Kombivir
Drug photo
Structure
The 1st tablet contains 150 mg of a lamivudin and 300 mg of a zidovudine – active ingredients.
The accompanying substances: starch sodium glycollate (type A), microcrystallic cellulose, anhydrous silicon colloid, magnesium stearate and white opadray YS-1-7706-G (as a cover).
Release form
Kombivir is made in the form of tablets in a cover, on 60 pieces in a pack.
Pharmacological action
Anti-virus.
Pharmacodynamics and pharmacokinetics
The operating Kombivir's ingredients – a zidovudine and lamivudin – are the selective highly effective drugs oppressing activity of a revertaza of VICh-1 and VICh-2. The synergism of a lamivudin with a zidovudine is shown in relation to suppression of replication of HIV in cellular culture. Under the influence of intracellular kinases both active ingredients are exposed to a consecutive metabolism before formation of the 5th -triphosphate (TF).
Zidovudina-TF and lamivudina-TF represent substrates for a HIV revertaza, and also are competitive inhibitors of this enzyme. However, antiviral efficiency of these drugs is mainly caused by a vklinivaniye of their monophosphatic form in a virus DNA chain that leads to a rupture of the existing chain.
Triphosphates of a zidovudine and lamivudin are characterized significantly by smaller affinity in relation to DNA polymerases of cells of a human body.
The synergism of two active ingredients of Kombivir slows down forming of resistance to a zidovudine at the patients who were earlier not passing anti-retrovirus treatment. This combination of drugs reduces quantity of VICh-1 in an organism and increases the number of cells of CD4+. Monotherapy by Kombivir, and also his combination with other reasonable in this case drugs (for example, Kombivir + Kaletra) considerably reduces risk of progressing of HIV and reduces mortality of patients.
Kombivir is rather fully and quickly soaked up from a gastrointestinal tract. Bioavailability of a zidovudine at adult patients is at the level of 60-70%, a lamivudin – 80-85%. After oral administration of Cmax of a zidovudine (1,8 mg/ml) Cmax of a lamivudin (1,5 mg/ml) — in 45 minutes is observed on average in 30 minutes. Both drugs get into cerebrospinal fluid and TsNS. After 2-4 hours after Kombivir's reception inside the ratio of concentration of a zidovudine / lamivudina in blood serum and liquor averages 0,5/0,12. Lamivudin's T1/2 varies within 5-7 hours. Removal, generally in not changed look, happens to urine.
At pathologies of kidneys, owing to an elimination delay, plasma concentration of a zidovudine / lamivudina are increased.
At pathologies of a liver cumulation of a zidovudine, because of delay of its linkng with glucuronic acid can be observed.
Indications to use
Kombivir apply for the purpose of treatment of HIV-positive patients at children's and adult age, at body weight more than 14 kilograms.
Contraindications
Kombivir's use is contraindicated to patients with personal hypersensitivity to a zidovudine, a lamivudin or other components of HP.
Also contraindications are serious conditions of anemia (at hemoglobin level less than 4,65 mmol/l) and neutropenias (at quantity of neutrophils less than 0,75 x 109/l).
Side effects
The carried-out treatment of HIV infection with use of a zidovudine and lamivudin, both at monotherapy, and at their combination can be followed by side effects. For certain connection of many negative manifestations with reception of a zidovudine, lamivudin, the other drugs used at therapy of HIV or their emergence because of a basic disease is not established. By-effects of Kombivir consider proceeding from effects of two of his active ingredients (a zidovudine and a lamivudin). For this time the additive toxicity of this combination of drugs is not established.
For the Zidovudine
Nervous system:
- depressions;
- headaches;
- feeling of alarm;
- dizziness;
- paresthesias;
- sleeplessness / drowsiness;
- spasms;
- reduction of intellectual activity.
Lymphatic and hemopoietic system:
- leukopenia;
- anemia (with probability of hemotransfusion);
- neutropenia;
- pancytopenia (with a marrowy hypoplasia);
- aplastic anemia;
- thrombocytopenia.
These negative manifestations are most often observed at reception of a zidovudine in high daily doses (1200-1500 mg), at the patients who are at late stages of development of HIV (in particular at the lowered marrowy potential prior to therapy), and also patients, quantity of cells have CD4 at which less than 100/mm3. For some patients it is necessary to lower a zidovudine dosage, and sometimes and to cancel it completely. Forming of a neutropenia is in most cases observed at patients with the serumal quantity of neutrophils lowered prior to therapy, and also levels of B12 vitamin and hemoglobin.
Metabolism:
- giperlaktatemiya;
- anorexia;
- lactic acidosis;
- increase/redistribution of fatty tissues (with a frequency depending on a set of circumstances including a combination of the anti-retrovirus HP applied in a specific case).
Cardiovascular system:
- cardiomyopathy symptomatology.
Respiratory system:
- asthma;
- cough.
Bodies of a gastrointestinal tract:
- abdominal pains;
- nausea;
- taste change;
- vomiting;
- meteorism/diarrhea;
- pigmentation of mucous membranes of an oral cavity;
- pancreatitis;
- dyspepsia.
Zhelchevyvodyashchy ways and liver:
- increase in levels of bilirubin and enzymes of a liver;
- liver pathologies (a heavy hepatomegalia with a steatosis).
Musculoskeletal system:
- mialgiya;
- myopathy.
Integuments:
- itch/rash;
- pigmentation of integuments and nail plates;
- hyperhidrosis;
- small tortoiseshell.
Urinogenital system:
- frequent urination;
- gynecomastia.
Others:
- febricula;
- pain syndrome (generalized);
- fever;
- stethalgias;
- adynamy;
- grippopodobny syndrome;
- fever.
For Lamivudin
Nervous system:
- paresthesias;
- headaches;
- peripheral neuropathy (with until the end of not found out communication with reception of a lamivudin).
Lymphatic and hemopoietic system:
- anemia;
- neutropenia;
- thrombocytopenia;
- erythrocyte aplasia (true).
Metabolism:
- lactic acidosis;
- giperlaktatemiya.
Bodies of a gastrointestinal tract:
- nausea/vomiting;
- diarrhea;
- pain in epigastric area;
- pancreatitis (with until the end of not found out communication with reception of a lamivudin);
- increase in serumal level of amylase;
- increase/redistribution of fatty tissues (with a frequency depending on a set of circumstances including a combination of the anti-retrovirus HP applied in a specific case).
Zhelchevyvodyashchy ways and liver:
- tranzitorny increase in levels of enzymes of a liver (ALT, nuclear heating plant).
Integuments:
Musculoskeletal system:
- muscular disturbances;
- arthralgia;
- rabdomioliz.
Others:
Kombivir, application instruction
Therapy with Kombivir's use can be carried out by exclusively medical specialists having practice of treatment of HIV infection.
Reception of tablets of Kombivir follows it is (orally) desirable to carry out inside in the whole look (for reliable dosing), in independence of meal time. In a case when at the patient the difficulties connected with a proglatyvaniye of tablets are observed their crushing with the subsequent addition in liquid, semisolid food or drink is allowed. The mix received thus needs to be used immediately in full.
To patients, whose weight makes not less than 30 kg, recommend reception of a dose of Kombivir, the equaling one tablet twice at 24 o'clock.
At the body weight of 21-30 kg (generally to children) appoint, as a rule, 0,5 tablets in the morning and 1 tablet in the evening.
At the body weight of 14-21 kg 0,5 tablets of drug a day recommend (children) two times reception.
At body weight less than 14 kg use schemes of treatment with separately calculated dosages of a zidovudine and a lamivudin.
In need of decrease in dosages of Kombivir, and also reduction of doses or full cancellation of one of its active ingredients (the zidovudine, lamivudin) should be passed to reception of separately taken drugs. In case of a zidovudine drug of the choice is Retrovir who is let out in the form of peroral solution or capsules, and in case of a lamivudin – Epivir made in the form of peroral solution or tablets in a cover.
Characteristic differences of use of Kombivir at therapy of elderly patients are not revealed, however this age category demands especially careful carrying out treatment taking into account age changes (disturbance of renal function, cordial activity, hematologic indicators, etc.).
Because selection of dosages of a zidovudine and lamivudin for patients with renal pathologies (at KK less than 50 ml/min.) has to take place in an individual order, recommend to use a zidovudine and lamivudin as separate drugs. It is necessary to adhere to the same recommendations at treatment of patients with heavy pathologies of a liver.
In case of forming of a neutropenia (with quantity of neutrophils less than 1,0Õ109/l) or hemoglobin lowerings (lower than 5,59 mmol/l) correction of a dosage of a zidovudine can be necessary. As doses of active ingredients in drug Kombivir are fixed, in this case also pass to reception of separate drugs.
Overdose
Because of specific use of Kombivir of data on his overdose it is not enough for thorough studying. The characteristic toxic symptomatology of acute overdose and lamivudiny is not found by a zidovudine, except for the cases relating to by-effects. All known episodes of overdoses as a result came to an end with normalization of a condition of the patient and did not lead to a lethal outcome.
At suspicion on possible overdose by Kombivir it is necessary to watch the general condition of the patient, for the purpose of timely detection of intoksikatsionny signs, and also to carry out the adequate supporting treatment. For removal of a lamivudin procedure of a continuous hemodialysis though for this time such clinical experience is absent can be effective. For removal of a zidovudine the peritoneal dialysis and a hemodialysis, apparently, will be ineffective, but it is for certain known that these methods force elimination of a glucuronide (a zidovudine metabolism product). More exact data on methods of stopping of conditions of overdose can be gathered from application instructions of a zidovudine and lamivudin as separate drugs.
Interaction
Because Kombivir is to the combined HP and includes two active ingredients – a zidovudine and lamivudin, any medicinal interactions observed at use of its operating drugs separately are inherent in it. The possibility of interactions of metabolic character with lamivudiny quite low as only its small part is exposed to metabolic transformations and contacts plasma proteins, and itself lamivudin is almost completely excreted in not changed form with urine.
Communication with plasma proteins of a zidovudine is also insignificant, but its elimination passes mainly by means of a hepatic metabolism before formation of a glucuronide (an inactive metabolite). The drugs which are metabolized a liver, in particular in the course of a glyukuronization can possibly suppress a metabolism of the zidovudine.
Some drugs belonging to classes of medicines which should be applied with extra care together with Kombivir are included below.
For the Zidovudine
Co-administration with lamivudiny increases time of action of a zidovudine and for 28% by 13% raises its plasma Cmax. At the same time AUC of a zidovudine remains at the former level. Influence of a zidovudine on pharmacokinetics of a lamivudin is not revealed.
The zidovudine does not influence pharmacokinetic transformations of Atovakvon. On the contrary, Atovakvon slows down metabolic processes of transformation of a zidovudine to its metabolite of a glucuronide, increasing zidovudine AUC in an equilibrium state by 33% and lowering plasma Cmax of a glucuronide by 19%. In case of use of a zidovudine in the range of daily doses of 500-600 mg and parallel carrying out three-week therapy of acute pneumocystic pneumonia with Atovakvon's use, increase of frequency of emergence of the by-effects connected with increase in plasma concentration of a zidovudine is improbable. At more long joint therapy it is necessary to control a clinical condition of the patient.
The combined use with Klaritromitsin leads to decrease in absorption of a zidovudine in this connection the interval between receptions of these drugs has to be not less than 120 minutes.
Joint treatment with Phenytoinum at some patients led to lowering of its plasma contents, and in one case observed its increase. For this reason at parallel reception of Phenytoinum and Kombivir there is a need of a constant control of plasma concentration of Phenytoinum.
Some researches show increase of T1/2 of a zidovudine and its AUC at simultaneous use with Probenetsid. Also reduction of renal excretion of a glucuronide and probably the zidovudine was noted.
There is separate evidence of decrease by 48±34% of AUC of a zidovudine at its combined use with Rifampicin. The clinical importance of this phenomenon is not established.
The concomitant use of a zidovudine with Stavudin can lead to suppression of intracellular process of phosphorylation of the last because of what it is necessary to avoid their joint appointment.
Acetylsalicylic acid, Morphine, Indometacin, Methadone, Codeine, Ketoprofen, Oxazepam, Naproxenum, Lorazepam, Clofibratum, Cimetidinum, Izoprinozin and Dapsone influence a zidovudine metabolism because of competitive suppression of a glyukuronization or direct oppression of its microsomal metabolism. In case of need parallel purpose of data of HP with Kombivir, in particular at long therapy, it is necessary to estimate all their possible interactions comprehensively.
The combined use with potentially myelosuppressive or nephrotoxic drugs (for example, at system administration of Dapsone, Pentamidine, Pyrimethaminum, Amphotericinum, Co-trimoxazole, Flutsitozina, Interferon, Gantsiklovir, Vincristinum, Doxorubicine and Vinblastine) can lead to increase in side effect of a zidovudine. In case of joint appointment of Kombivir and any of above-mentioned drugs the constant control of renal functionality and hematologic indicators is necessary. Also correction of the dosing mode of one or several medicines can be necessary.
At some patients even against Kombivir's reception opportunistic infections which demand purpose of parallel preventive antimicrobic treatment can form. Choice drugs in such cases are: Pentamidine (aerosol), Co-trimoxazole, Acyclovir and Pyrimethaminum. Limited conclusions of the carried-out clinical tests show lack of increase of frequency of side effects from a zidovudine at its simultaneous use with these drugs.
For Lamivudin
The preferential way of removal of a lamivudin occurs by means of cationic transport system. For this reason it is necessary to take into account a possibility of interaction of Kombivir with drugs with a similar way of removal.
Parallel reception of a lamivudin with Zaltsitabin can suppress intracellular phosphorylation of the last in this connection their co-administration is not recommended.
The combined use with Co-trimoxazole in therapeutic dosages, can lead to increase in plasma maintenance of a lamivudin by 40%. At normal renal function correction of daily doses of a lamivudin is not required. Influence of a lamivudin on pharmacokinetics of Co-trimoxazole is not revealed. In case of need purposes of joint therapy by these two drugs patients with insufficiency of kidneys should show extra care. Effects of treatment lamivudiny with parallel reception of Co-trimoxazole in high doses for the purpose of therapy of a toxoplasmosis and pneumocystic pneumonia were not studied.
Terms of sale
It is possible to buy Kombivir only at presentation of the recipe.
Storage conditions
For safety of tablets it is necessary to adhere to temperature indicators to 30 °C.
Period of validity
From the date of production – 2 years.
Special instructions
In case of need dosing of active ingredients of Kombivir in an individual order, it is necessary to use separate drugs of a zidovudine and lamivudin. In this case doctors have to be guided by application instructions of the used medicines.
Even against Kombivir's use or any other anti-retrovirus medicines, at patients opportunistic infections, and also other complications inherent in HIV infection can form. For this reason patients have to reside under supervision of the specialists practicing on carrying out therapy of HIV infection.
It is necessary to inform the patients passing treatment using Kombivir on possible interaction of its active ingredients with other medicines in case of their parallel appointment.
Also patients have to obtain the complete information about ways of transfer of a virus and need of observance of appropriate security measures at sexual contacts, pregnancy, hemotransfusions and its components, a lactation and so forth as therapy by anti-retrovirus drugs, including Kombivir, does not prevent quite high possibility of transfer of HIV between people.
At the patients accepting a zidovudine emergence of a neutropenia, anemia and a leukopenia is possible (as a rule, after a neutropenia). These painful states were most often shown at purpose of big daily dosages of a zidovudine (1200-1500 mg/) by the patient who is at late stages of development of HIV infection at which observed the lowered marrowy reserve before purpose of treatment. In this regard at the patients accepting Kombivir it is necessary to control hematologic indicators constantly. The above described changes of a hematologic picture arise approximately in 30-45 days after an initiation of treatment. At early stages of forming of HIV infection these hematologic by-effects are noted seldom and therefore to control indicators of the general blood test enough with a frequency of 30-90 days, being coordinated with the general condition of patients. At later stages of development of HIV it is necessary to check blood indicators at least each two weeks (for the first 90 days of treatment), and in the subsequent at least each 30 days. Patients with the previous suppressed marrow, for example, at number of neutrophils less than 1,0Õ109/l or small amount of hemoglobin to 5,59 mmol/l, and also the situations of forming of a heavy miyelosupressiya or anemia observed against Kombivir's reception can demand individual selection of dosages of a zidovudine. In this case it is necessary to pass from Kombivir to reception of a zidovudine and lamivudin as monodrugs.
At therapy with Kombivir's use observed the rare facts of development of pancreatitis, with still not established nature of emergence caused by complications of reception of medicine or a current of a basic disease. At identification of the symptomatology including nausea/vomiting, abdominal pains, increase in biochemical markers and so forth therapy by Kombivir immediately stop, to an exception or confirmation of the diagnosis pancreatitis.
In certain cases the patients passing the combined anti-retrovirus treatment tested at themselves the phenomena of accumulation/redistribution of fatty tissues, including dorsotservikalny fatty adjournment ("a buffalo hump"), obesity of the central type, thinning of a hypodermic and fatty layer on extremities and a face, increase of serumal levels of glucose of blood and lipids, and also increase in mammary glands. These manifestations can be noted as separately, and all together. Forming of one or several of the above-mentioned complications integrated by the general syndrome which is often carried to a lipodystrophy is possible at use of all medicines belonging to the class of nukleozidny inhibitors of a revertaza and inhibitors of protease though the received data confirm a number of distinctions in ability to a call of these side effects between various representatives of the applied classes HP. It is also necessary to note that emergence of a syndrome of a lipodystrophy depends on a set of concurrent factors among which an important role, and also synergy value can, play: stage of development of HIV, advanced age and time of carrying out anti-retrovirus treatment. The remote effects of the specified negative phenomena for this time are not studied. Carrying out clinical inspection of patients has to include the analysis of physical signs of possible redistribution of fatty tissues, with the accompanying determination of levels of glucose of blood and serumal lipids. Disturbances from a lipometabolism need the therapy appointed proceeding from their clinical manifestations.
Seldom when passing anti-retrovirus treatment using analogs of nucleosides, both in monotherapy, and in the combined treatment (including Kombivir), cases of forming of lactic acidosis and a serious hepatomegalia with liver dystrophy which can become the reason of a lethal outcome were recorded. In most cases these pathologies were registered at female patients. The clinical symptomatology of lactic acidosis was shown by the general weakness, appetite loss, inexplicable sharp weight reduction, and also gastrointestinal and respiratory disturbances (breath increase, an asthma). In this regard Kombivir's appointment the patients who are in risk group of defeats of hepatic function should see off with extra care. At detection of symptoms of lactic acidosis or symptoms of a hepatotoxic (including a steatosis and a hepatomegalia, even in the absence of increase in hepatic transaminases) Kombivir's reception should be interrupted before establishment of the exact diagnosis.
At the very beginning of therapy by anti-retrovirus drugs at patients with an immunodeficiency of difficult character the process of an inflammation against a residual or symptomless opportunistic infection able can escalate to lead to a significant aggravation of symptoms of the patient or aggravation of symptomatology of a disease. As a rule, such manifestations take place for the first weeks (more rare — months) the carried-out treatment. The most significant place is taken by such negative phenomena as a tsitomegalovirusny retinitis, pneumocystic pneumonia and a focal/generalized mikobakterialny infection. All revealed symptoms of a possible inflammation need supervision, and if necessary — treatment.
Care of use of Kombivir is demanded by the patients having dekompensirovanny cirrhosis owing to chronic hepatitis B because exacerbations of hepatitis in case of cancellation of a lamivudin can sometimes be noted. During treatment it is necessary to carry out periodically monitoring of functionality of a liver and to watch markers of replication of hepatitis B.
At parallel reception of a zidovudine and Ribavirin observed aggravation of the existing anemia with the mechanism of development of this phenomenon not clear so far. In this regard it is necessary to avoid their joint appointment, in particular to patients in whose anamnesis there are facts a zidovudine - the induced anemia. In this case there will be reasonable a change of the therapeutic anti-retrovirus mode for the purpose of an exception of the scheme of a zidovudine.
Kombivir's influence on ability of the patient to manage motor transport and to be engaged in exact or dangerous works though in each separate case of the patient itself it is obliged to estimate adequately the general condition of the organism is improbable and to consider all possible side effects of the carried-out therapy.
Analogs
- Atripla;
- Abakavir/Lamivudin-Tev;
- Kiveksa;
- Duovir-N;
- Trizivir;
- Maktrivir;
- Zidolam-N;
- Tenvir-Em;
- Eviplera;
- Truvada;
- Tenokhop-E.
Zdravzona
- Kombivir No. 60 of a tablet
