Ziagen

General characteristics. Structure:

Aktivyne of substance: абакавир (in the form of an abakavir of sulfate) 20 mg;
excipients: sorbite; sodium saccharin; sodium citrate; citric acid; methylparahydroxybenzoate; propylene glycol; fragrances with a smell of banana and strawberry; the purified water
in bottles on 240 ml, complete with the dosing syringe and the adapter for the syringe; in a box 1 bottle.

Description
Transparent or slightly opalescent slightly yellowish solution with a fruit smell.

Pharmacological properties:

Pharmacodynamics. At the received in vitro of strains VICh-1 steady against an abakavir, mutations in several codons of a gene of the return transcriptase (RT) - M184V, K65R, L74V and Y115F were found. Resistance of HIV to an abakavir of in vitro forms slowly. For clinically significant increase in the inhibiting concentration (IC50) (increase in IC50 by 8 times of rather "wild" virus strain) multiple mutations are required. The strains steady against an abakavir can have reduced sensitivity to a lamivudin, a zaltsitabin and a didanozin, but completely keep sensitivity to a zidovudine and a stavudin. Cross resistance to an abakavir and inhibitors of HIV protease or nenukleozidny inhibitors of the return transcriptase is improbable. Inefficiency of the mode of the first line including абакавир ламивудин and a zidovudine, is preferential connected with a single mutation - M184V that keeps a possibility of a wide choice of therapy of the second line.
Abakavir gets into cerebrospinal fluid (SMZh) and reduces the content of VICh-1 RNA in it. In combination with other anti-retrovirus drugs it can prevent development of neurologic complications of HIV infection and slow down emergence of resistant strains within TsNS.
According to a research, at 20 HIV-positive people is the patients accepting абакавир in a dose of 300 mg 2 times a day and only one dose (300 mg) before the 24-hour period of collecting tests for the analysis, average geometrical value of a terminal elimination half-life (T1/2) intracellular karbovira-TF (triphosphate) in an equilibrium state makes 20,6 h (a similar indicator for concentration of an abakavir in serum - 2,6 h). Equilibrium pharmacokinetic indicators at reception of an abakavir of 600 mg of 1 times a day were identical with those at reception of an abakavir of 300 mg twice a day in cross clinical trial at 27 HIV-positive patients. Intracellular contents karbovira-TF in mononukleara of peripheral blood was higher at use of an abakavir in a dose than 600 mg of 1 times 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%, the maximum daily concentration in equilibrium state (Cmax, 24, ss) - for 99% that testifies to a possibility of purpose of such mode of administration of drug to HIV-positive patients. Efficiency and safety of the drug Ziagen® on condition of a single dose of a daily dose was shown in clinical trial (CNA30021).
Action mechanism
Abakavir - the nukleozidny analog inhibiting the HIV return transcriptase and selectively suppressing replication of VICh-1 and VICh-2, including VICh-1 strains steady against a zidovudine, a lamivudin, a zaltsitabin, a didanozin and not Virapinum. Abakavir is exposed to intracellular metabolism, turning into an active form, карбовир-5-triphosphate (TF). According to the researches in vitro, antiviral effect of drug is caused by inhibition of the HIV return transcriptase that leads to break of synthesis of virus DNA on a matrix of RNA and a stop of replication of HIV. In the conditions of in vitro абакавир works synergistically with not Virapinum and a zidovudine and shows the additive effect with didanoziny, zaltsitabiny, lamivudiny and stavudiny.

Pharmacokinetics. Absorption
Abakavir is quickly and well soaked up at intake. Absolute bioavailability of an abakavir at intake at adults makes about 83%. Time of achievement of the maximum concentration (Tmax) at reception of an abakavir inside in the form of tablets makes about 1,5 h, and in the form of solution - about 1 hour. The area under a curve "concentration time" (AUC) for the tableted form of an abakavir does not differ from that for an abakavir in the form of solution for intake. At reception of an abakavir inside in a dose of 300 mg 2 times in days of Cmax at achievement of an equilibrium state average 3 mkg/ml, and AUC within 12 hours between reception of doses - on average 6,02 mkg of h/ml. After a single dose of tablets of an abakavir in a dose of 600 mg of Cmax averages about 4,26 mkg/ml, and AUC - on average 11,95 mkg of h/ml.
Meal slows down absorption of an abakavir and reduces Cmax, but does not influence AUC. Therefore абакавир it is possible to accept both with food, and without it.
Distribution and linkng with proteins of a blood plasma
The volume of distribution of an abakavir at intravenous administration makes about 0,8 l/kg that testifies to its ability easily to get into fabrics.
In researches at HIV-positive patients it is shown what абакавир well gets into cerebrospinal fluid, at the same time the ratio of AUC of an abakavir in SMZh to AUC of an abakavir in plasma makes 30? 44%. In a pharmacokinetic research I of a phase it was established that in 1,5 hours after reception of an abakavir in a dose of 300 mg 2 times a day its concentration in SMZh made 0,14 mkg/ml. At use of an abakavir in a dose of 600 mg 2 times a day concentration of drug in SMZh increased from 0,13 mkg/ml in 30 minutes? 1 h after reception to 0,74 mkg/ml at its measurement through 3? 4 h after reception of an abakavir. Thus, even if the concentration of an abakavir observed in SMZh in 4 hours after administration of drug in a dose of 600 mg 2 times a day is not the therapy which is most reached at such mode, it already exceeds IC50 (0,08 mkg/ml or 0,26 µmol/l) by 9 times.
In the researches in vitro it is established what in therapeutic doses абакавир moderately (approximately for 49%) contacts proteins of a blood plasma of the person. It demonstrates that interaction of an abakavir with other drugs by their replacement from connection with proteins of plasma is improbable.
Metabolism
Abakavir is metabolized preferential in a liver and in kidneys, in not changed look less than 2% of the accepted drug dose are allocated. In a human body абакавир 5 glucuronides making about 66% of total quantity of the 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. These metabolites are excreted with urine.
Removal
The elimination half-life of an abakavir averages about 1,5 h. Long reception of an abakavir inside in a dose of 300 mg 2 times a day does not lead to significant cumulation of drug. Removal of an abakavir is carried out by means of metabolism in a liver with the subsequent excretion of metabolites preferential kidneys. About 83% of the entered dose are removed by kidneys in the form of metabolites and an abakavir in an invariable look, and the remained quantity is removed by intestines.
Special groups of patients
Children
Abakavir is well and quickly soaked up at intake at children. All pharmacokinetic parameters at children are comparable to such indicators at adults with slightly bigger variability of plasma concentration. Pharmacokinetic researches at children showed that administration of drug of 1 times a day is equivalent on AUC0-24 indicators to the reception of the same dose of drug divided into two times a day for the existing dosage forms of the drug Ziagen® (solution for intake and a tablet, film coated). It will provide slightly higher average concentration of drug at children in plasma, guaranteeing that at the majority therapeutic concentration will be equivalent to the mode of dosing of 300 mg two times a day at adults.
There are no sufficient data on safety to recommend use of an abakavir for children 3 months are younger. There are limited data showing that the dose of 2 mg/kg at newborns is younger than 30 days provides similar or bigger value of indicators of AUC in comparison with a dose of 8 mg/kg at children of advanced age.
Elderly people
The pharmacokinetics of an abakavir at patients is more senior than 65 years was not studied. At treatment of elderly patients it is necessary to consider more frequent abnormal liver function, kidneys and heart at this age, and also associated diseases and the accepted medicines.
Patients with a renal failure
Abakavir is metabolized preferential in a liver; less than 2% it are removed by kidneys in not changed look. Pharmacokinetics of an abakavir in an end-stage of a renal failure approximately same, as at normal function of kidneys. Therefore at a renal failure of dose adjustment it is not required.
Patients with an abnormal liver function
Abakavir is metabolized generally in a liver. Results of a research of pharmacokinetics of an abakavir at patients with the compensated cirrhosis (5? 6 points on a scale of Chayld-Pyyu) demonstrate increase in AUC on average by 1,89 time and an elimination half-life by 1,58 times. The abnormal liver function does not influence an indicator of AUC of metabolites of an abakavir, however the speed of their education and removal at the same time decreases.
Patients with an abnormal liver function of easy severity in the therapeutic purposes can accept 200 mg of an abakavir 2 times a day.
The pharmacokinetics of an abakavir at patients with abnormal liver functions of moderate and heavy degree was not studied, thus, use of an abakavir contraindicated at these groups of patients.
Clinical performance
The analysis of data of a randomized double blind comparative research of combinations of the drug Ziagen® with lamivudiny both a zidovudine and an indinavira with lamivudiny and a zidovudine, applied within 48 weeks at the adult HIV-positive patients who were earlier not receiving anti-retrovirus therapy showed comparable virologic efficiency of the compared combinations. However in subgroup of patients with the VICh-1 RNA initial level in serum exceeding 100 000 copies/ml, the mode containing индинавир was more effective. At the initial level of virus RNA less than 100000 copies/ml efficiency of both modes was identical.
In a multicenter double blind controlled research (CNA30021) including 770 HIV-positive patients who were earlier not accepting anti-retrovirus drugs comparison of the single and double modes of a drug dosing of Ziagen® was carried out. Patients were randomizirovana in two groups. In the first Ziagen® group appointed in a dose 600 mg of 1 times a day, in the second - 300 mg 2 times a day; along with the drug Ziagen® patients in both groups received ламивудин in a dose 300 mg of 1 times a day and эфавиренз in a dose of 600 mg of 1 times a day. Depending on the initial level of virus RNA in blood serum - 2 subgroups of patients were allocated: with the VICh-1 RNA level no more than 100 000 copies of ml and with the VICh-1 RNA level more than 100 000 copies/ml. Duration of treatment made not less than 48 weeks. Results of a research are given below. 

Share of patients with the VICh-1 RNA level in blood serum less than 50 copies/ml in 48 weeks after an initiation of treatment (ITT analysis)

Subgroups of patients with a miscellaneous   of RNA of Group of patients
initial level of virus      Ziagen® (1 times a day) +             Ziagen® (2 times a day) + ламивудин
                                              ламивудин + эфавиренз (N = 384)   + эфавиренз (N = 386)
Less than 100 000 copies/ml           141/217 (65%)                       145/217 (67%)
More than 100 000 copies/ml           112/167 (67%)                       116/169 (69%)
Total number of patients            253/384 (66%)                       261/386 (68%)

Thus, it was shown that the mode of a drug dosing Ziagen® does not influence efficiency of treatment neither in the general population of patients, nor in subgroups with the different initial level of virus loading. Frequency of the undesirable phenomena was identical in both groups of the patients accepting Ziagen® in a dose of 600 mg of 1 times a day or 300 mg 2 times a day.
At patients with virologic inefficiency of therapy (concentration of VICh-1 RNA more than 50 copies/ml by 48th week of therapy) the genotypic analysis of isolates of a virus was carried out. Frequency of virologic inefficiency was low - at 10% and 8% of patients in the groups accepting Зиаген® 600 mg 1 and 2 times a day respectively. Stability to nukleozidny inhibitors of the return transcriptase was most often caused by mutations in the 184th codon (M184V or M184I). L74V mutation was the second for frequency. Mutations of Y115F and K65R were most less often noted.
The comparative research of three combinations of the nukleozidny inhibitors of the return transcriptase (an abakavir with lamivudiny, an abakavira with a zidovudine or a lamivudina with a zidovudine) accepted by children in combination with nelfinaviry or placebo, showed that the abakavir-containing modes authentically surpass in efficiency a combination of a lamivudin with a zidovudine. It was established that decrease in concentration of VICh-1 RNA less than 400 copies/ml in 24 weeks of therapy was observed at 73% in group of the children accepting a combination of an abakavir with lamivudiny at 70% of the children accepting абакавир with a zidovudine and only at 44% of the children accepting ламивудин with a zidovudine.
The combination of an abakavir with lamivudiny and a zidovudine at the children who were earlier receiving various modes of highly active anti-retrovirus therapy (VAART) was characterized by moderate, but lasting antiviral effect. At the patients who were earlier receiving VAART, degree of efficiency of the drug Ziagen® depends on the scheme and duration of the previous treatment which could lead to formation of cross resistance to the drug Ziagen®.

Indications to use:

Treatment of HIV infection at adults and children as a part of the combined anti-retrovirus therapy.

Route of administration and doses:

Inside.
Drug has to be appointed by the doctor having experience of treatment of HIV infection. Зиаген® it is possible to apply irrespective of meal.
To children and adults to whom administration of drug of Ziagen® in tablets is not shown or to patients in whom the proglatyvaniye of a tablet causes difficulties appoint Ziagen® in the form of solution for intake.
Adults and teenagers with body weight more than 30 kg
The recommended drug Ziagen® dose - 300 mg (15 ml) 2 times a day or 600 mg (30 ml) of 1 times a day.
Special groups of patients
Children
Aged from 3 months weighing up to 30 kg is also more senior
The recommended dose - 8 mg/kg 2 times a day or 16 mg/kg of 1 times a day. The maximum daily dose - 600 mg (30 ml).
Aged up to 3 months
Data on use of the drug Ziagen® in this age group are very limited.
Patients with a renal failure
Correction of the mode of dosing is not required.
Patients with an abnormal liver function
Abakavir is metabolized preferential in a liver. The recommended drug Ziagen® dose for patients with abnormal liver functions of easy severity (5? 6 points on a scale of Chayld-Pyyu) make 200 mg (10 ml of solution) 2 times a day. Considering need of use of smaller doses of the drug Ziagen® for patients with abnormal liver functions of easy degree, for a correct drug dosing it is appointed in the form of solution for intake. Administration of drug of Ziagen® is contraindicated to patients with abnormal liver functions of moderate and heavy degree as the drug pharmacokinetics in this population of patients is not studied.

Features of use:

Drug has to be appointed by the doctor having experience of treatment of HIV infection.
Hypersensitivity
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 the carriage of an allele of HLA-B*5701 is associated with significant increase in 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 the drugs containing абакавир were not appointed that allowed to reduce significantly the frequency of emergence of clinically suspected reaction 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 reaction of the 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 at 48? 61% of patients carriers of an allele of HLA-B*5701 develop reaction of hypersensitivity in comparison with 0? 4% of patients at whom this allele is absent.
Doctors 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 is recommended to be carried out prior to repeated purpose of an abakavir at patients with the unknown HLA-B*5701-status who earlier well transferred therapy abakaviry.
Use of the abakavir-containing drugs is not recommended at the patients having HLA-B*5701 allele. In exceptional cases, when the potential advantage exceeds risk, purpose of the abakavir-containing drugs at such patients can be discussed, at the same time the patient has to be under careful medical observation.
The clinical diagnosis of the suspected reaction of hypersensitivity has to remain a basis for making decision on 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
Hypersensitivity to an abakavir is characterized by emergence of the symptoms indicating multiorgan defeat. Most of patients note fever and/or rash as a part of a syndrome.
Other symptoms of hypersensitivity to an abakavir are fatigue, an indisposition, disturbances from digestive tract, including vomiting, nausea, diarrhea and an abdominal pain; disturbances from respiratory system, including an asthma, a pharyngalgia, cough, damage of lungs (generally in the form of the local infiltrative changes revealed at a thorax X-ray analysis). Symptoms of hypersensitivity can appear after an initiation of treatment abakaviry at any time, however most often they arise within the first six weeks.
If at hypersensitivity reaction development patients continue to accept the drug Ziagen®, then clinical manifestations become more expressed and can accept life-threatening character. In most cases similar symptoms disappear at the drug Ziagen® termination.
Treatment
At emergence of symptoms of hypersensitivity to an abakavir, the patient, regardless of a carriage of an allele of HLA-B*5701, DOLZHEN NEMEDLENNO to see the attending physician behind consultation. Diagnosis of reaction of hypersensitivity to an abakavir demands immediate drug withdrawal. Treatment resuming by the drug Ziagen® or other drug containing абакавир (such as Kiveksa, Trizivir®), at patients with reaction of hypersensitivity in the anamnesis is strictly contraindicated as within several hours after administration of drug perhaps repeated development of reaction in more severe form, up to life-threatening arterial hypotension or a lethal outcome.
If it is impossible to exclude hypersensitivity to an abakavir, then in order to avoid late diagnosis and for minimization of risk of development of life-threatening states абакавир cancel forever even if other diagnosis is possible (for example a respiratory disease and lungs, a grippopodobny syndrome, a gastroenteritis or undesirable effect of other drugs). Treatment resuming by the drug Ziagen® or other drug containing абакавир (such as Kiveksa, Trizivir®), inadmissibly even if repeated development of symptoms of hypersensitivity is noted when resuming reception of other drugs used together with the medicine containing абакавир.
The precautionary card with information for patients on reaction of hypersensitivity to an abakavir has to be included in the package of packaging of the drug Ziagen®.
Special instructions on treatment after a break in therapy by the drug Ziagen®
Regardless of HLA-B*5701 allele carriage if after drug withdrawal of Ziagen® treatment resuming is supposed this drug, it is necessary to find out the reason of cancellation and to be convinced that at the patient hypersensitivity symptoms were not observed. If it is impossible to exclude hypersensitivity reaction, then treatment by the drug Ziagen® or other drug containing абакавир (such as Kiveksa, Trizivir®), it is forbidden.
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 the drug Ziagen® or other abakavir-containing drug (such as Kiveksa, Trizivir®) at these patients is not recommended. However, if in such cases the issue of repeated purpose of an abakavir is resolved positively, then treatment by him is carried out only at direct medical observation.
Reaction of hypersensitivity is noted, though is extremely rare, even when resuming treatment by the abakavir-containing drug at patients at whom symptoms of this reaction were not observed earlier, and having rummaged in administration of 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.
Screening on a carriage of an allele of HLA-B*5701 is recommended to be carried out before repeated purpose of an abakavir at the patients with the unknown HLA-B*5701-status who were earlier well transferring therapy abakaviry. Repeated purpose of an abakavir 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 exceeds all possible risks.
Necessary information for patients
The doctor appointing drug has to inform the patient of the following information on hypersensitivity reaction:

• the patient has to be informed on a possibility of emergence of life-threatening symptoms of hypersensitivity and risk of a lethal outcome, and also on 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 have to be warned about the inadmissibility of resuming of use of the drug Ziagen® or other drugs containing абакавир (such as Kiveksa, Trizivir®), regardless of the HLA-B*5701-status;
• in order to avoid repeated use of the drug Ziagen® by the patients who transferred hypersensitivity reaction they are recommended to return the remained tablets of the drug Ziagen® or solution of the drug Ziagen® for intake to the doctor;
• the patients who for any reason interrupted treatment with the drug Ziagen® (especially in connection with possible undesirable reactions or complications of treatment), before resuming of administration of drug have to see the attending physician.
Remind each patient of need of acquaintance with the precautionary card enclosed in drug Ziagen® packaging. Besides, remind patients that the precautionary card needs to be taken out from packaging and to carry constantly with itself.

Precautionary card for the patient

Attention!

Зиаген®, solution for intake
абакавир
Always you carry with yourself this card

As Ziagen® contains абакавир, at some patients accepting Ziagen® hypersensitivity reaction (serious allergic reaction), quite often life-threatening can develop if not to cancel drug.
IMMEDIATELY SEE the ATTENDING PHYSICIAN behind consultation concerning a possibility of further administration of drug of Ziagen® if: 1.u you skin rash developed OR
1.u you one or more of the listed below symptoms appeared: likhoradka;
odyshka, pharyngalgias or cough;
toshnota or vomiting, abdominal pain, diarrhea;
povyshenny fatigue, pain or febricula.

If you stopped administration of drug of Ziagen® as a result of this reaction, ANY MORE NEVER ACCEPT Ziagen® or any other drug containing абакавир (Trizivir®, Kiveksa) as it can immediately lead to life-threatening falling of arterial pressure or by death.
Lactoacidosis, hepatomegalia and fatty dystrophy of a liver
There are messages on development of lactoacidosis, a hepatomegalia and fatty dystrophy of a liver, including with a lethal outcome, owing to anti-retrovirus therapy by analogs of nucleosides, including абакавир, ламивудин and a zidovudine, accepted as separately, and in a combination. In most cases these complications arise at women.
The symptoms indicating lactoacidosis include the general weakness, a loss of appetite, bystry weight loss of not clear etiology, disturbance from digestive tract and disturbance from respiratory system (an asthma and a tachypnea).
Use of the drug Ziagen® and other abakavir-containing drugs for any patient demands care, especially with risk factors of damage of a liver. At emergence of clinical or laboratory signs of lactoacidosis or a hepatotoxic (it can be shown by a hepatomegalia and fatty dystrophy of a liver even for lack of the expressed increase in activity of aminotransferases) treatment by the drug Ziagen® needs to be stopped.
Redistribution of a hypodermic fatty tissue
The combined anti-retrovirus therapy can be followed by development of one or several of the listed symptoms: obesity, redistribution of subcutaneous fat with its adjournment on a trunk, a neck ("a buffalo hump"), considerable reduction of a hypodermic fatty layer on extremities and a face, a gynecomastia, increase in concentration of lipids in serum and concentration of glucose in blood.
All these symptoms belong to manifestations of a lipodystrophy. One or several of these symptoms can arise at treatment by any inhibitors of HIV protease and nukleozidny inhibitors of the return transcriptase. However the risk of these undesirable reactions depends on the used drug. 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 synergistic role. The remote effects of the specified side effects are unknown now.
At clinical inspection of patients it is necessary to pay attention to redistribution of a hypodermic fatty tissue. Laboratory inspection has to include definition of concentration of lipids in serum and concentration of glucose in blood. At disturbance of lipidic exchange appoint the corresponding treatment.
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 performing such therapy can lead (ART) 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 the pneumonia caused by Pneumocystis jiroveci (before P. carinii). Emergence of any symptoms of an inflammation demands immediate inspection and, if necessary, treatment.
Opportunistic infections
Use of the drug Ziagen® 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.
Transfer of HIV infection
Performing anti-retrovirus therapy, including the drug Ziagen®, does not exclude a possibility of transfer of HIV sexually or at contact with the infected blood and therefore does not cancel need of observance of the appropriate measures of precaution.
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 clinical trials, increase in risk of the myocardial infarction connected with reception of an abakavir was not observed. The biological mechanisms explaining potentially increased risk are unknown. Generally, the available data obtained from cohort observations and controlled clinical trials do not allow to define unambiguously communication between therapy 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 minimization of all upgradeable risk factors (such as arterial hypertension, dislipidemiya, diabetes mellitus and smoking).
Influence on ability to manage vehicles, mechanisms
Data on influence of an abakavir on ability to manage motor transport and to handle mechanisms are not available.

Side effects:

Hypersensitivity
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 reaction, in rare instances from the death was noted. Hypersensitivity to an abakavir is characterized by multiorgan defeat.
At most of patients with hypersensitivity at development of this reaction fever and rash (usually makulopapulezny or urtikarny) are noted though in certain cases these manifestations are absent.
Symptoms of reaction of hypersensitivity can appear after an initiation of treatment abakaviry at any time, however most often they arise within the first 6 weeks of treatment (a median of time of the beginning of this reaction - 11 days).
Manifestations of reaction of hypersensitivity are given below. The symptoms meeting not less than at 10% of patients with hypersensitivity are highlighted in bold type.
From skin and appendages of skin: rash (usually makulopapulezny or urtikarny).
From digestive tract: nausea, vomiting, diarrhea, abdominal pain, ulceration of a mucous membrane of a mouth.
From respiratory system: short wind, cough, pharyngalgia, respiratory distress syndrome of adults, respiratory insufficiency.
From a nervous system: headache, paresthesias.
From system of a hemopoiesis and lymphatic system: lymphopenia.
From a liver and a pancreas: increase in activity of enzymes of a liver, liver failure.
From a musculoskeletal system: mialgiya, it is rare - рабдомиолиз, arthralgias, increase in activity of a kreatinfosfokinaza.
From an urinary system: increase in concentration of creatinine in serum, a renal failure.
Others: fever, feeling of fatigue, indisposition, hypostases, lymphadenopathy, arterial hypotonia, conjunctivitis, anaphylactic reactions.
Resuming of administration of drug of Ziagen® 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 life-threatening arterial hypotension, up to a lethal outcome.
The nature of other undesirable phenomena other than hypersensitivity reaction, but observed at the patients receiving Ziagen® up to the end is not clear. Whether these undesirable phenomena are a consequence of use of the drug Ziagen® or other drugs which are at the same time appointed with it, or they are caused by a disease, so far is not established.
Many of the undesirable phenomena given below connected with administration of drug of Ziagen® (nausea, vomiting, diarrhea, fever, fatigue, rash) can be observed also at hypersensitivity reaction development. Therefore at emergence of any of these symptoms careful inspection of the patient for confirmation or an exception of reaction of hypersensitivity is shown. The majority of the undesirable reactions given below do not limit drug Ziagen® use. The undesirable phenomena given below are listed depending on anatomo-physiological classification and frequency of occurrence. Frequency of occurrence is defined as follows: very often (≥1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10000 and <1/1000), is very rare (<1/10000, including separate cases). With undesirable reactions and syndromes which can arise against the background of anti-retrovirus therapy including analogs of nucleosides, it is possible to examine in the section "Special Instructions and Precautionary Measures at Use".
Data of clinical trials
Disturbances of metabolism and food: often - appetite loss.
Neurologic disturbances: often - a headache.
Gastrointestinal disturbances: often - nausea, vomiting, diarrhea.
System manifestations and local reactions: often - fever, drowsiness, fatigue.
In controlled clinical trials it was shown that change of laboratory indicators at treatment by the drug Ziagen® is observed also seldom, as well as in control group of the patients who are not receiving drug.
Data of post-registration observation
Disturbances of metabolism and food: often - a giperlaktatemiya; seldom - lactoacidosis, accumulation/redistribution of fatty tissue. Frequency of these undesirable reactions depends on many factors, including on the anti-retrovirus drugs used in a combination with abakaviry.
Disturbances from digestive tract: seldom - pancreatitis (relationship of cause and effect using an abakavir is definitely not established).
Disturbances from skin: often - rash (in the absence of system manifestations); very seldom - a polymorphic exudative erythema, including Stephens-Johnson's syndrome and a toxic epidermal necrolysis.

Interaction with other medicines:

The researches in vitro and the analysis of the main ways of metabolism of an abakavir indicate that its interaction with other drugs mediated by P450 cytochrome is improbable. Abakavir does not suppress metabolic reactions with participation of an isoenzyme 3A4 of P450 cytochrome. In the researches in vitro it is shown what абакавир does not enter interactions with drugs, metaboliziruyemy isoenzymes of CYP3A4, CYP2S9, CYP2D6. Clinical trials did not reveal induction of hepatic metabolism of exogenous substances under the influence of an abakavir. Thus, interaction of an abakavir with the inhibitors of HIV protease and other drugs which are metabolized with participation of the main isoenzymes of P450 cytochrome is improbable.
Ethanol: ethanol slows down metabolism of an abakavir that leads to increase in the area under pharmacokinetic curve (AUC) for 41%. However the clinical importance of this change is small. абакавир does not influence ethanol metabolism.
Methadone: according to pharmacokinetic researches, use of an abakavir in a dose of 600 mg 2 times a day in a combination with methadone reduce the maximum concentration (Cmax) of an abakavir in serum by 35%, increases time of achievement of the maximum concentration in serum (Tmax) by 1 h, but does not change AUC. The clinical importance of these changes is small. In the same research it is established what абакавир increases system clearance of methadone for 22%. In most cases these changes are also regarded as clinically insignificant, however in certain situations change of a dose of methadone can be required.
Retinoids: retinoids, for example изотретиноин, eliminirutsya with alcohol dehydrogenase participation therefore can enter interaction with abakaviry, however now special researches were not conducted.

Contraindications:

• Hypersensitivity to an abakavir or any other component of drug;
• abnormal liver functions of moderate and heavy degree;
• the age is younger than 3 months as experience of use of the drug Ziagen® in this age group is limited.
Use at pregnancy and a lactation
Pregnancy
Safety of use of an abakavir for women during pregnancy is not studied so far. There are experimental data about toxic influence of an abakavir on development of embryos of rats, however these effects were not reproduced at rabbits. In need of use of the drug Ziagen® during pregnancy it is necessary to estimate a ratio of estimated advantage for mother and potential risk for a fruit.
There are concentration of lactic acid given about slight tranzitorny increase in serum of newborns and children of chest age whose mothers during pregnancy and childbirth accepted nukleozidny inhibitors of the return transcriptase. Perhaps, it is connected with mitochondrial disturbances. The clinical importance of this phenomenon is not established so far. Besides, newborns have extremely rare messages on an arrest of development, epileptic attacks and other neurologic disturbances though relationship of cause and effect of these disturbances with reception of nukleozidny inhibitors of the return transcriptase by mothers during pregnancy and in labor is not established. These data do not cancel the existing recommendations about use of anti-retrovirus drugs during pregnancy for prevention of vertical transfer of HIV.
Lactation
Pilot studies on rats in the period of a lactation showed that абакавир and its metabolites are allocated with breast milk. It is supposed though it is not proved so far that абакавир and its metabolites get also into women's milk. Data on safety of use of an abakavir for children aged up to 3 months are absent. Some specialists recommend to HIV-positive women to avoid in any situations feeding of the child a breast to prevent his infection with HIV. Thus, the women applying абакавир are also not recommended to nurse the child.

Overdose:

Symptoms
In clinical trials undesirable reactions at use of the drug Ziagen® in single doses to 1200 mg and daily allowance to 1800 mg were not revealed. Effect of drug in higher doses is not studied so far.
Treatment
In case of overdose establish by the drug Ziagen® for patients observation for identification of symptoms of poisoning and an early treatment. If necessary carry out a symptomatic treatment. Efficiency of peritoneal dialysis and a hemodialysis for removal of an abakavir is unknown.

Storage conditions:

Period of validity 2 years. Not to apply 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:

Solution for intake, 20 mg/ml.
On 240 ml of drug in a bottle from polyethylene of high density with the screw-on cap equipped with protection against opening by children. On one bottle together with the adapter, the dosing syringe and the application instruction in a cardboard pack.