Kiveksa
Producer: Glaxo Operetaions UK Limited (Glakso Opereyshns YuK Limited) Great Britain
Code of automatic telephone exchange: J05AR02
Release form: Firm dosage forms. Tablets.
General characteristics. Structure:
Acting substances: Abakavira mg sulfate 702; Lamivudin of 300 mg;
Auxiliary microcrystallic 309 mg of a veshchestva:tsellyuloz; Karboksimetilkrakhmal of sodium mg type A 55; Magnesium mg stearate 9;
Cover: Опадрай orange YS-1-13065-A of the following structure of 41 mg; Gipromelloza 26,4mg; Titanium dioxide 9,2mg; Macrogoal 400 3,3mg; Polysorbate 80 (Е 433) 0,4mg;
Dye sunset-yellow aluminum varnish (Sunset Yellow aluminum lake, E 110, Cl 15985) 1,7
1 - 600 mg of an abakavir in 1 tablet are equivalent (coefficient of recalculation 1,17).
Description:
The tablet of the extended form, biconvex, coated orange color, on one party of a tablet - GS FC2 engraving, other party has a smooth surface.
Pharmacological properties:
Pharmacodynamics. Abakavir and ламивудин treat group of nukleozidny inhibitors of the return transcriptase and are powerful selection VICh-1 and VICh-2 inhibitors. Abakavir and ламивудин are consistently metabolized under the influence of intracellular kinases to the corresponding triphosphates (TF) which act as active metabolites. Lamivudin-TF and karbovir-TF (active triphosphate of an abakavir) act as substrate and are competitive inhibitors of HIV the return transcriptase (RT). However, the main antiviral effect of drugs is caused by embedding of monophosphate in DNA chain that leads to replication break. Triphosphates of an abakavir and lamivudin have considerably smaller affinity to DNA polymerases of cells of the owner.
Swore at a research during which 20 HIV-positive patients accepted абакавир (300 mg twice a day daily and once in 24 hours prior to capture for carrying out the analysis), showed that the average geometrical a terminal intracellular elimination half-life karbovira-TF at an equilibrium state makes 20,6 h. At the same time the average geometrical an elimination half-life of an abakavir in this research made 2,6 h of plasma. Equilibrium pharmacokinetic indicators at reception of an abakavir of 600 mg were identical with those at reception of an abakavir of 600 mg once a day once a day were identical with those at reception of an abakavir of 300 mg twice a day in cross clinical trial on 27 HIV-positive patients. Intracellular content of karbovir-triphosphate in mononukleara of peripheral blood was higher at reception of an abakavir in a dosage of 600 mg once a day in comparison with reception of an abakavir of 300 mg twice a day (increase in the area under a curve "concentration time" in equilibrium state in 24 hours (AUC24, ss) for 32% of the maximum daily concentration in equilibrium state (Cmax 24,ss) - for 99%). At the patients accepting ламивудин 300 mg once a day daily the terminal intracellular elimination half-life lamivudina-TF increased from 16 to 19 h, and the elimination half-life of a lamivudin from plasma increased from 5 to 7 h. The research of indicators of pharmacokinetics of the lamivudin accepted in a dose of 300 mg once a day within 7 days in comparison with reception of a lamivudin of 150 mg twice a day within 7 days, conducted on 60 healthy volunteers showed that AUC24, ss and Cmax 24, ss values lamivudin-TF in mononukleara of peripheral blood were identical to intracellular concentration, however the minimum values at reception of a lamivudin of 300 mg were below once a day, than at reception of a lamivudin of 150 mg twice a day.
Variability of concentration of metabolites of a lamivudin in a cell is higher, than in plasma. These results are confirmed by the data obtained at reception of 300 mg of a lamivudin and 600 mg of an abakavir once a day daily (efficiency and safety of this combination at administration of drugs was daily also confirmed also during basic clinical trial of CNA30021 once a day).
Lamivudin acts synergistically with a zidovudine, effectively suppressing replication of HIV in culture of cells. In the conditions of in vitro абакавир works synergistically in a combination with amprenaviry, not Virapinum and a zidovudine and it is additive with didanoziny, zaltsitabiny, stavudiny and lamivudiny.
Resistance of VICh-1 to a lamivudin is caused by a mutation in M184V codon located close to an active center virus FROM. This mutation is observed both in the conditions of in vitro, and at the VICh-1-infitsirovannykh patients to whom the combination therapy including ламивудин was carried out. At a mutation in M184V codon sensitivity to a lamivudin considerably decreases and significantly ability of a virus to replication according to the researches in vitro decreases. Also in the researches in vitro it is established that isolates of a virus, resistant to a zidovudine, can become susceptible to effect of drug if resistance to a lamivudin at these isolates develops afterwards. However clinical value of similar changes finally is not defined so far.
Abakavir-rezistentnye VICh-1 isolates were received in the conditions of in vitro. These isolates are characterized by certain genotypic changes in codons FROM (codons of M184V, K65R, L74V and Y115F).
Resistance of HIV to an abakavir of in vitro and in vivo forms slowly. For clinically significant increase in the inhibiting concentration concerning 50% of strains of IC50 (increase in IC50 (the inhibiting concentration in 50% of cases) by 8 times of rather "wild" virus strain) multiple mutations of a virus genome are required. Isolates, resistant to an abakavir, can also have hyposensitivity to a lamivudin, a zaltsitabin, a tenofovir, an emtritsitabin and/or a didanozin, however keep sensitivity to a zidovudine and a stavudin.
Development of cross resistance between abakaviry and lamivudiny and anti-retrovirus drugs of other classes (for example: the protease inhibitors [PI] and nenukleozidny inhibitors of the return transcriptase [NNIOT]) it is improbable. HIV isolates with reduced sensitivity to an abakavir were emitted at patients with uncontrollable replication of a virus at whom the previous treatment by other nukleozidny inhibitors of the return transcriptase was inefficient.
The clinical isolates of a virus having three or more mutations connected with resistance to the nukleozidny inhibitors of the return transcriptase (NIRT) most likely are also steady against an abakavir. The cross resistance caused by M184V a mutation FROM is limited to a class of the OT nukleozidny inhibitors. A zidovudine, ставудин, абакавир and тенофовир keep the anti-retrovirus activity concerning the lamivudin-resistant VICh-1 isolates bearing only M184V a mutation.
Pharmacokinetics. Kiveksa in tablets of a bioekvivalentn to an abakavir and a lamivudin, applied as monodrugs. It is confirmed with data of a comparative research of bioequivalence during which healthy volunteers (n=30) once accepted Kiveks's drug (on an empty stomach) or 2 tablets on 300 mg of an abakavir and 2 tablets on 150 mg of a lamivudin (on an empty stomach), or Kiveksu after meal containing a large amount of fats.
At reception significant distinctions in extent of absorption (the area under curve [AUC] "concentration during plasma/time") and the maximum peak concentration (Cmax) of each of components on an empty stomach were not revealed. Also clinically significant changes of pharmacokinetic parameters in connection with administration of drug of Kiveks on an empty stomach or together with food were not revealed. These data demonstrate that drug can be accepted irrespective of meal.
Absorption
Abakavir and ламивудин are quickly and well soaked up after oral administration. Absolute bioavailability of an abakavir and lamivudin at adults at oral administration makes 83% and 80 - 85% respectively. Average time before achievement of the maximum concentration in serum (tmax) makes about 1,5 h and 1,0 h for an abakavir and a lamivudin respectively. After single oral administration of 600 mg of an abakavir average Cmax makes 4,26 mkg/ml, and average AUC ∞ - 11,95 mkg · h/ml. After multiple oral administration of a lamivudin of 300 mg once a day within seven days average equilibrium Cmax makes 2,04 mkg/ml, and average AUC24 - 8,87 mkg · h/ml.
Distribution in an organism
Researches showed that at intravenous administration the average seeming volume of distribution of an abakavir and lamivudin makes 0,8 and 1,3 l/kg respectively. In the conditions of in vitro studying was established that at introduction in therapeutic concentration абакавир badly or moderately (∼49%) contacts proteins of a blood plasma of the person. Lamivudin shows linear change of pharmacokinetic indicators when using therapeutic doses and badly contacts proteins of a blood plasma (less than 36%). It indicates low probability of option of interaction with other medicines at which there is a replacement of drugs from communication with proteins of plasma.
The available data demonstrate that абакавир and ламивудин get into the central nervous system (CNS) and get to cerebrospinal fluid (SMZh). It was established that AUC for SMZh makes from 30 to 44% of AUC value for plasma. Peak concentration of an abakavir in SMZh at administration of drug in a dose of 600 mg twice a day by 9 times exceeds IC50 of an abakavir which makes 0,08 mkg/ml or 0,26 µmol/l. The average relation of concentration of a lamivudin in SMZh to its concentration in serum later 2 and 4 h after oral administration of drug makes about 0,12. True extent of penetration of a lamivudin into TsNS, also as well as clinical value of this phenomenon are not established so far.
Metabolism
Abakavir is metabolized, mainly, in a liver. At the person абакавир 5 glucuronides, making about 66% of the general entered drug dose are metabolized generally under the influence of alcohol dehydrogenase with formation of 5-carboxylic acid and by conjugation with glucuronic acid with education. The specified metabolites are removed with urine.
Lamivudin is practically not exposed to metabolism and is preferential brought in not changed look by kidneys. Probability of metabolic interactions with lamivudiny low as in a liver a small part (less than 10%) of the accepted drug dose is metabolized.
Removal from an organism
The average elimination half-life of an abakavir makes about 1,5 hours. After multiple oral administration of an abakavir (300 mg twice a day) considerable accumulation of an abakavir is not observed. Removal of an abakavir is carried out by means of metabolism in a liver with the subsequent removal of metabolites preferential with urine. In urine about 83% of the accepted dose of an abakavir in the form of metabolites and in not changed look are found. Other part is removed with a stake.
The elimination half-life of a lamivudin makes from 5 to 7 hours. The average general clearance of a lamivudin is equal to about 0,32 l/h/kg most of which part is made by the renal clearance (more than 70%) which is carried out by organic cationic transport system.
Special groups of patients
Abnormal liver functions
There are data on pharmacokinetics of an abakavir and lamivudin received at separate use of drugs. The pharmacokinetics of an abakavir was studied at patients with abnormal liver functions of easy degree (5-6 on a scale of Chayld-Pyyu). During the research it was established that AUC of an abakavir on average increased by 1,89 times, and an elimination half-life - by 1,58 times. At diseases of a liver of AUC of separate metabolites of drug did not change. However the speed of education and removal of these metabolites decreased.
Patients with abnormal liver functions of easy degree need to reduce a daily dose of an abakavir. For treatment of such patients it is necessary to use the drug containing only абакавир (Ziagen). Researches of pharmacokinetics of an abakavir at patients with abnormal liver functions of average and heavy degree were not conducted. It is supposed that at such patients concentration of an abakavir in plasma will be characterized by considerable variability and it will be essential raised. In this regard, use of drug of Kiveks is contraindicated at patients with abnormal liver functions of average and heavy degree.
The data obtained at use of a lamivudin for patients with abnormal liver functions of moderate and heavy degree demonstrate that considerable changes of pharmacokinetic indicators of drug at an abnormal liver function do not happen.
Renal failures
There are data on pharmacokinetics of an abakavir and lamivudin received at separate use of drugs. Abakavir is metabolized, mainly, in a liver. About 2% of an abakavir are removed in not changed look by kidneys. Pharmacokinetic indicators of an abakavir at patients with an end-stage of a renal failure and normal function of kidneys practically do not differ. Researches showed that at patients with an impaired renal function concentration (AUC) of a lamivudin increases in plasma due to decrease in clearance. Due to the need of a dose decline of a lamivudin at patients with clearance of creatinine less than 50 ml/min., such patients should appoint monodrug of a lamivudin (Epivir).
Indications to use:
The infection caused by the human immunodeficiency virus (HIV) as a part of the combined anti-retrovirus therapy of adults and teenagers is more senior than 12 years.
Route of administration and doses:
Therapy has to be carried out by the doctor having experience of treatment of HIV.
Due to the impossibility of dose adjustment when using of the combined tablets with the fixed dosages of ingredients adults and teenagers whose weight makes less than 40 kg should not appoint Kiveks's drug.
Kiveks's pill can be taken irrespective of meal.
The combined drugs with the fixed doses of ingredients should not be used when there can be a need for dose adjustment, for example, at clearance of creatinine less than 50 ml/min., and also at a liver failure. In case of the termination of administration of drug of Kiveks or in need of dose adjustment it is necessary to appoint as monodrugs абакавир (Ziagen) or ламивудин (Epivir). In similar situations the doctor has to study application instructions of the specified medicines.
Groups of patients
Adults and children of 12 years are also more senior
On 1 tablet once a day daily.
Children up to 12 years
Kiveksa for treatment of children aged up to 12 years due to the lack of a possibility of dose adjustment is not recommended to use drug. For therapy selection attending physicians are recommended to address application instructions of a lamivudin and abakavir.
Elderly patients
The pharmacokinetics of an abakavir and lamivudin at patients is more senior than 65 years is not studied. At treatment of patients of advanced age it is necessary to consider the increased frequency of disturbances of work of a liver, kidneys, hearts, other associated diseases, and also use of other medicines.
Patients with a renal failure
While with a renal failure dose adjustment of an abakavir is not required from patients, the dose of a lamivudin has to be lowered in proportion to decrease in clearance of creatinine. In this regard, Kiveksa at clearance of creatinine is not recommended to use drug less than 50 ml/min.
Patients with an abnormal liver function
Patients with an abnormal liver function of easy degree will probably need reduction of a dose of an abakavir. Due to the impossibility of reduction of a dose when using drug of Kiveks, it is necessary to use the drug containing only абакавир. Drug is contraindicated to patients with abnormal liver functions of moderate and heavy degree.
Features of use:
Hypersensitivity to an abakavir
According to the clinical trials conducted prior to screening on existence of an allele of HLA-B*5701 approximately at 5% of the patients accepting абакавир hypersensitivity to drug, in rare instances with a lethal outcome develops.
Risk factors
In clinical trials it was shown that HLA-B*5701 allele carriage considerably increases risk of development of reaction of hypersensitivity to an abakavir. In prospective clinical trial of CNA106030 (PREDICT-1) to patients with existence of an allele of HLA-B*5701 drugs of an abakavir were not appointed that allowed to reduce significantly the frequency of emergence of clinically suspected reactions of hypersensitivity from 7,8% (66 patients from 847) to 3,4% (27 patients from 803) (p <0,0001), and also the frequency of development of the reactions of hypersensitivity confirmed with skin and application test from 2,7% (23 patients from 842) to 0,0% (0 patients from 802) (p <0,0001). Thus, based on results of this research, it was shown that reactions of hypersensitivity to an abakavir develop at patients carriers of an allele of HLA-B*5701 with a frequency of 48-61% in comparison with patients at whom this allele is absent (frequency of emergence of reactions of hypersensitivity of 0-4%).
Clinical physicians are recommended to carry out screening on HLA-B*5701 allele carriage at HIV-positive patients to whom the drugs containing абакавир were not appointed earlier.
Screening on a carriage of an allele of HLA-B*5701 is recommended to be carried out before repeated purpose of the abakavir-containing drug at patients with the unknown HLA-B*5701-status which was earlier well transferring therapy by the abakavir-containing drug.
Use of drugs of an abakavir is not recommended at such patients and has to be considered only in exceptional cases at careful medical observation when the potential advantage exceeds risk of use of drug.
The clinical diagnosis of the suspected reaction of hypersensitivity has to remain a basis for decision-making of use of the drugs containing абакавир with all patients. Even in case of lack of an allele of HLA-B*5701 абакавир it is necessary to cancel and not to resume its reception in all cases when reaction of hypersensitivity cannot be excluded, being guided by clinical data, because of potential risk of development of serious undesirable effects or even a lethal outcome.
Clinical picture
Reaction of hypersensitivity is characterized by emergence of symptoms of multiorgan defeat. At the same time at most of patients emergence of fever and/or rash is noted.
Treat other possible symptoms of hypersensitivity: weakness, indisposition, symptoms of a gastrointestinal tract disease (such, as: nausea, vomiting, diarrhea, abdominal pains), symptoms of defeat of a respiratory organs (such, as: asthma, pharyngalgia, cough), and also radiological signs of defeat of bodies of a thorax (mainly, limited infiltrates). Symptoms of reaction of hypersensitivity at treatment abakaviry can be observed at any time, however, as a rule, appear within the first six weeks of administration of drug. At treatment continuation weight of symptoms increases, and they can accept life-threatening character. In most cases similar symptoms disappear at the termination of reception of an abakavir.
Some patients with hypersensitivity originally believed that they suffer from respiratory (pneumonia, bronchitis, pharyngitis) or grippopodobny diseases, a gastroenteritis or reaction to other medicines. In this regard, reaction of hypersensitivity was diagnosed not at once, and patients continued (or renewed) administration of drug. It involved development of heavier reaction of hypersensitivity (up to a lethal outcome). Taking it into account, it is necessary to consider a possibility of development of such reaction and to exclude it at the patients having symptoms of these diseases. If it is impossible to exclude hypersensitivity reaction existence, to resume administration of drug of Kiveks or any other medicine containing абакавир (Ziagen, Trizivir), does not follow.
The symptoms caused by hypersensitivity reaction amplified at continuation of treatment and usually disappeared after the termination of reception of an abakavir.
Resuming of reception of an abakavir after reaction of hypersensitivity within several hours leads to bystry return of symptoms. The recurrence of reaction of hypersensitivity can carry heavier, in comparison with the first reaction, character and to be followed by a life-threatening lowering of arterial pressure (up to a lethal outcome). Patients who had such reaction of hypersensitivity have to stop and never resume administration of drug of Kiveks, and also any other medicines containing абакавир (Ziagen, Trizivir).
There are single messages on development of reaction of hypersensitivity after resuming of reception of the abakavir cancelled at emergence of separate key symptoms of hypersensitivity (rash, fever, a weakness/indisposition, gastrointestinal frustration or symptoms of defeat of a respiratory organs). It was seldom or never reported about development of reaction of hypersensitivity after resuming of administration of drug by patients at whom before symptoms of hypersensitivity it was not noted.
Treatment
Patients, regardless of the HLA-B*5701-status which had signs and symptoms of hypersensitivity HAVE TO see immediately the attending physician behind consultation. At diagnosis of hypersensitivity it is NECESSARY to stop administration of drug of Kiveks immediately. NEVER it is NECESSARY to resume treatment by Kiveks's drug and other medicines containing абакавир (such as Ziagen, Trizivir), after hypersensitivity reaction emergence. It is connected with threat of emergence within several hours after resuming of administration of drug of the expressed symptoms (including life-threatening hypotension) which can lead to a lethal outcome.
For prevention of the delayed identification and decrease in risk of development of hypersensitivity, life-threatening, it is necessary to stop completely administration of drug of Kiveks at impossibility of an exception of hypersensitivity, even at potential existence of other diseases (diseases of a respiratory organs, grippopodobny diseases, a gastroenteritis, reactions to reception of other medicines). It is not necessary to resume treatment by Kiveks's drug and other medicines containing абакавир (such as Ziagen, Trizivir), even in case of symptoms of hypersensitivity at repeated reception of other medicines.
The warning card with information for patients on reaction of hypersensitivity is in packaging.
Special instructions on treatment after a break in therapy by Kiveks's drug.
In case of the treatment termination, regardless of HLA-B*5701 allele carriage, Kiveks's drug, before resuming of administration of drug it is necessary to study carefully a cause of failure from use of drug and to be convinced of absence at the patient of symptoms of reaction of hypersensitivity. It is not necessary to resume administration of drug of Kiveks and other medicines containing абакавир (such as Ziagen, Trizivir), at impossibility of an exception of reaction of hypersensitivity.
Not numerous cases of development of reaction of hypersensitivity when resuming treatment are described the abakaviry ambassador of his cancellation in connection with emergence any one of typical symptoms of hypersensitivity (rash, fever, an indisposition, fatigue, gastrointestinal disturbances and disturbances from respiratory system). As in all such cases it is impossible to exclude reaction of hypersensitivity and, in view of data on its heavier current at repeated use of an abakavir, therapy resuming by Kiveks's drug or абакавир at these patients it is not recommended by the containing drug (such as Ziagen, Trizivir) to others.
Reaction of hypersensitivity was noted, though is extremely rare, even when resuming treatment by this drug by patients at whom symptoms of this reaction were not observed earlier, and having rummaged in reception of the drug containing абакавир was connected with other reasons. In that case resuming of administration of drug is possible, however demands existence from the patient or people of bystry access to medical care surrounding it.
It is recommended to carry out screening on a carriage of an allele of HLA-B*5701 before repeated purpose of the abakavir-containing drug at the patients with the unknown HLA-B*5701-status who were earlier well transferring therapy by the abakavirom-containing drug.
Repeated purpose of the abakavir-containing drug is not recommended to patients carriers of an allele of HLA-B*5701 and can be considered only in exceptional cases under careful medical control when the potential advantage of treatment by drug outweighs all possible risks.
Important information for patients
The doctor appointing drug has to be convinced that information on reaction of hypersensitivity given below is brought to the attention the patient in full:
Patients have to be warned about risk of development of reaction of hypersensitivity on абакавир which can lead to emergence of life-threatening complications or death, and also about the increased risk of reaction of hypersensitivity at HLA-B*5701 allele carriers.
The patient needs to be warned that even in the absence of an allele of HLA-B*5701 hypersensitivity reaction can develop. Thus, ALL patients at emergence of symptoms which can be caused by hypersensitivity reaction have to see the attending physician immediately.
Patients with hypersensitivity to an abakavir never have to accept Kiveks's drug and other medicines containing абакавир (such as Ziagen, Trizivir) regardless of the HLA-B*5701-status.
In order to avoid risk of resuming of administration of drug patients at whom hypersensitivity reaction was noted have to return the remained tablets to the doctor who appointed this drug.
The patients who stopped administration of drug of Kiveks for any reason (for example, in connection with development of side effects) before resuming of administration of drug have to consult with the attending physician.
Each patient has to get acquainted with the Warning card which is applied to drug. Patients should remind that they have to have always at themselves the Warning card which is applied to drug.
Lactoacidosis, hepatomegalia and fatty dystrophy of a liver
When using the anti-retrovirus nukleozidny analogs (including an abakavira and a lamivudina) accepted as separately, and in a combination development of lactoacidosis, a hepatomegalia and heavy fatty dystrophy of a liver, including the cases which ended with a lethal outcome was noted. The similar phenomena were noted, mainly, at women.
Clinical signs of the developing lactoacidosis are: general weakness, anorexia, sudden causeless decrease in body weight, symptoms of defeat of a respiratory organs (asthma, hurried breathing) and digestive tract.
It is necessary to be careful at purpose of drug of Kiveks to all patients, in particular what have risk factors of damage of a liver. Administration of drug 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 level of aminotransferases belong).
Lipodystrophy
At some patients to whom the combined anti-retrovirus therapy was carried out, redistribution/accumulation of fat in an organism, increase in amount of fat on the back surface of a neck and back ("buffalo hump"), reduction of number of peripheral fatty deposits, emaciation of the person, increase in mammary glands, increase in level of glucose and level of lipids in serum was noted.
The lipodystrophy can develop at reception of any drugs from a class of inhibitors of proteases or nukleozidny inhibitors of the return transcriptase. However, the available data demonstrate that the risk of development of these side effects at reception of different drugs of the specified classes is not identical.
Besides, development of a lipodystrophy is promoted by a set of factors. Important and, perhaps, a mutually exponential role is played by existence of HIV infection, advanced age and duration of performing anti-retrovirus therapy.
During clinical inspection it is necessary to pay attention to signs of redistribution of fat in an organism. It is necessary to watch closely the level of lipids in serum and blood glucose level. If necessary carry out the corresponding treatment of disturbances of a lipometabolism.
Patients with the accompanying viral hepatitis In
Clinical trials and post-marketing data on use of a lamivudin demonstrate that some patients with the accompanying viral hepatitis of B (HBV) can have clinical or laboratory signs of a recurrence of hepatitis after the termination of reception of a lamivudin. The termination of reception of a lamivudin can have more serious consequences at patients with dekompensirovanny damage of a liver. Thereof at patients with the accompanying viral hepatitis In at drug withdrawal of Kiveks it is necessary to control indicators of functional hepatic trials and to regularly determine the level of replication of a virus of hepatitis B.
Immunity recovery syndrome
In the presence at HIV-positive patients with a heavy immunodeficiency of asymptomatic or oligosymptomatic opportunistic infections at the time of the beginning of anti-retrovirus therapy can lead (ART), performing such therapy to strengthening of symptomatology of opportunistic infections or other serious consequences. Usually these reactions arise within the first weeks or months after the beginning the ART. Typical examples are the Cytomegaloviral retinitis, the generalized or focal infection caused by mycobacteria, and pneumonia, the caused Pneumocystis jiroveci (P. carinii). Emergence of any symptoms of an inflammation demands immediate inspection and, if necessary, treatment.
Opportunistic infections
Use of drug of Kiveks or other anti-retrovirus drugs does not exclude a possibility of development of opportunistic infections or other complications of HIV infection therefore patients have to remain under observation of the doctor having experience of treatment of these diseases.
Transmission of infection
Modern anti-retrovirus therapy, including Kiveks's drug, does not interfere with transfer of HIV at sexual contacts or contact with the infected blood. It is necessary to remember need of observance of the appropriate measures of safety.
Myocardial infarction
As a result of a prospective, observation, epidemiological research for the purpose of studying of frequency of developing of a myocardial infarction communication previous, within 6 months, reception of an abakavir with the increased risk of development of a myocardial infarction was found in the patients receiving the combined anti-retrovirus therapy. According to the generalized analysis of the clinical trials sponsored by the company Glaksosmitklyayn increase in risk of the myocardial infarction interfaced to reception of an abakavir was not observed. The biological mechanisms explaining potentially increased risk are unknown. Generally, the available data obtained from observation of cohorts and controlled clinical trials do not allow to define unambiguously therapy communication abakaviry and risk of a myocardial infarction.
Nevertheless, with care it is necessary to appoint anti-retrovirus therapy, including the drugs containing абакавир, to patients with possible risk of developing of coronary heart disease. Acceptance of all measures is necessary for minimizing risk factors (such as arterial hypertension, dislipidemiya, diabetes mellitus and smoking).
Influence on ability of concentration of attention at control of motor transport/mechanisms
Special researches of influence of a lamivudin on ability of concentration of attention at control of motor transport/mechanisms were not conducted. It is improbable that drug will negatively influence ability to carry out the tasks demanding concentration of attention, motor or cognitive skills. Nevertheless, at assessment of ability of the patient to concentrate attention it is necessary to consider its general condition, and also the nature of side effects which can appear against the background of administration of drug of Kiveks.
Side effects:
As Kiveksa is the combined drug, manifestation of the side effects characteristic of an abakavir and a lamivudin is possible. For many listed below side effects remains not clear whether their emergence is connected with effect of active agents of this drug, simultaneous use of other medicines (which are applied to treatment of HIV), or they are manifestation of a basic disease.
Hypersensitivity to an abakavir
In the clinical trials conducted prior to screening on existence of an allele of HLA-B*5701 approximately at 5% of the patients accepting абакавир reaction of hypersensitivity which in rare instances led to a lethal outcome developed. This reaction is characterized by emergence of the symptoms testimonial of multiorgan defeat.
Almost at all patients who have hypersensitivity reactions fervescence and/or emergence of rash is observed (usually spotty and papular or urtikarny), however, cases of emergence of reaction of the hypersensitivity which was not followed by emergence of rash and fervescence are noted.
Symptoms of reaction of hypersensitivity can arise during treatment abakaviry at any time, however usually they appear within the first six weeks from the moment of the beginning of administration of drug (the average value makes 11 days).
Signs and symptoms of reaction of hypersensitivity are listed below. The signs and symptoms noted not less than at 10% of patients with hypersensitivity reaction are highlighted in bold type.
From skin: rash (usually spotty and papular or urtikarny)
From digestive tract: nausea, vomiting, diarrhea, an abdominal pain, ulcerations in an oral cavity
From respiratory system: short wind, cough, pharyngalgia, respiratory distress syndrome, respiratory insufficiency
From a nervous system: headache, paresthesias.
From system of blood: lymphopenia.
From gepatobiliarny system: increase in indicators of functional trials of a liver, liver failure
From a musculoskeletal system: mialgiya, seldom myolysis, arthralgia, increase in level of a kreatinfosfokinaza.
From an urinary system: increase in level of creatinine, renal failure.
Others: temperature increase, feeling of fatigue, indisposition, hypostasis, lymphadenopathy, lowering of arterial pressure, conjunctivitis, anaphylaxis.
Patients with hypersensitivity reaction can take it for a disease of a respiratory organs (pneumonia, bronchitis, pharyngitis, a respiratory viral infection), a gastroenteritis or for the undesirable reactions connected with reception of other drugs in the beginning. Continuation of administration of drug of Kiveks at development of reaction of hypersensitivity the same as resuming of its reception after subsiding of symptoms, is fraught with grave consequences, up to death. Therefore at emergence of any of the listed symptoms careful inspection of the patient is necessary for a hypersensitivity reaction exception. If it is impossible to exclude hypersensitivity reaction, then repeated purpose of drug of Kiveks or other abakavir-containing drugs (such as Ziagen, Trizivir), strictly contraindicated.
If at hypersensitivity reaction development patients continue to accept Kiveks's drug, then clinical manifestations become more expressed, and at drug withdrawal of Kiveks they usually are exposed to involution.
Resuming of administration of drug of Kiveks by patients with reaction of hypersensitivity in the anamnesis leads to development of repeated reaction within several hours. Repeated reaction of hypersensitivity can proceed more hard, than the first and be shown by life-threatening arterial hypotonia, up to a lethal outcome. At hypersensitivity reaction development the patient, regardless of HLA-B*5701 allele carriage, has to refuse forever the use of drug of Kiveks and other drugs containing абакавир (such as Ziagen, Trizivir).
Sometimes reaction of hypersensitivity develops when resuming therapy by drug after its cancellation caused by emergence of only one of the main symptoms of this reaction (rash, fever, an indisposition, fatigue, disturbances from digestive tract or respiratory system).
In rare instances this reaction arises when resuming administration of drug of Kiveks by patients at whom before drug withdrawal no symptoms of hypersensitivity were noted.
Side effects of an abakavir or lamivudin are given below in tables and grouped in systems of an organism and absolute frequency. Side effects share on: very widespread (> 1/10), extended (> 1/100, <1/10), not widespread (> 1/1,000, <1/100), rare (> 1/10,000, <1/1000) and very rare (<1/10,000).
Many of the presented side effects (nausea, vomiting, diarrhea, temperature increase, apathy, rash) often arise at patients with hypersensitivity to an abakavir. Therefore patients with any of these symptoms should be inspected carefully for the purpose of a hypersensitivity reaction exception. If administration of drug of Kiveks was stopped in connection with emergence of one of these symptoms, and, then, the decision on resuming of reception of an abakavir was made, it should be begun only under direct observation of the doctor.
Data of clinical trials
System of an organism Abakavir Lamivudin
Disturbances in circulatory and Not widespread: neutropenia,
to lymphatic system anemia, thrombocytopenia
Disturbances in immune system Widespread:
hypersensitivity to
to drug
Disturbances of metabolism and Widespread: anorexia
frustration of food
Defeats of a nervous system Widespread: headache Widespread: headache
Gastrointestinal Widespread: nausea, Widespread: nausea, vomiting,
frustration vomiting, diarrhea upper part pain
stomach, diarrhea
Gepatobiliarny disturbances Not widespread: temporary
increase in enzymes of a liver (nuclear heating plant, ALT)
Damages of skin and Widespread: rash
hypodermic fabrics
Disturbances of the general state Widespread: increase Widespread: feeling
and disturbances, connected temperatures, apathy, fatigue, indisposition,
with way of introduction feeling of fatigue temperature increase
Post-registration data
System of an organism Abakavir Lamivudin
Disturbances in circulatory Very rare: true
and lymphatic system erythrocyte aplasia
Disturbances of metabolism and Widespread: giperlaktatemiya Widespread: giperlaktatemiya
frustration of food Rare: lactoacidosis Rare: lactoacidosis
Defeats of a nervous system Very rare: paresthesias, it is described
peripheral neuropathy
(though a causal relationship with treatment
it is not established)
Gastrointestinal Rare: pancreatitis, however Rare: increase in level
frustration a causal relationship with abakaviry serumal amylase, pancreatitis
it is not established (though a causal relationship with lamivudiny
it is not established)
Damages of skin and Widespread: rash (without Widespread: alopecia
hypodermic fabrics of system symptoms) Very much
rare: exudative
mnogoformny erythema, syndrome
Stephens-Johnson, toxic
epidermal necrolysis
Defeats musculoskeletal Widespread: arthralgia,
device and connecting damages of muscles
fabrics Rare: рабдомиолиз
At some patients to whom the combined anti-retrovirus therapy was carried out redistribution/accumulation of fat in an organism was observed. Frequency of this phenomenon depends on many factors, including on a combination of anti-retrovirus drugs. Lactoacidosis cases were noted.
Interaction with other medicines:
The range of interactions of drug of Kiveks is caused by the nature of interactions of an abakavir and lamivudin among which, today, clinically significant are not revealed. Abakavir and ламивудин are slightly metabolized by enzymes of system of P450 cytochrome (for example: CYP 3A4, CYP 2C9 or CYP 2D6) have also no the inhibiting or inducing effect on this fermental system. Therefore the probability of interaction of drug with anti-retrovirus nenukleozidny inhibitors of proteases and other medicines which metabolism happens with the participation of the main enzymes of system of P450 cytochrome is small.
The probability of metabolic interactions with lamivudiny is low as it is a little metabolized, badly contacts proteins of plasma and is removed almost only by kidneys. Lamivudin is brought, mainly, by means of active organic cationic secretion. It is necessary to consider a possibility of interaction with other medicines, especially when kidneys are the main way of removal of drugs.
The medicinal interactions caused by existence of an abakavir
Ethanol
Metabolism of an abakavir is broken at a concomitant use with ethanol that leads to increase in AUC of an abakavir approximately by 41%. Considering a profile of safety of an abakavir, these data are not regarded as clinically significant. Abakavir does not exert impact on ethanol metabolism.
Methadone
In a research of pharmacokinetics of drugs at a concomitant use of an abakavir (in a dose of 600 mg twice a day) and methadone reduction of Cmax of an abakavir by 35% and reduction of tmax for one hour was noted, however AUC remained invariable. Changes of pharmacokinetics of an abakavir were not recognized as clinically significant. In this research абакавир increased average general clearance of methadone for 22%. This change was not recognized clinically significant at most of patients, however there can sometimes be a need for methadone dose adjustment.
The medicinal interactions caused by existence of a lamivudin
Trimethoprimum
Reception of Trimethoprimum / сульфаметаксозола 160 mg / 800 mg (co-trimoxazole) causes increase in exposure of a lamivudin for 40% that is caused by existence of Trimethoprimum. However, except for patients with a renal failure, dose adjustment of a lamivudin is not required. Lamivudin does not exert impact on pharmacokinetics of Trimethoprimum and a sulfametaksozol. Combined use of a lamivudin with higher doses of the co-trimoxazole used for treatment of the pneumonia (caused by Pneumocystis carinii) and a toxoplasmosis is not studied.
Zaljtsitabin
Lamivudin can suppress intracellular phosphorylation of a zaltsitabin at a concomitant use of these drugs. In this regard, it is not recommended to accept Kiveks's drug in combination with zaltsitabiny.
Contraindications:
Hypersensitivity to an abakavir or a lamivudin, or other components of drug.
Abnormal liver functions of moderate and heavy degree.
Age less than 12 years (lack of a possibility of dose adjustment).
Use at pregnancy and a lactation
Pregnancy
Safety of use of drug of Kiveks at pregnant women is not established. Data in reproductive researches of a lamivudin and abakavir on animals were obtained. In this regard, the question of purpose of drug during pregnancy has to be considered only if the advantage for mother exceeds possible risk for a fruit. Drug should be used according to the current recommendations about use of anti-retrovirus therapy at pregnant women for the purpose of prevention of vertical transfer of HIV.
Lactation
As HIV gets into breast milk, women are not recommended to nurse the child in order to avoid transfer of a virus to the child through breast milk. Lamivudin is allocated with milk in the concentration close to concentration in blood serum. It is expected that абакавир it will also be allocated with milk though it is not confirmed.
Overdose:
Symptoms. Symptoms of acute overdose of an abakavir and a lamivudin correspond to the symptoms listed in the section "Side effect".
Treatment. In case of overdose the patient has to be under observation of the doctor (for the purpose of identification of signs of toxic effect of drug). If necessary carry out a standard maintenance therapy. Because ламивудин it can be brought out of an organism by dialysis, treatment of overdose has to include a continuous hemodialysis (though researches for the purpose of studying of opportunities of a hemodialysis at overdose of drug were not conducted). Now it is not known whether peritoneal dialysis and a hemodialysis promote removal from an organism of an abakavir.
Storage conditions:
Period of validity 3 years. Not to use after the expiry date specified on packaging. At a temperature not above 30 °C. To store in the place, unavailable to children.
Issue conditions:
According to the recipe
Packaging:
Tablets, film coated, 600 mg +300 mg.
On 10 tablets in the blister from PVC/PVDH / aluminum foil. On 3 blisters with the application instruction and an individual card of the patient with information on reactions of hypersensitivity in a cardboard pack or
On 30 tablets in the bottles from polyethylene of high density corked by covers with the device against opening of a bottle by children. On 1 bottle with the application instruction and an individual card of the patient with information on reactions of hypersensitivity in a cardboard pack.
