Kombivir

Kombivir – the antiviral combined medicine active concerning the human immunodeficiency virus (HIV).

Form of release and structure

Dosage form of Kombivir – a tablet, film coated: oval, white or almost white color, on one of the parties the text divided by risky – "GXFC3" (on 10 pieces in blisters PVC, on 6 blisters in a cardboard pack Is scarlet/) is engraved.

Contain in 1 tablet:

• Active ingredients: ламивудин – 150 mg, a zidovudine – 300 mg;
• Auxiliary components: anhydrous colloid silicon, microcrystallic cellulose, sodium carboxymethylstarch (type A), magnesium stearate;
• Film cover: опадрай white (titanium dioxide, gipromelloz, polysorbate 80, macrogoal 400).

Indications to use

Kombivir apply to therapy of HIV infection at children (weighing not less than 14 kg) and adult.

Contraindications

• Heavy anemia (the indicator of hemoglobin is lower than 4,65 mmol/l or 7,5 g/dl);
• Heavy neutropenia (the quantity of neutrophils are less ^0,75×109/л);
• Body weight at children less than 14 kg;
• Hypersensitivity to a zidovudine, a lamivudin or any of medicine components.

The zidovudine reduces the level of transfer of HIV from mother to the child at Kombivir's reception by pregnant women, with the subsequent therapy of the newborn. However there are no similar data on a lamivudin, its safety of use at pregnancy is not established. Also there are no data on the combined use of a zidovudine and a lamivudin. Therefore to pregnant women, especially in the I trimester, drug is recommended to use, only if the expected advantage for mother is higher than probable risk for a fruit.

As ламивудин, the zidovudine and a human immunodeficiency virus get into breast milk, to HIV-positive women who are treated by Kombivir, under any conditions it is impossible to nurse the child.

At abnormal liver functions of heavy degree and at a renal failure with the clearance of creatinine (CC) of ≤50 ml/min. it is recommended to use separately drugs of a zidovudine and lamivudin.

At therapy of elderly patients it is necessary to observe extra care taking into account age changes, such as a renal failure or changes of hematologic indicators.

Route of administration and dosage

Specialists with experience of therapy of HIV-positive patients have to carry out treatment by Kombivir.

Pill Kombivir is taken inside, swallowing entirely, irrespective of meal. For patients who cannot swallow a tablet entirely it should be crushed and added to a small amount of liquid or food and to accept immediately right after crushing.

The recommended dosing mode for adults and children depending on body weight:

• ≥30 kg – 1 таб. 2 times/days;
• 21-30 kg – ^1/2 таб. in the morning and 1 таб. in the evening;
• 14-21 kg – ^1/2 таб. 2 times/days.

If it is necessary to reduce Kombivir's dose, to cancel ламивудин or a zidovudine, or to lower a dose of one of these components, it is recommended to apply monodrugs of a lamivudin (Epivir – tablets or solution to intake) and a zidovudine (Retrovir – solution to intake or the capsule).

At anemia (hemoglobin of ≤5,59 mmol/l (9 g/dl) or neutropenias (neutrophils ^{≤1,0 x 109/l}) dose adjustment of a zidovudine therefore at such indicators it is necessary to use monodrugs of a zidovudine and lamivudin is perhaps necessary.

Side effects

For today there are no data on the additive toxicity of a zidovudine and lamivudin therefore Kombivir can cause the side effects characteristic of each of these components separately.

Side effects of a lamivudin:

• Hemopoietic and lymphatic system: infrequently – anemia, thrombocytopenia, a neutropenia; very seldom – a true erythrocyte aplasia;
• Metabolism and food: often – a giperlaktatemiya; seldom – lactic acidosis, accumulation/redistribution of lipidic fabric (frequency depends on various factors, including a specific anti-retrovirus combination of drugs);
• Nervous system: often – a headache; very seldom – paresthesias, there are messages on peripheral neuropathy, but its communication with reception of a lamivudin is unknown;
• Digestive Tract (DT): often – pain in epigastriums, nausea, vomiting, diarrhea; seldom – increase in level of serumal amylase, pancreatitis (there are no reliable data about communication with therapy lamivudiny);
• Gepatobiliarny system: infrequently – tranzitorny increase in alaninaminotranspherase (ALT) and aspartate aminotransferase (nuclear heating plant);
• Skin and hypodermic fatty tissue: often – an alopecia, rash;
• Musculoskeletal system and connecting fabric: often – muscular disturbances, an arthralgia; seldom – рабдомиолиз;
• General and local reactions: often – a febricula, fatigue, fever.

Side effects of a zidovudine:

• Hemopoietic and lymphatic system: often – a leukopenia, a neutropenia and anemia (perhaps, hemotransfusion will be required); infrequently – a pancytopenia (with a marrow hypoplasia) and thrombocytopenia; seldom – a true erythrocyte aplasia; very seldom – aplastic anemia;
• Metabolism and food: often – a giperlaktatemiya; seldom – anorexia, lactic acidosis, accumulation/redistribution of lipidic fabric (frequency depends on various factors, including a specific anti-retrovirus combination of drugs);
• Mentality: seldom – an alarming state, a depression;
• Nervous system: very often – a headache; often – dizziness; seldom – paresthesias, drowsiness, sleeplessness, spasms, decrease in intellectual activity;
• Cardiovascular system: seldom – a cardiomyopathy;
• Respiratory system, bodies of a thorax and mediastinum: infrequently – an asthma; seldom – cough;
• GIT: very often – nausea; often – an abdominal pain, vomiting, diarrhea; infrequently – a meteorism; seldom – a food faddism, pigmentation of a mucous oral cavity, dyspepsia, pancreatitis;
• Gepatobiliarny system: often – increase in levels of bilirubin and liver enzymes; seldom – damages of a liver, such as the expressed hepatomegalia with a steatosis;
• Skin and hypodermic fatty tissue: infrequently – an itch, rash; seldom – a xanthopathy and nails, a small tortoiseshell, perspiration;
• Musculoskeletal system and connecting fabric: often – a mialgiya; infrequently – a myopathy;
• Kidneys and urinary tract: seldom – a frequent urination;
• Reproductive system and mammary glands: seldom – a gynecomastia;
• General and local reactions: often – a febricula; infrequently – an adynamy, fever, a generalized pain syndrome; seldom – a stethalgia, a fever, a grippopodobny syndrome.

Special instructions

In case of need selection of a dose use of separate drugs of a zidovudine and lamivudin is individually recommended. The attending physician has to be guided by the application instruction of these medicines.

As Kombivir's use or other anti-retrovirus drugs does not exclude development in patients of opportunistic infections and other complications of HIV infection, patients should be under regular observation of the medical personnel having experience of therapy of HIV infection.

There are no data on influence of a zidovudine and lamivudin on female fertility.

Therapy by Kombivir, as well as other anti-retrovirus drugs, does not prevent a possibility of transfer of HIV at transfusion of the infected blood or sexual contacts therefore it is necessary to observe the appropriate measures of precaution.

Special instructions on Kombivir's use at various states / diseases:

• Hematologic disturbances: reception of a zidovudine can provoke development of a neutropenia, anemia and a leukopenia (usually secondary owing to a neutropenia); more often such effects are observed in case of purpose of high doses of a zidovudine (1,2-1,5 g/days) at late stages of a disease at decrease in a marrowy reserve prior to therapy therefore at the patients receiving Kombivir it is necessary to carry out thorough control of indicators of blood. As such hematologic pathologies usually develop 4-6 weeks later from an initiation of treatment, patients with the developed clinical picture of HIV infection are recommended to control blood indicators at least 1 time in 2 weeks in the first three months of therapy, then – at least 1 time a month. At HIV infection at an early stage from system of blood side effects are noted seldom therefore the general blood test is admissible to be done, being guided by health of patients, 1 times in 1-3 months. In case of development of a miyelosupressiya or heavy anemia in the course of therapy by Kombivir, and also at patients with the previous oppression of marrow (hemoglobin is lower than 5,59 mmol/l (9 g/dl) or neutrophils less ^1,0×109/л) perhaps it will be necessary to select specially a zidovudine dose and as in drug Kombivir separately it cannot be made, it is recommended to use monodrugs of a zidovudine and lamivudin;
• Pancreatitis: rare episodes of development of pancreatitis in the patients accepting a zidovudine and ламивудин are described, but whether the complication is established authentically, connected with administration of drugs or with a basic disease – HIV infection. Therapy should be stopped immediately in case of the clinical signs or these laboratory researches indicating development of pancreatitis (nausea, vomiting, pain in epigastric area, increase in level of biochemical markers), to an exception of suspicion of pancreatitis;
• Acidosis lactic / the expressed hepatomegalia with a steatosis: there are data about rare, but with probability of a lethal outcome, cases of lactic acidosis and the expressed hepatomegalia with fatty dystrophy of a liver (most of them is registered at women). Clinical symptoms of lactic acidosis are: general weakness, loss of appetite and sudden inexplicable loss of weight, gastrointestinal disturbances, increase of breath and asthma. It is necessary to suspend Kombivir's use if at the patient clinical and laboratory symptoms of acidosis lactic or hepatotoxics (including a hepatomegalia and a steatosis are observed even if levels of transaminases are not increased). With risk factors of damage of a liver drug needs to be taken with caution;
• Redistribution of a hypodermic fatty tissue: at some patients the following symptoms can be observed (separately or in a complex): accumulation/redistribution of lipidic fabric, including a dorsotservikalny adiposity at the neck basis – "a buffalo hump", the central type of obesity, increase in mammary glands, thinning of a front hypodermic and fatty layer and reduction of a lipidic layer on extremities, increase in levels of glucose and serumal lipids in blood. At the same time the syndrome of a lipodystrophy is caused by a multifactorial etiology; for example, advanced age, a stage of HIV infection and duration of a course of anti-retrovirus therapy are perhaps synergistic, and play an important role in accumulation/redistribution of lipids owing to Kombivir's use. Now the remote effects of noted side effects are unknown. Disturbances of a lipometabolism it is necessary to treat depending on their clinical manifestations. It is necessary to determine levels of glucose and lipids in blood serum, and also to perform clinical examination of patients which has to include assessment of physical signs of redistribution of lipidic fabric;
• Immunity recovery syndrome: at the beginning of therapy by anti-retrovirus drugs of patients with HIV infection at a heavy immunodeficiency against the background of a residual or symptomless opportunistic infection the aggravation of inflammatory process is probable, it can seriously worsen a state or aggravate symptomatology. Usually such effects are observed for the first weeks or months from the beginning of anti-retrovirus treatment, the most significant of them – the generalized and/or localized (focal) mikobakterialny defeat, a Cytomegaloviral retinitis and a pneumocystosis. Any signs of inflammatory processes should be revealed immediately and in case of need at once to start therapy;
• The accompanying viral hepatitis In: Kombivir is recommended to apply with care at the dekompensirovanny cirrhosis caused by chronic hepatitis B as the exacerbation of hepatitis in case of cancellation of a lamivudin in rare instances can develop. Periodic monitoring of work of a liver and markers of replication of a virus of hepatitis B is necessary;
• The accompanying viral hepatitis With: at a concomitant use of a zidovudine and a ribavirin aggravation of anemia (the mechanism of development of effect is not found out) therefore the combined use of a ribavirin and Kombivir it is not recommended, especially in the presence of data in the anamnesis about a zidovudine - the induced anemia was observed. It is necessary to consider the possibility of cancellation of a zidovudine as a result of change of the mode of anti-retrovirus therapy;
• Driving of motor transport and control of difficult mechanisms: special researches of influence of a zidovudine and lamivudin for the period of reaction and speed of psychomotor reaction were not conducted, proceeding from pharmacological properties of these drugs such influence is improbable, but it is necessary to consider a clinical condition of the patient and the nature of side effects of a zidovudine and lamivudin.

Medicinal interaction

Kombivir are a part of drug a zidovudine and ламивудин therefore he can enter the interactions characteristic of any of its components.

Only small part of a lamivudin participates in a metabolism and contacts proteins of plasma. Almost completely drug in an invariable look is removed by kidneys therefore the probability of metabolic interactions is small. Nevertheless it is necessary to consider the following interactions with lamivudiny:

• The medicines which are removed with the help a cation - transport system – interaction with lamivudiny because of use of one way of removal is possible;
• Co-trimoxazole (160 mg of Trimethoprimum + 800 mg of sulfamethoxazole) – for 40% increases concentration in plasma of a lamivudin (reception in therapeutic doses). At normal function of kidneys dose adjustment of a lamivudin is not necessary, patients with a renal failure have at the same time Co-trimoxazole and Kombivir are applied with care. ламивудин does not exert impact on pharmacokinetics of sulfamethoxazole or Trimethoprimum. The effect of combined use of drugs for therapy of a toxoplasmosis and a pneumocystosis was not studied;
• Zaltsitabin – is not recommended to use in a combination with Kombivir as ламивудин his intracellular phosphorylation can oppress.

The zidovudine contacts proteins of plasma slightly, preferential it eliminirutsya by means of hepatic metabolism to an inactive glucuronide.

Interactions with a zidovudine:

• Atovakvon – a zidovudine does not influence its pharmacokinetics, but атоваквон reduces extent of metabolism of a zidovudine to its glucuronide (AUC of a zidovudine increases in an equilibrium state for 33%, and _Cmax in plasma of a glucuronide decreases by 19%). At use of a zidovudine from 500-600 mg/days in a complex with a 3-week course of therapy of an acute pneumocystosis atovakvony increase in frequency of the side effects connected with the increased concentration in zidovudine plasma is improbable. In case of need more long course of joint therapy it is necessary to watch a clinical condition of the patient carefully;
• Klaritromitsin – reduces absorption of a zidovudine (not less than 2 hours are required to observe an interval between receptions of a klaritromitsin and a zidovudine);
• Lamivudin – raises time of influence of a zidovudine for 13%, increases by 28% it _Cmax in plasma, but at the same time considerably does not change the general exposure of a zidovudine (AUC); the zidovudine does not influence pharmacokinetics of a lamivudin;
• Phenytoinum – decrease in blood of concentration of Phenytoinum was in certain cases noted, and in a separate case concentration of Phenytoinum increased (therefore, at simultaneous use of Kombivir and Phenytoinum control of concentration of Phenytoinum in blood is necessary);
• Probenetsid – can increase average ^T1/2 of a zidovudine and AUC because of oppression of formation of a glucuronide, to reduce renal excretion of a glucuronide and, perhaps, a zidovudine;
• Rifampicin – perhaps reduces AUC of a zidovudine by 48±34%, but clinical value of this effect is unknown;
• Stavudin – the inhibition of process of intracellular phosphorylation of a stavudin a zidovudine is possible at their concomitant use therefore such combination is not recommended;
• Acetylsalicylic acid, morphine, methadone, codeine, indometacin, ketoprofen, oxazepam, lorazepam, Naproxenum, Cimetidinum, Clofibratum, изопринозин – can break metabolism of a zidovudine because of competitive inhibition of a glyukuronization or direct suppression of microsomal metabolism. Before purpose of these drugs along with Kombivir, especially for long therapy, it is necessary to estimate effects of possible medicinal interactions;
• Potentially nefrotoksichny or myelosuppressive drugs (especially at therapy of acute states): pentamidine (at system introduction), dapsone, Pyrimethaminum, co-trimoxazole, Amphotericinum, флуцитозин, ганцикловир, interferon, Vincristinum, vinblastine, doxorubicine – can increase risk of side effects of a zidovudine (in case of their co-administration with Kombivir careful control of function of kidneys and hematologic indicators is necessary, if necessary it is required to lower a dose of one or several drugs).

As, despite Kombivir's reception, at some patients opportunistic infections can develop, perhaps their prevention will require purpose of an additional antimicrobic course of treatment. Co-trimoxazole, Pyrimethaminum, pentamidine (aerosol) and an acyclovir as by results of clinical tests the expressed increase in frequency of side effects of a zidovudine at simultaneous use with these drugs is absent are for this purpose recommended.

Terms and storage conditions

To store in the place, unavailable to children, at a temperature not above 30 °C.

Period of validity – 2 years.