Ziagen

General characteristics. Structure:

Active agent: Abakavira sulfate it is equivalent to an abakavir of 300 mg

Excipients:

Cellulose microcrystallic 414,6mg 
Karboksimetilkrakhmal of sodium, A 24 type 
Magnesium mg stearate 8  
Silicon dioxide colloid bezvodnyy1 2,4 
Film cover
Опадрай yellow 142 mg

Structure of a film cover:

Color of Opadraya Name of the Quantity components, mg
Yellow Gipromelloza 8,4
Titanium dioxide 3,6
Triacetin 1,1
Ferrous oxide yellow 0,9
Polysorbate 80 0,1

 

Notes:
1 The amount of silicon of dioxide of colloid anhydrous can fluctuate ranging from 0,8 to 2,4 mg in 1 tablet, depending on it the amount of cellulose microcrystallic is adjusted.
2 The quantity of a cover of Opadraya yellow can fluctuate ranging from 8 to 16 mg in 1 tablet.
Description
Biconvex, a kapsulovidny form of a tablet, film coated yellow color with the engraved text of "GX 623" on each party of a tablet and tablet, risky on each party.

Pharmacological properties:

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 (karbovir-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 DNA on a matrix of virus 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.

Pharmacodynamics. In the strains of the HIV steady against an abakavir received by in vitro, 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 and in vivo forms slowly. For clinically significant 8-fold increase in 50% of the inhibiting concentration (IC50) multiple mutations of a virus genome 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 a combination 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 the modes 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.

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 near 1,5ch.
The area under a pharmacokinetic 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 a day the maximum concentration (Cmax) at achievement of an equilibrium state averages 3 mkg/ml, and AUC during the 12-hour period between reception of doses - on average 6,02 mkg · h · ml-1 (within a day - about 12 mkg · h · ml-1). 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 · h · ml-1.
According to a research at 20 HIV-positive 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 at 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 clinical trial with cross design 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 AUC 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 such mode of administration of drug by 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).
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.
Reception of the crumbed tablet with a small amount of semisolid food or liquid does not influence pharmacokinetics and, therefore, clinical performance. This conclusion is based on physical and chemical and pharmacokinetic parameters of active agent and solubility in water of tablets of an abakavir, at the same time it is supposed that the patient will crumb and will add all tablet to food or liquid and will accept immediately inside.
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 SMZh, at the same time the ratio of AUC of an abakavir in SMZh and AUC of an abakavir in plasma makes 30-44%. In a pharmacokinetic research I of a phase it was established that through 1,5ch after reception of an abakavir in a dose of 300 mg its concentration in SMZh made 2 times a day 0,14mkg/ml. At use of an abakavir in a dose of 600 mg 2 times a day concentration of drug in SMZh increased with 0,13mkg/ml at its measurement through 0,5-1ch to 0,74mkg/ml at measurement through 3-4ch 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. Less than 2% of the accepted dose of drug are allocated with kidneys in not changed look. 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 by kidneys.
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 through kidneys. About 83% of the entered dose are removed by kidneys in the form of metabolites and an abakavir in not changed look, and the remained quantity - through 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 the corresponding 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 2 times a day for the existing dosage forms (solution for intake and a tablet, film coated). It will provide slightly higher average concentration of drug at children in plasma, guaranteeing that at most of children therapeutic concentration will be equivalent to the mode of dosing of 300 mg 2 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 functions, 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% him 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 dose adjustment 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 an abnormal liver function of easy degree (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 (10 ml of solution for intake) an abakavira 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 initial content of VICh-1 RNA in serum exceeding 100000 copies/ml, the mode containing индинавир was more effective. At the initial content 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 group the drug Ziagen® 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 - with the VICh-1 RNA level less than 100000 copies/ml and with the content of VICh-1 RNA more than 100000 copies/ml were allocated. 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 (the ITT analysis *)

                                                                         Groups of patients
Subgroups of patients with different       Ziagen® (1 time a day) +            Ziagen® (2 times a day) + 
                                                 ламивудин + эфавиренз (N = 384)  ламивудин + эфавиренз (N = 386)
initial level of virus RNA  
Less than 100000 copies/ml                       141/217 (65%)                              145/217 (67%)
More than 100000 copies/ml                       112/167 (67%)                               116/169 (69%)
Total number of patients                       253/384 (66%)                               261/386 (68%)

* ITT-the analysis (Intent To Treat) - the analysis of these patients who received at least one dose of the studied drug.
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 patients - 600 mg of 1 times accepting the drug Ziagen® in a dose a day or 300 mg 2 times a day.
To patients at whom therapy was virologic inefficient (concentration of HIV RNA more than 50 copies/ml by 48th week of therapy) the genotypic analysis of the emitted virus isolates was carried out. Level of virologic inefficiency was low - at 10% and 8% of patients in the groups accepting the mg drug Зиаген® 600 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% 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:

The drug Ziagen® is accepted inside, irrespective of meal.
To patients in whom the proglatyvaniye of a tablet causes difficulties appoint the drug Ziagen® in the form of solution for intake. However division and dyeing of tablets with addition of a small amount of semisolid food or liquid is as an alternative allowed. All amount of the received mix needs to be accepted inside immediately.
Adults, children and teenagers with body weight more than 30 kg
The recommended drug Ziagen® dose - 600 mg/days. Drug 2 times a day or 600 mg (2 tablets) of 1 times a day appoint in a dose 300 mg (1 tablet).
Children
Children at the age of 3 months are also more senior than from 14 to 30 kg with body weight

• children with the body weight from 14 to 21 kg: the recommended dose of the drug Зиаген® 1/2 of a tablet (to pull down precisely after risk) 2 times a day or 1 tablet of 1 times a day;
• children with body weight more than 21 kg, but less than 30 kg: the recommended dose of the drug Зиаген® 1/2 of a tablet (to pull down precisely after risk) in the morning and 1 tablet in the evening or 1 1/2 tablets of 1 times a day.
For children with body weight less than 14 kg or the patients incapable to swallow tablets, use of the drug Ziagen® in the form of solution for intake is recommended.
Data on use of the drug Ziagen® for children are aged younger than 3 months are limited.
Patients with a renal failure
With a renal failure dose adjustment of the drug Ziagen® is not required from patients.
Patients with an abnormal liver function
Abakavir is metabolized preferential in a liver. The recommended drug Ziagen® dose for patients with an abnormal liver function of easy degree (5-6 points on a scale of Chayld-Pyyu) makes 200 mg (10 ml of solution for intake) 2 times a day. Considering need of use of smaller doses of the drug Ziagen® for patients with an abnormal liver function 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 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 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, results of this research showed that at 48-61% of patients carriers of an allele of HLA-B*5701 reaction of hypersensitivity in comparison with 0-4% of patients at whom this allele is absent develops.
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 also recommended to be carried out before repeated purpose of an abakavir to patients with the unknown HLA-B*5701-status who earlier well transferred therapy abakaviry.
Resuming of reception 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 multiorgan defeat. The most frequent symptoms - fever and rash - are noted at most of patients.
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 emergence of symptoms of hypersensitivity treatment abakaviry continues, they become more expressed and can accept life-threatening character. After drug withdrawal hypersensitivity symptoms usually are exposed to involution.
Treatment
At emergence of symptoms of hypersensitivity to the patient's abakavir, regardless of a carriage of an allele of HLA-B*5701, DOLZHEN immediately 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 hypotonia 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®.

Precautionary card for the patient

Attention!
Зиаген®, tablets, film coated
 Abakavir
Always you carry with yourself this card

As the drug Ziagen® contains абакавир, at some patients accepting the drug 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
2.u you one or more of the listed below symptoms appeared: likhoradka;
odyshka, pharyngalgias or cough;
◦ nausea or vomiting, abdominal pain, diarrhea;
◦ increased fatigue, pain or febricula.

If you stopped administration of drug of Ziagen® as a result of this reaction, ANY MORE NEVER ACCEPT the drug Ziagen® or any other drug containing абакавир (Trizivir®, Kiveksa) as it can immediately lead to life-threatening falling of arterial pressure or by death.
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 under direct medical observation.
Reaction of hypersensitivity is noted, though is extremely rare, even when resuming treatment by the abakavir-containing drug of patients at whom symptoms of this reaction were not observed earlier and at which having rummaged in administration of drug, containing абакавир, was connected with other reasons. In that case resuming of administration of drug is possible, however existence of bystry access to medical care is required from the patient or people 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 outweighs 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 card with the prevention needs to be taken out from packaging and to carry constantly with itself.
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.
The lipodystrophy has a difficult etiology and can develop under the influence of different factors which can synergistically work. An important role in its development is played by HIV infection, advanced age of the patient and duration of anti-retrovirus treatment.
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 glucose level 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 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 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 development 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 the observation cohort and controlled clinical trials do not allow to define unambiguously therapy communication abakaviry with risk of development 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 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.
Almost at most of patients with hypersensitivity at development of this reaction fever and/or rash (usually makulo-papular 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 allocated with a bold-face type.
Disturbances from skin and a hypodermic fatty tissue
Rash (usually makulo-papular or urtikarny).
From digestive tract 
Nausea, vomiting, diarrhea, abdominal pain, ulceration of a mucous membrane of a mouth.
Disturbances from respiratory system, bodies of a thorax and a mediastinum 
Short wind, cough, pharyngalgia, respiratory distress syndrome of adults, respiratory nedosetatochnost.
Disturbances from a nervous system
Headache, paresthesias.
Disturbances from hemopoietic and lymphatic system
Lymphopenia.
Disturbances from a liver and a pancreas
Increase in activity of enzymes of a liver, liver failure.
Disturbances from a musculoskeletal system 
Mialgiya, it is rare - a myolysis, arthralgias, increase in activity of a kreatinfosfokinaza.
Disturbances from kidneys and 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.
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 Ziagen® at hypersensitivity reaction development, just 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 the drug Ziagen® or other abakavir-containing drugs (such as Kiveksa, Trizivir®) it is strictly contraindicated.
If at hypersensitivity reaction development patients continue to accept the drug Ziagen®, then clinical manifestations become more expressed, and at drug withdrawal of Ziagen® they usually are exposed to involution.
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 by life-threatening arterial hypotension, 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 the drug Ziagen® and other drugs containing абакавир (such as Kiveksa, Trizivir®).
Sometimes reaction of hypersensitivity develops when resuming therapy by the drug Ziagen® 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 Ziagen® by patients at whom before drug withdrawal no previous hypersensitivity reaction symptoms were noted.
The nature of other undesirable phenomena other than hypersensitivity reaction, but observed at the patients receiving the drug 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 effects 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. If the drug Ziagen® was cancelled owing to suspicion on hypersensitivity reaction, resuming of administration of drug is forbidden. It is possible to resume therapy by the drug Ziagen® after interruption in connection with emergence of above-mentioned symptoms only after an exception of reaction of hypersensitivity and under direct medical observation.
The majority of the undesirable reactions given below do not limit drug Ziagen® use. Depending on the frequency of identification they can be divided into the following categories: 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). Categories of frequency were created on the basis of clinical trials of drug and post-registration observation.
Data of clinical trials
Disturbances from a metabolism and food
Often: appetite loss.
Disturbances from a nervous system 
Often: headache.
Disturbances about groans of digestive tract 
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 were not receiving drug.
Data of post-registration observation
Disturbances of metabolism and food 
Often: giperlaktatemiya.
Seldom: lactoacidosis, accumulation and/or 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's syndrome -
Johnson and 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 reduce activity of isoenzymes of CYP3A4, CYP2C9 and 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 AUC by 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 total 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.

Contraindications:

• Hypersensitivity to the abakavir or any other component which is a part of drug;
• abnormal liver function of moderate and heavy degree;
• children's age up to 3 months and with body weight less than 14 kg.
Use at pregnancy and a lactation
Pregnancy
Safety of use of an abakavir for women during pregnancy is not studied so far. 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 breast 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 by a breast to prevent transfer of HIV to the children. 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 of the drug Ziagen® for the patient establish 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 3 years. Not to use drug 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, 300 mg.
On 10 tablets in the blister from PVC / aluminum foil. On 6 blisters together with the application instruction in a cardboard pack.