tract: infrequently - tranzitorny increase in activity of liver enzymes of alaninaminotranspherase (ALT), aspartate aminotransferase (ACT), is rare - hepatitis.

Disturbances from skin and hypodermic fabrics: often - rash, an alopecia.

Disturbances from skeletal and muscular system and connecting fabric: often - an arthralgia, muscular disturbances; seldom - рабдомиолиз.

The general frustration and disturbances in an injection site: often - fatigue, a febricula, fever.

Zidovudine. Disturbances from blood and lymphatic system: often - anemia (hemotransfusion can be required), a neutropenia and a leukopenia. These side effects arise at use of a zidovudine in high doses (1200-1500 mg/days), at patients with late stages of HIV infection more often (especially at a reduced marrowy reserve prior to treatment) and, in particular, patients with number of cells have CD4+ less than 100 in мкл. At some patients it is necessary to reduce a zidovudine dose up to cancellation. The neutropenia arises more often at those patients who have a number of neutrophils, concentration of hemoglobin and concentration of B12 vitamin in serum are reduced at the time of an initiation of treatment by a zidovudine. Infrequently - thrombocytopenia and a pancytopenia (with a marrow hypoplasia); seldom - a true erythrocyte aplasia; very seldom - aplastic anemia.

Disturbances from a metabolism and food: often - a giperlaktatemiya; seldom - lactoacidosis, anorexia; redistribution/accumulation of fatty tissue (frequency of this side effect depends on a set of factors, including on a specific combination of anti-retrovirus drugs).

Disturbances of mentality: seldom - alarm and a depression.

Disturbances from a nervous system: very often - a headache; often - dizziness; seldom - sleeplessness, paresthesias, drowsiness, decrease in intellectual activity, a spasm.

Disturbances from an organ of sight: frequency is unknown - macular hypostasis, an amblyopia, photophobia.

Disturbances from an acoustic organ and labyrinth disturbances: вертиго, hearing loss;

From cardiovascular system: seldom - a cardiomyopathy.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: infrequently - an asthma; seldom - cough.

Disturbances from digestive tract: very often - nausea; often - vomiting, an abdominal pain and diarrhea, infrequently - a meteorism; seldom - pigmentation of a mucous membrane of a mouth, a food faddism (dysgeusia) and dyspepsia, pancreatitis.

Disturbances from a liver and biliary tract: often - increase in activity of "hepatic" enzymes and concentration of bilirubin; seldom - damages of a liver, such as the expressed hepatomegalia with a steatosis.

Disturbances from skin and hypodermic fabrics: infrequently - rash, an itch; seldom - pigmentation of nails and skin, a small tortoiseshell and perspiration.

Disturbances from skeletal and muscular system and connecting fabric: often - a mialgiya; infrequently - a myopathy.

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

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

The general frustration and disturbances in an injection site: often - a febricula; infrequently - fever, a generalized pain syndrome and an adynamy; seldom - a fever, a stethalgia and a grippopodobny syndrome.

Interaction with other medicines:

As the drug Zilakomb® contains ламивудин and a zidovudine, he can enter any interactions characteristic of each of its components. The probability of metabolic interaction with lamivudiny is small since 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 not changed look. The zidovudine also 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 the drug Zilakomb® are listed below.
 
Interaction with participation of a lamivudin. Lamivudin is preferential brought by means of organic cations of transport system, respectively, it is necessary to remember a possibility of interaction of the drug Zilakomb® with the medicines having the same way of removal. Trimethoprimum. The concomitant use of a lamivudin and Trimethoprimum (one of drug components co-trimoxazole) leads to increase in concentration of a lamivudin in plasma for 40% at reception of this drug in therapeutic doses. However with normal function of kidneys of individual selection of a dose of a lamivudin it is not required to patients. Lamivudin does not influence pharmacokinetics of Trimethoprimum or sulfamethoxazole. It is necessary to be careful at simultaneous use of co-trimoxazole and the drug Zilakomb® for patients with a renal failure. Combined use of a lamivudin and co-trimoxazole in high doses for treatment of pneumocystic pneumonia and a toskoplazmoz was not studied and it should be avoided.
 
Zaltsitabin. Lamivudin can oppress intracellular phosphorylation of a zaltsitabin at a concomitant use. Thus, it is not recommended to use drug of Zilakomb in a combination with zaltsitabiny.
 
Emtritsitabin. Use of this combination of drugs for therapy of HIV infection cannot be recommended because of similarity of a lamivudin with emtritsitabiny.
 
Ranitidine. Clinically significant interaction is improbable. Ranitidine is only partially removed by renal system of transport of organic cations. Correction of doses of drugs is not required.
 
Kladribin. In vitro ламивудин oppresses process of intracellular phosphorylation of a kladribin, thus there is a risk of decrease in efficiency of a kladribin at simultaneous use with lamivudiny in clinical practice. Some clinical finds also confirm a possibility of interaction of a lamivudin with kladribiny. Simultaneous use of a lamivudin and kladribin is not recommended.
 
Didanozin. Interaction is not studied. Correction of doses of drugs is not required. Flukonazol. Interaction is not studied.
 
Phenobarbital. Interaction is not studied.
 
Valproic acid. Interaction is not studied.
 
Interaction with participation of a zidovudine. Atovakhon. The zidovudine does not exert impact on pharmacokinetics of an atovakhon. However pharmacokinetic data demonstrate to what атовахон reduces extent of metabolism of a zidovudine to its glucuronide (in an equilibrium condition of AUC of a zidovudine increases by 33%, Smakh in plasma of a glucuronide decreases by 19%). At purpose of a zidovudine in doses from 500-600 mg/days and the accompanying course of treatment of acute pneumocystic pneumonia atovakhony, increase in frequency of the side reactions connected with the increased concentration of a zidovudine in plasma is improbable.
 
Klaritromitsin. Absorption of a zidovudine decreases at a concomitant use of a klaritromitsin in the form of tablets. It is necessary to observe an interval between receptions of a klaritromitsin and a zidovudine at least in 2 h.
 
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% it Smakhv to 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 Zilakomb® and Phenytoinum.
 
Probenetsid. According to some information, пробенецид increases average T1/2 of a zidovudine and AUC as a result of oppression of formation of a glucuronide. In the presence of a probenetsid renal excretion of a glucuronide and, perhaps, the zidovudine decreases. Rifampicin. Limited data show what at the combined reception of a zidovudine and AUC rifampicin of a zidovudine decreases by 48±34%. However clinical value of this observation is unknown.
 
Stavudin. The zidovudine can inhibit process of intracellular phosphorylation having become the Udi at their concomitant use. Thus, the accompanying use of a combination of a stavudin and the drug Zilakomb® is not recommended.
 
Ribavirin. The Nukleozidny analogs breaking DNA replication such as рибавирин, can reduce in vitro antiviral activity of a zidovudine. Simultaneous use of such medicines with a zidovudine is not recommended. Increase of the anemia caused ribaviriny at inclusion of a zidovudine in complex therapy of HIV infection was observed. It is not recommended to use a zidovudine in combination with ribaviriny in connection with increase in risk of development of anemia.
 
Doxorubicine. Simultaneous use of a zidovudine and doxorubicine is not recommended because of mutual easing of activity of each of in vitro medicines.
 
Emtritsitabin. Clinically significant interaction is absent.
 
Didanozin. Interaction is not studied. Correction of doses of drugs is not required.

Flukonazol. At simultaneous use with flukonazoly increase in AUC of a zidovudine by 74% at the expense of UDF-glyukuronoziltransferaza's (UDF GT) inhibition is observed. Taking into account limited data the clinical importance is unknown. Control of toxic effects of a zidovudine is necessary.
 
Phenobarbital. Interaction is not studied. Perhaps insignificant decrease in plasma concentration of a zidovudine due to induction of UDF GT. There are not enough data for recommendations about correction of doses of drugs.
 
Valproic acid. At simultaneous use with valproic acid increase in AUC of a zidovudine by 80% at the expense of UDF GT inhibition is observed. Taking into account limited data the clinical importance is unknown. Control of toxic effects of a zidovudine is necessary.
 
Ranitidine. Interaction is not studied.
 
Acetylsalicylic acid, codeine, morphine, indometacin, ketoprofen, Naproxenum, oxazepam, lorazepam, Cimetidinum, Clofibratum, dapsone, inosine пранобекс are capable to change metabolism of a zidovudine as a result of competitive inhibition of process of a glyukuronization or direct suppression of metabolism of a zidovudine microsomal enzymes of a liver. Before purpose of these drugs in combination with the drug Zilakomb®, especially for prolonged treatment, it is necessary to estimate possible medicinal interaction.
 
Simultaneous use, especially for therapy of acute states, a zidovudine and potentially nefrotoksichny or myelosuppressive drugs (for example, system administration of pentamidine, dapsone, Pyrimethaminum, co-trimoxazole, Amphotericinum In, a flutsitozina, a gantsiklovira, interferon, Vincristinum, vinblastine and doxorubicine) can also increase risk of side effects of a zidovudine. At co-administration of the drug Zilakomb® 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.
 
Since at some patients, despite administration of drug of Zilakomb®, opportunistic infections can develop, purpose of additional therapy for the purpose of prevention of infections can be required. Apply co-trimoxazole, pentamidine in the form of an aerosol to such prevention, 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:

• the zidovudine and Zilakomb® are contraindicated to patients with heavy degree of a neutropenia (number of neutrophils less than 0,75x109/l) or anemias (hemoglobin less than 75 g/l or 4,65 mmol/l);
• hypersensitivity to a lamivudin, a zidovudine or any other component of drug.

Overdose:

There are no data on cases of overdose of the drug Zilakomb®. At the same time, there are limited data on effects of acute overdose of a lamivudin and a zidovudine. Any of these cases did not end with a lethal outcome, and the condition of all patients was normalized. Any specific characters or symptoms were not described.

Treatment: it is recommended to control a condition of the patient for early detection of symptoms of intoxication and to carry out a standard maintenance therapy. As ламивудин it is removed by means of dialysis, at overdose it is possible to apply a continuous hemodialysis, however there is no corresponding clinical experience yet. Apparently, the hemodialysis and peritoneal dialysis are ineffective at removal from a zidovudine organism, but accelerate elimination of its metabolite (glucuronide).

Storage conditions:

To store in the dry place protected from light at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 300,0 mg + 150,0 mg. Packaging: on 10 tablets in a blister strip packaging from a film of PVC and aluminum foil. On 6 blister strip packagings together with the application instruction in a pack from a cardboard.