Active substanceAbacavirAbacavir
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  • Dosage form: & nbsptablets, film-coated.
    Composition:

    COMPOSITION per 1 tablet

    The core of the tablet

    Active substance Abacavir sulfate 351 mg equivalent to abacavir 300 mg

    Excipients

    Microcrystalline cellulose 414.6 mg

    Carboxymethyl starch sodium, type A 24 mg

    Magnesium stearate 8mg

    Silicon dioxide colloidal anhydrous 2,4 mg

    Film sheath

    Fill yellow 14 mg

    Composition of the film shell:

    Color Decoy: Yellow

    Hypromellose 8.4 mg

    Titanium dioxide 3.6 mg

    Triacetin 1.1 mg

    Iron oxide yellow 0,9 mg

    Polysorbate 80 0.1 mg

    Notes:

    The amount of silicon dioxide of a colloidal anhydrous can range from 0.8 to 2.4 mg in 1 tablet, depending on this, the amount of microcrystalline cellulose is adjusted.

    The amount of Otoparic yellow envelope can range from 8 to 16 mg in 1 tablet.

    Description:

    Biconvex, coated tablets, capsular shaped yellow with an engraved inscription "GX623" on each side of the tablet and a risk on each side of the tablet.

    Pharmacotherapeutic group:antiviral [HIV] agent
    ATX: & nbsp

    J.05.A.F.06   Abacavir

    Pharmacodynamics:

    Mechanism of action

    Abacavir is a nucleoside analogue that inhibits HIV reverse transcriptase and selectively suppresses the replication of HIV-1 and HIV-2, including HIV-1 strains resistant to zidovudine, lamivudine, zalcitabine, didanosine and nevirapine. Abacavir undergoes intracellular metabolism, transforming into an active form, carbovir-5'-triphosphate (carbovir-TF). According to in vitro studies, the antiviral effect of the drug is due to the inhibition of HIV reverse transcriptase, which leads to the breakdown of DNA synthesis on the RNA template and stopping the replication of HIV.There was no antagonism in the antiviral activity of abacavir in cell culture when combined with nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, or an HIV protease inhibitor, amprenavir .

    In vitro-derived HIV-1 strains resistant to abacavir, mutations in several codons of the reverse transcriptase (RT) gene, M184V, K65R, L74V and Y115F, were detected. The resistance of HIV to abacavir in vitro and in vivo is slow. For a clinically significant increase in the 50% inhibitory concentration (IC50) (an increase in IC50 of 8-fold relative to the "wild" strain of the virus), multiple mutations are required. Strains resistant to abacavir may have decreased sensitivity to lamivudine, zalcitabine and / or didanosine, but retain a sensitivity to zidovudine and stavudine. Cross-resistance to abacavir and HIV or NNRTI is unlikely. Inefficiency of the first-line regime, including abacavir, lamivudine and zidovudine, is mainly associated with a single mutation-M184V, which preserves the possibility of a wide choice of regimens for second-line therapy.

    Abacavir penetrates into the cerebrospinal fluid (CSF) and reduces the content of HIV-1 RNA in it. In combination with other antiretroviral drugs, it can prevent the development of neurological complications of HIV infection and slow the emergence of resistant strains within the central nervous system (CNS).

    According to the study, 20 HIV-infected patients abacavir at a dose of 300 mg twice a day and only one dose (300 mg) before the 24-hour sampling period for analysis, the geometric mean of the terminal half-life (T1 / 2) of intracellular carbovir-TF at equilibrium is 20.6 h a similar index for the concentration of abacavir in serum - 2.6 h). Equilibrium pharmacokinetic indices when taking abacavir 600 mg once a day were identical with those with abacavir 300 mg twice a day in a clinical study with a cross-over design in 27 HIV-infected patients. Intracellular carbovir-TF content in peripheral blood mononuclear cells was higher with abacavir 600 mg 1 time per day as compared with the abacavir 300 mg 2 times a day (increased AUC in equilibrium for 24 hours (AUC24iSS) 32%of the maximum daily concentration in the equilibrium state (Cmax24, ss) by 99%), which indicates the possibility of such a regimen of taking the drug with HIV-infected patients.

    The efficacy and safety of the Ziagen® preparation, provided a single dose was given once, was shown in a clinical trial (CNA30021).
    Pharmacokinetics:

    Suction

    Abacavir is quickly and well absorbed when taken orally. Absolute bioavailability of oral abacavir in adults is about 83%. The time to reach the maximum concentration (Tmax) when taking abacavir orally in the form of tablets is about 1.5 hours, and in the form of a solution for oral administration - about 1 hour. The area under the pharmacokinetic concentration-time curve (AUC) for the tablet form of abacavir does not differ from that for abacavir in the form of an oral solution. When taking the tablet form of abacavir orally at a dose of 300 mg 2 times a day, the maximum concentration in the blood plasma (Cmax) reaches an average of 3 μg / ml when the equilibrium state is reached, and the AUC for the 12-hour interval between doses is an average of 6.02 μg * h / ml. After a single admission of abacavir tablets in a dose of 600 mg Cman average of about 4.26 μg / ml, and AUCoo - an average of 11.95 μg * h / ml. Eating slows the absorption of abacavir and reduces Cmah, but does not affect the AUC. therefore abacavir can be taken with or without food. Receiving a crushed tablet with a small amount of semi-solid food or liquid does not affect the pharmacokinetics and, therefore, the clinical effectiveness. This conclusion is based on the physicochemical and pharmacokinetic parameters of the active ingredient and the water solubility of abacavir tablets, with the assumption that the patient will grind and add the whole tablet to the food or liquid and take it immediately inside.

    Distribution and binding to blood plasma proteins

    Studies involving HIV-infected patients showed that abacavir well penetrates into the CSF, while the ratio of AAB abacavir in CSF to AUC abacavir in blood plasma is 30-44%. In the Phase I pharmacokinetic study, it was found that 1.5 hours after taking abacavir 300 mg twice daily, its mean concentration in the CSF was 0.14 μg / ml. When using abacavir in a dose of 600 mg 2 times a day, the concentration of the drug in the CSF increased from 0.13 μg / ml 0.5-1 hour after administration to 0.74 μg / ml when measured 3-4 hours after administration of abacavir .Thus, even if the concentration of abacavir observed in the CSF 4 hours after taking the drug at a dose of 600 mg twice a day is not the maximum achieved with this treatment regimen, it already exceeds IC50 (0.08 μg / ml or 0.26 mkmol / l) 9 times.

    In in vitro studies, it has been found that in therapeutic doses abacavir moderately (approximately 49%) binds to human plasma proteins. This indicates that the interaction of abacavir with other drugs by their displacement from the compound with plasma proteins is unlikely.

    Metabolism

    Abacavir is metabolized predominantly in the liver, in unchanged form it is released by the kidneys of less than 2% of the accepted dose of the drug. In the human body abacavir is metabolized mainly by the action of alcohol dehydrogenase with the formation of the 5'-carboxylic acid and by conjugation with glucuronic acid to form 5'-glucuronide, which is about 66% of the total administered dose of the drug. These metabolites are excreted by the kidneys.

    Excretion

    On average, the half-life of abacavir is about 1.5 hours. Prolonged intake of abacavir orally at a dose of 300 mg 2 times a day does not lead to significant cumulation of the drug.Abacavir excretion is carried out by metabolism in the liver, followed by excretion of metabolites mainly by the kidneys. About 83% of the administered dose is excreted by the kidneys in the form of metabolites and abacavir in unchanged form, and the remaining quantity is excreted through the intestine.

    Special patient groups

    Children

    Abacavir is well and rapidly absorbed when ingested in children. All pharmacokinetic parameters in children are comparable to those in adults with slightly greater variability in plasma concentrations. Pharmacokinetic studies in children showed that taking the drug 1 time per day is equivalent in AUC0-24 to receiving the same dose of the drug, divided into 2 times a day. for the existing dosage forms of the preparation Ziagen® (oral solution and film-coated tablets). This will provide slightly higher average concentrations of the drug in children in plasma, ensuring that in the majority, therapeutic concentrations will be equivalent to a dosing regimen of 300 mg twice daily for adults. There is insufficient safety data to recommend the use of abacavir in children younger than 3 months.There is limited evidence that a dose of 2 mg / kg in infants younger than 30 days provides similar or greater AUC values ​​than do 8 mg / kg in older children.

    Elderly patients

    The pharmacokinetics of abacavir in patients older than 65 years have not been studied. In the treatment of elderly patients, it is necessary to take into account more frequent violations of the liver, kidney and heart function at this age, as well as concomitant diseases and medications taken.

    Patients with impaired renal function

    Abacavir is metabolized primarily in the liver, less than 2% of it is excreted by the kidneys unchanged. The pharmacokinetics of abacavir in the terminal stage of renal failure is about the same as with normal kidney function. Therefore, if the renal function is not corrected, dose adjustment is not required.

    Patients with impaired hepatic function

    Abacavir is metabolized mainly in the liver. The results of a study of the pharmacokinetics of abacavir in patients with mild liver function disorder (5-6 points on the Child-Pugh scale) indicate an AUC increase of 1.89 times on average and a half-life of 1.58 times.The index of AUC metabolites of abacavir is not affected by liver dysfunction, however, the rate of their formation and excretion decreases. Patients with a mild liver function disorder may receive 200 mg of abacavir 2 times a day for therapeutic purposes. The pharmacokinetics of abacavir in patients with impaired liver function of medium and severe degree has not been studied, thus, the use of abacavir is not recommended in these patient groups.


    Clinical efficacy

    Analysis of data from a randomized, double-blind, comparative study of combinations of Ziagen® with lamivudine and zidovudine and indinavir with lamivudine and zidovudine, administered for 48 weeks in adult HIV-infected patients who had not previously received antiretroviral therapy, showed comparable virological efficacy of the compared combinations. However, in a subset of patients with a baseline HIV-1 RNA content in serum exceeding 100,000 copies / ml, the regimen containing indinavir, was more effective. With the initial content of viral RNA less than 100,000 copies / ml, the effectiveness of both regimes was the same.

    In a multicenter, double-blind, controlled study (CNAZ0021), which included 770 HIV-infected patients who had not previously taken antiretroviral drugs, a single-dose and double-dose regimen of the Ziagen® preparation was compared. Patients were randomized into two groups. In the first group, the preparation Ziagen® was administered at a dose of 600 mg once a day, in the second 300 mg twice a day; At the same time as Ziagen®, patients in both groups received lamivudine in a dose of 300 mg once a day and efavirenz in a dose of 600 mg once a day. Depending on the initial level of viral RNA, 2 subgroups of patients were isolated in the blood serum - less than 100,000 copies / mL of HIV-1 RNA and more than 100,000 copies / ml of HIV-1 RNA. The duration of treatment was at least 48 weeks. The results of the study are presented below.

    The proportion of patients with serum levels of HIV-1 RNA less than 50 copies / ml at 48 weeks after initiation of treatment (TTT analysis *)


    Patient groups

    Subgroups of patients with different baseline levels of viral RNA

    Ziagen® (once a day) + lamivudine + efavirenz (N = 384)

    Ziagen® (2 times a day) + lamivudine + efavirenz (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 %)

    [1]GGT analysis (Intent The Treat) - analysis of patients who received at least one dose of the study drug.

    Thus, it was shown that the dosage regimen of Ziagen® does not affect the effectiveness of treatment in either the general population of patients or in subgroups with different initial levels of viral load. The incidence of adverse events was the same in both groups of patients who received Ziagen® at a dose of 600 mg once a day or 300 mg twice a day.

    Patients in whom the therapy was found to be virologically ineffective (HIV RNA concentration> 50 copies / ml at week 48), genotypic analysis of isolated virus isolates was performed. The level of virological inefficiency was low - in 10% and 8% of patients in groups receiving

    preparation Zhetenen® 600 mg 1 and 2 times a day, respectively. Resistance to nucleoside reverse transcriptase inhibitors was most often due to mutations in the 184 codon (M184V or Ml 841). The second most frequent mutation was L74V. The least frequently observed mutations Y115F and K65R.

    A comparative study of three combinations of nucleoside reverse transcriptase inhibitors (abacavir with lamivudine,abacavir with zidovudine or lamivudine with zidovudine) taken by children in combination with nelfinavir or placebo, showed that abacavir-containing regimens significantly outperformed the combination of lamivudine and zidovudine. It was found that a decrease in HIV-1 RNA concentration of less than 400 copies / ml after 24 weeks of therapy was observed in 73% of children taking a combination of abacavir with lamivudine, in 70 % children who took abacavir with zidovudine, and only 44% of children taking lamivudine with zidovudine.

    The combination of abacavir with lamivudine and zidovudine in children who previously received various regimens of highly active antiretroviral therapy (HAART) was characterized by a moderate but persistent antiviral effect,

    In patients previously treated with HAART, the effectiveness of Ziagen® depends on the pattern and duration of previous treatment, which could lead to cross-resistance to Ziagen®.

    Indications:

    HIV infection in adults and children in combination antiretroviral therapy.

    Contraindications:

    Hypersensitivity to abacavir or any other component included in the preparation;

    the age of up to 3 months and with a body weight of less than 14 kg, since the experience of using Zenith8 in this age group is limited;

    hepatic insufficiency of medium and severe degree (class B and C on the Child-Pugh scale), due to the lack of clinical data and the recommended dosing regimen;

    hepatic insufficiency of mild degree (class A on the Child-Pugh scale), due to the inability to provide a dosing regimen.

    Pregnancy and lactation:

    Pregnancy

    The use of abacavir during pregnancy and after childbirth was studied in more than 2000 women. The data available in the Registry on the use of antiretroviral drugs during pregnancy do not indicate an increased risk of developing major congenital malformations associated with abacavir use compared to the frequency of developmental defects in the comparison group. However, adequate and well-controlled studies in pregnant women are not available, the safety of abacavir in women during pregnancy has not yet been established. There is evidence of the effects of abacavir in reproductive studies in animals.If you need to use Ziagen ® during pregnancy, you should evaluate the ratio of expected benefits to the mother and the potential risk to the fetus. There is evidence of a slight transient increase in the concentration of lactate in the blood plasma of newborns and infants whose mothers during pregnancy and childbirth took NRTIs. Perhaps this is due to mitochondrial disorders.

    The clinical significance of this phenomenon has not been established to date. In addition, there are extremely rare reports of developmental delay, epileptic seizures and other neurological disorders (eg, muscle tone increase) in newborns, although the causal relationship of these disorders to NRTIs in mothers during pregnancy and childbirth has not been established. These data do not cancel the existing recommendations on the use of antiretroviral drugs during pregnancy to prevent vertical transmission of HIV.

    Breastfeeding period

    Specialists do not recommend breastfeeding to HIV-infected patients to avoid HIV transmission to the child. Because the abacavir, its metabolites and HIV penetrate into breast milk, breastfeeding is contraindicated.

    Dosing and Administration:

    The drug Ziagen ® is taken orally, regardless of food intake.

    The drug should be prescribed by a doctor with experience in the treatment of HIV infection. To ensure the accuracy of the dosage of the drug, the tablet is recommended to be swallowed completely without division, but as an alternative, the division and grinding of tablets with the addition of a small amount of semi-solid food or liquid is allowed. All the amount of the mixture should be taken immediately. For the treatment of children and those patients who are difficult to swallow tablets, the medicinal form is intended - a solution for ingestion.

    Adults, children and adolescents with a body weight of at least 30 kg

    The recommended dose of Ziagen ® is 600 mg / day. The drug is prescribed in a dose of 300 mg (1 tablet) 2 times a day or 600 mg (2 tablets) once a day.

    Special patient groups

    Children

    Children aged 3 months and older with a body weight of 14 to 30 kg

    Children with a body weight of 14 to 21 kg: the recommended dose of Ziagen ® is 1/2 tablet (break down exactly according to risk) 2 times a day or 1 tablet 1 time per day;

    Children weighing more than 21 kg, but less than 30 kg: the recommended dose of Ziagen ® is 1/2 tablet (broken down exactly at risk) in the morning and 1 tablet in the evening or 1/4 tablets once a day;

    for children weighing less than 14 kg or patients unable to swallow tablets, the use of Ziagen® in the form of a solution for oral administration is recommended.

    Children up to 3 months old

    Data on the use of Ziagen ® in this age group is very limited.

    Patients with impaired renal function

    In patients with impaired renal function, dose adjustment of Ziagen® is not required.

    Patients with impaired hepatic function

    Abacavir is metabolized predominantly in the liver. The recommended dose of Ziagen ® for patients with mild liver function disorders (5-6 points on the Child-Pugh scale) is 200 mg (10 ml of solution) 2 times a day. Considering the need to use smaller doses of Ziagen ® in patients with mild liver function disorders, it is prescribed as a solution for oral administration to correctly dispense the drug. There is no data on the pharmacokinetics and safety of abacavir in patients with moderate or severe liver dysfunction.Thus, the use of abacavir in patients with impaired liver function of medium and severe degree is contraindicated.

    Side effects:Hypersensitivity

    According to clinical studies conducted before the screening for the presence of an allele HLA-B*5701, in about 5% of patients who took abacavir, there was a reaction of hypersensitivity, in rare cases with fatal outcome. Hypersensitivity to abacavir is characterized by multiple organ dysfunction.

    Almost the majority of patients with hypersensitivity develop fever and / or a rash (usually maculopapular or urticaria), although in some cases these manifestations are absent.

    Symptoms of hypersensitivity reactions may appear at any time after initiation of abacavir treatment, but most often they occur during the first 6 weeks of treatment (median time of onset of this reaction is 11 days).

    The hypersensitivity reactions are shown below. Symptoms that occur not less than 10 % patients with hypersensitivity, in bold.

    Disturbances from the skin and subcutaneous fat

    Rash (usually maculopapular or urticaria).

    From the gastrointestinal tract

    Nausea, vomiting, diarrhea, abdominal pain, ulceration of the oral mucosa. Disturbances from the respiratory system, chest and mediastinal organs Shortness of breath, cough, sore throat, adult respiratory distress syndrome, respiratory failure.

    Disturbances from the nervous system Headache, paresthesia.

    Disturbances from the hematopoietic and lymphatic system Lymphopenia.

    Disorders from the liver and pancreas

    Increased activity of liver enzymes, liver failure.

    Disorders from the musculoskeletal system

    Myalgia, rarely - myolysis, arthralgia, increased activity of creatine phosphokinase.

    Disorders from the kidneys and urinary system

    Increased serum creatinine concentration, renal failure.

    Other

    Fever, fatigue, malaise, edema, lymphadenopathy, arterial hypotension, conjunctivitis, anaphylactic reactions.

    Patients with a hypersensitivity reaction at first can take it for a respiratory disease (pneumonia, bronchitis, pharyngitis,respiratory viral infection), gastroenteritis, or for unwanted reactions associated with taking other drugs. Continued use of Ziagen® in the development of a hypersensitivity reaction, as well as the resumption of its administration after the symptoms subsided, is fraught with serious consequences, up to a fatal outcome. Therefore, if any of these symptoms appear, a thorough examination of the patient is necessary to exclude the hypersensitivity reaction. If you can not exclude hypersensitivity reaction, then re-appointment of the drug

    Ziagen® or other abacavir-containing drugs (such as Kivexa, Trizivir®) is strictly contraindicated.

    If the patients continue to take Ziagen ® during the development of the hypersensitivity reaction, the clinical manifestations become more pronounced, and when Ziagen ® is withdrawn, they usually undergo a reverse development. The resumption of Ziagen® with patients with a history of hypersensitivity leads to a re-reaction within a few hours. Repeated hypersensitivity reactions can occur more severely than the first, and manifest life-threatening arterial hypotension, up to a lethal outcome.When a hypersensitivity reaction develops, the patient, regardless of the carrier of the allele HLA-B*5701, must permanently abandon the use of Ziagen ® and other preparations containing abacavir (such as Kivexa, Trizivir®).

    Occasionally, the hypersensitivity reaction develops when the Ziagen® therapy resumes after its withdrawal, caused by the appearance of just one of the main symptoms of this reaction (rash, fever, malaise, fatigue, gastrointestinal or respiratory system disorders).

    In rare cases, this reaction occurs when the Ziagen® preparation is resumed by patients who had no previous symptoms of hypersensitivity reaction prior to discontinuation of the drug.

    The nature of other adverse events other than the hypersensitivity reaction, but observed in patients receiving Ziagen®, is not fully understood. Whether these adverse events are due to the use of Ziagen® or other drugs concomitantly prescribed with it or caused by the disease itself has not been established to date.

    Many of the following undesirable effects associated with taking Ziagen® (nausea, vomiting, diarrhea, fever, fatigue, rash) may also occur with the development of a hypersensitivity reaction. Therefore, when any of these symptoms appear, a thorough examination of the patient is performed to confirm or exclude a hypersensitivity reaction. If the drug Ziagen ® was canceled due to suspicion of a hypersensitivity reaction, resumption of the drug is prohibited. Renewal therapy with Ziagen ® after interruption in connection with the appearance of the above symptoms can only be after the elimination of the hypersensitivity reaction and under direct medical supervision.

    Most of the undesirable reactions listed below do not limit the use of Zenit®. Depending on the frequency of detection, they can be divided into the following categories: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), rarely > 1/10 000 and <1/1 000), very rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

    Clinical Trials Data

    Disorders from the metabolism and nutrition Often: loss of appetite.

    Disturbances from the nervous system Often: headache.

    Violations from the groan of the gastrointestinal tract Often: nausea, vomiting, diarrhea.

    Systemic manifestations and local reactions Often: fever, drowsiness, fatigue.

    In controlled clinical trials, it was shown that the change in laboratory parameters in the treatment with Zenit® is observed as rarely as in the control group of patients who did not receive the drug.

    Post-registration data

    Metabolic and nutritional disorders Often: hyperlactatemia.

    Rarely: lactic acidosis, accumulation and / or redistribution of adipose tissue.

    The frequency of these undesired reactions is dependent on many factors, including the antiretroviral drugs used in combination with abacavir.

    Disorders from the gastrointestinal tract

    Rarely: pancreatitis (a cause-and-effect relationship with the use of abacavir is not exactly established).

    Disturbances from the skin

    Often: rash (in the absence of systemic manifestations).

    Very rarely: polymorphic erythema exudative, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

    Overdose:Symptoms

    In clinical studies, there were no undesirable reactions with Zenat® in single doses up to 1200 mg and diurnal up to 1800 mg. The effect of the drug in higher doses has not been studied to date.

    Treatment

    In the case of an overdose of Zenit®, the patient is monitored for symptoms of poisoning and timely treatment. If necessary, perform symptomatic treatment. The efficacy of peritoneal dialysis and hemodialysis for abacavir removal is unknown.

    Interaction:

    In vitro studies and analysis of the main metabolic pathways of abacavir indicate that its interaction with other drugs, mediated by cytochrome P450, is unlikely. Abacavir does not suppress metabolic reactions involving isoenzyme ZA4 cytochrome P450 In in vitro studies it is shown that abacavir does not interact with drugs that are metabolized by the isoenzymes CYP3A4, CYP2C9 and CYP2D6. Clinical studies have not revealed induction of hepatic metabolism of exogenous substances under the influence of abacavir. Thus, the interaction of abacavir with HIV protease inhibitors and other drugs metabolized with the participation of the main cytochrome P450 isoenzymes is unlikely.Clinical studies have shown no clinically relevant interactions between abacavir, zidovudine and lamivudine.

    Powerful inducers of enzymes, such as rifampicin, phenobarbital and phenytoin when exposed to UDP-glucuronyl transferase, the concentration of abacavir in plasma can be slightly reduced.

    Ethanol: ethanol slows the metabolism of abacavir, which leads to an increase in AUC by 41%. However, the clinical significance of this change is small. On the metabolism of ethanol abacavir does not affect.

    Methadone: according to pharmacokinetic studies, the use of abacavir in a dose of 600 mg twice a day in combination with methadone reduces CmAbacavir in serum by 35%, increases Tmah in the serum for 1 h, but does not change the AUC. The clinical significance of these changes is small. The same study found that abacavir increases the systemic clearance of methadone by 22%. In most cases, these changes are also considered clinically insignificant, but in certain situations, a dose change in methadone may be required.

    Retinoids: retinoids, for example isotretinoin, are eliminated with alcohol dehydrogenase, so they can interact with abacavir,however, to date no special studies have been conducted.

    Ribavirin: due to the fact that abacavir and ribavirin have the same phosphorylation pathways, interaction between these substances is expected, which can lead to a decrease in intracellular phosphorylation of ribavirin metabolites and potentially leads to a decrease in the likelihood of achieving a stable virologic response in HIV-infected patients infected with hepatitis C who received pegylated interferon and ribavirin therapy. Controversial data have been published on the simultaneous use of abacavir and ribavirin. According to some data, it is assumed that HIV-infected patients receiving abacavir-containing drugs may have a low risk of responding to antiviral therapy with pegylated interferon and ribavirin. Care must be taken when taking of these drugs.

    Special instructions:

    Hypersensitivity. According to clinical studies conducted before the introduction of screening for the presence of the HLA-B * 5701 allele, approximately 5% of patients receiving abacavir, hypersensitivity to the drug develops, in rare cases with a fatal outcome. Risk factors In clinical studies, it has been shown that the carriage of the HLA-B * 5701 allele significantly increases the risk of developing a hypersensitivity reaction to abacavir. In a prospective clinical trial, CNA106030 (PREDICT-1), patients with the presence of the HLA-B * 5701 allele preparations containing abacavirwere not assigned, which significantly reduced the incidence of a clinically suspected hypersensitivity reaction from 7.8% (66 patients out of 847) to 3.4% (27 patients out of 803) (p <0.0001), and the incidence of a hypersensitivity reaction confirmed skin-application test, from 2.7% (23 patients out of 842) to 0.0% (0 patients from 802) (p <0.0001). Based on the results of this study, it was shown that 48-61% of patients carrying the HLA-B * 5701 allele develop a hypersensitivity reaction compared with 0-4% of patients who do not have this allele.

    It is recommended that doctors screen for carriage of the HLA-B * 5701 allele in HIV-infected patients who have not previously been prescribed drugs containing abacavir. Screening is also recommended before reassignment of abacavir to patients with unknown HLA-B * 5701 status who previously tolerated abacavir well.

    The use of abacavir drugs is not recommended in patients carrying the HLA-B * 5701 allele and should be considered only in exceptional cases under close medical supervision when the potential benefit exceeds the risk associated with the use of the drug.

    The clinical diagnosis of suspected hypersensitivity reactions should remain the basis for deciding the use of drugs containing abacavir, in all patients. Even in the absence of the HLA-B * 5701 allele abacavir it is necessary to cancel and not to resume its reception in all cases when the hypersensitivity reaction can not be ruled out, guided by clinical data, because of the potential risk of developing serious adverse reactions or even death.

    The skin-application test as an experimental technique was used in the PREDICT-1 study, but it is useless in the clinical management of patients and, therefore, should not be used in clinical practice.

    Clinical picture

    The reaction of hypersensitivity to abacavir is characterized by the appearance of symptoms indicating multiorgan lesion.Most patients report a fever and / or rash as part of the syndrome.

    Other symptoms of hypersensitivity to abacavir are fatigue, malaise, disorders of the gastrointestinal tract, including vomiting, nausea, diarrhea, and abdominal pain; disorders of the respiratory system, including shortness of breath, sore throat, cough, lung damage (mainly in the form of local infiltrative changes detected by chest x-ray).

    Symptoms of hypersensitivity may appear at any time after initiation of abacavir treatment, but most often they occur within the first six weeks. Patients should be under careful observation with consultations every 2 weeks, especially during the first 2 months of therapy with Ziagen®.

    If, when hypersensitivity symptoms appear, abacavir treatment continues, they become more pronounced and can take a life-threatening character. In most cases, these symptoms disappear when discontinuing abacavir.

    Treatment

    Patients, regardless of HLA-B * 5701 status who showed signs and symptoms of hypersensitivity, should immediately contact your doctor for advice.When making a diagnosis of hypersensitivity, patients SHOULD immediately stop taking Ziagen ®. NEVER SHOULD renew treatment with Ziagen® and other medications containing abacavir (such as Kivexa, Trizivir®), after the occurrence of a hypersensitivity reaction. This is due to the threat of even more severe symptoms (including life-threatening arterial hypotension) that may lead to death within a few hours after the resumption of the drug.

    To prevent late detection and reduce the risk of developing a life-threatening hypersensitivity reaction, Ziagen® should be completely discontinued if it is impossible to exclude hypersensitivity, even with the potential for other diagnoses (respiratory diseases, flu-like illnesses, gastroenteritis, reactions to other medications). Special care must be taken for those patients who have simultaneously started taking Ziagen® and other medications known to cause skin reactions (eg, NNRTIs).This is due to the fact that at present it is difficult to differentiate the rash caused by these drugs and the hypersensitivity reaction to abacavir.

    Do not resume treatment with Ziagen® and other medications containing abacavir (such as Kivexa, Trizivir®), even if hypersensitivity symptoms appear when re-ingesting alternative medications.

    Special instructions for treatment after a break in therapy with Ziagen®

    Regardless of the carriage of the HLA-B * 5701 allele, if after discontinuation of the drug containing abacavir The resumption of treatment with this drug is expected, it is necessary to find out the reason for the cancellation and make sure that the patient was not observed symptoms of hypersensitivity. If the hypersensitivity reaction can not be excluded, the resumption of treatment with Ziagen11 or another drug containing abacavir (such as Kivexa, Trizivir®) is prohibited.

    A few cases of the development of a hypersensitivity reaction during the resumption of treatment with abacavir after its withdrawal due to the appearance of any one of the typical symptoms of hypersensitivity (rash, fever, malaise, fatigue,gastrointestinal disturbances and disorders of the respiratory system). The most common isolated symptom of a hypersensitivity reaction was a skin rash. Since in all such cases it is impossible to exclude the hypersensitivity reaction and, given the data on its more severe course with repeated use of abacavir, the resumption of therapy with Ziagen® or another abacavir-containing drug (such as Kivexa, Trizivir®) is not recommended in these patients. However, if in such cases the question of re-appointment of abacavir is solved positively, then treatment is carried out only under direct medical supervision.

    The hypersensitivity reaction is noted, although extremely rare, even with the resumption of treatment with abacavir-containing drug in patients who have not previously experienced symptoms of this reaction and who have a break in taking the drug containing abacavir was associated with other causes. In this case, the resumption of taking the drug is possible, but it is necessary to have quick access to medical care from the patient or those around him.

    Screening for carriage of the HLA-B * 5701 allele is recommended prior to re-administration of abacavir in patients with unknown HLA-B * 5701 status who previously tolerated abacavir well. The re-administration of abacavir to HLA-B * 5701 allele patients is not recommended and can only be considered in exceptional cases under close medical supervision, when the potential benefit of treatment with the drug exceeds all possible risks.

    Necessary information for patients

    The physician prescribing the drug should familiarize the patient with the following information about hypersensitivity reaction: the patient should be aware of

    capabilities the appearance of life-threatening hypersensitivity symptoms and the risk of death, as well as the increased risk of hypersensitivity reactions in carriers of the HLA-B * 5701 allele;

    the patient should be warned that even in the absence of the HLA-B * 5701 allele, a hypersensitivity reaction may develop. Thus, ALL patients should, in the event of symptoms that may be due to the hypersensitivity reaction, MUST immediately contact their doctor;

    patients with hypersensitivity to abacavir should be warned about the inadmissibility of resuming the use of Ziagen ® or other preparations containing abacavir (such as Kivexa, Trizivir®), regardless of HLA-B * 5701 status;

    to avoid re-application of Ziagen® with patients who underwent a hypersensitivity reaction, they are recommended to return the remaining Ziagen® tablets to the doctor;

    patients who for any reason interrupted treatment with Ziagen® (especially in connection with possible adverse reactions or complications of treatment) should consult a doctor before resumption of the drug.

    Each patient should read the instructions for use and card attached to the drug. Also, patients should be reminded that they should always carry a warning card attached to the drug.

    Lactic acidosis and severe hepatomegaly with steatosis. There are reports of the development of lactic acidosis and severe hepatomegaly with steatosis, including fatal outcome, due to antiretroviral therapy with nucleoside analogs.including abacavir, taken either individually or in combination. In most cases, these complications occur in women.

    Symptoms that may indicate the development of lactic acidosis include general weakness, lack of appetite, rapid weight loss of unclear etiology, gastrointestinal disturbances (nausea, vomiting and abdominal pain), respiratory system disorders (dyspnea and tachypnea), or neurologic symptoms (including movement).

    Lactic acidosis has a high mortality in the absence of emergency treatment and can be associated with pancreatitis, hepatic or renal insufficiency. Lactic acidosis, as a rule, manifested itself after several months of therapy. It is necessary to stop therapy with nucleoside analogues in case of symptomatic manifestations

    hyperlactatemia and metabolic or lactic acidosis, progression of hepatomegaly or a rapid increase in aminotransferase activity.

    The use of Ziagen ® requires caution for any patient (especially overweight women) with hepatomegaly, hepatitis or other known risk factors for liver damage and steatosis of the liver (including the use of certain drugs and alcohol).

    Patients with co-infected hepatitis C receiving interferon alfa and ribavirin therapy can be a particular risk group. Patients with high risk require careful monitoring.

    If clinical or laboratory signs of lactic acidosis occur with or without hepatitis (hepatomegaly and steatosis may appear even in the absence of a pronounced increase in aminotransferase activity) treatment with Ziagen® should be stopped.

    Mitochondrial dysfunction

    In vitro and in vivo studies have shown that nucleoside and nucleotide analogues can cause a different degree of mitochondrial damage. Mitochondrial dysfunction was observed in HIV-negative children who received intrauterine and / or post-nucleoside analogues. The main undesirable reactions were hematologic disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipazemia). These undesirable reactions are often transient. Some neurological disorders with late onset have been reported (increased muscle tone, convulsions, behavioral disorders).Whether these neurological disorders are transient or persistent is currently unknown. Any child, even HIV-negative, exposed to prenatal exposure to nucleoside and nucleotide analogues, must undergo a clinical and laboratory examination in order to exclude mitochondrial dysfunction in case of revealing the corresponding signs or symptoms. These data do not influence the current national recommendations on the use of antiretroviral therapy in pregnant women for the prevention of vertical transmission of HIV infection.

    Redistribution of subcutaneous fat

    In some patients receiving combined antiretroviral therapy, there may be a redistribution and / or accumulation of subcutaneous fat, including central obesity, dorsocervical fat deposition ("buffalo buffalo"), a reduction in the subcutaneous fat layer on the face and extremities, enlargement of the mammary glands , increased serum lipid concentrations and glucose concentrations in the blood.

    Although one or more of the above unwanted reactions associated with a general syndrome,which is often referred to as lipodystrophy, can cause all drugs of HIV and NRTI classes, the data suggest that there are differences between individual representatives of these classes of drugs in the ability to induce these undesirable reactions.

    It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, the elderly age and the duration of antiretroviral therapy play an important, possibly synergistic role.

    The long-term effects of these undesirable reactions are currently unknown.

    When clinically examining patients, attention should be paid to the redistribution of subcutaneous fat. Laboratory examination should include the determination of serum lipid concentrations and blood glucose concentrations. If the lipid metabolism is disturbed, an appropriate treatment is prescribed.

    Pancreatitis

    Cases of pancreatitis have been documented, although the cause-and-effect relationship with the use of abacavir has not been accurately established.

    Therapy with three NRTIs In patients with high viral load (> 100,000 copies / mL), the appointment of a triple combination containing abacavir, lamivudine and zidovudine, requires special consideration.

    There were recorded cases of high rates of virological failure and the emergence of resistance in the early stages, when a combination of abacavir with tenofovir, dizoproxil fumarate and lamivudine was used as a regimen of therapy once a day.

    Diseases of the liver

    The efficacy and safety of Ziagen® were not established in patients with severe concomitant liver disease. The drug Ziagen ® is contraindicated in patients with impaired liver function of medium and severe degree.

    Patients with pre-existing liver dysfunction, including active chronic hepatitis, have an increased incidence of liver dysfunction during combined antiretroviral therapy, and should be monitored in accordance with accepted practice. It is necessary to consider the possibility of suspension or termination of treatment, in the case of manifestations of worsening liver disease in such patients. Concomitant Hepatitis B or C Patients with concomitant chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of severe and potentially lethal adverse reactions from the liver.In the case of concomitant antiviral therapy for hepatitis B or C, you should also read the appropriate instructions for the use of these drugs.

    Care should be taken when concurrent administration of abacavir and ribavirin.

    Kidney Diseases

    The drug Ziagen ® should not be given to patients with terminal chronic renal failure.

    Immunodeficiency Syndrome

    If HIV-infected patients with severe immunodeficiency have asymptomatic opportunistic infections or their residual effects at the time of initiation of antiretroviral therapy, such therapy may lead to an increase in the symptoms of opportunistic infections or other severe consequences. Typically, these reactions occur within the first weeks or months after initiation of antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and / or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (formerly R. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

    Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

    Osteonecrosis

    Although the etiology of this disease is multifactorial (including the intake of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis were most often seen in patients at a late stage of HIV infection and / or long-term combined antiretroviral therapy. Patients should consult a doctor if they experience pain and stiffness in the joints or difficulty moving.

    Opportunistic infections

    The use of Ziagen ® or other antiretroviral drugs does not preclude the development of opportunistic infections or other complications of HIV infection, so patients should remain under the supervision of a physician with experience in the treatment of HIV-associated diseases.

    Transmission of HIV infection

    The provision of antiretroviral therapy, including Ziagen®, does not exclude the possibility of sexual transmission of HIV or in contact with infected blood, and therefore does not negate the need for appropriate precautions.

    Myocardial infarction

    As a result of a prospective observational epidemiological study in order to study the incidence of myocardial infarction in patients receiving combined antiretroviral therapy, a previous abacavir connection was detected within 6 months with an increased risk of myocardial infarction. According to the generalized analysis of clinical studies, there was no increase in the risk of developing myocardial infarction associated with the use of abacavir. Biological mechanisms that explain a potentially increased risk are unknown. In general, the available data from cohort observations and controlled clinical studies do not allow one to unequivocally determine the relationship between abacavir therapy and the risk of myocardial infarction. However, care should be taken to prescribe antiretroviral therapy, including drugs containing abacavir, patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize all modifiable risk factors (such as hypertension, dyslipidemia, diabetes and smoking).

    Warning a card with information for patients about the hypersensitivity reaction is in the package.

    Patient Warning Card

    Attention!

    Ziagen®, film-coated tablets Abacavir

    Always carry this card with you.

    Since the preparation Ziagen® contains abacavir, some patients taking Ziagen ® can develop a hypersensitivity reaction (a serious allergic reaction), often life-threatening, if not abolish the drug. IMMEDIATELY CONTACT YOUR DOCTOR'S DOCTOR for advice about the possibility of further taking Ziagen® if:

    1) you have a skin rash

    OR

    2) you have one or more symptoms from at least two of the following groups:

    - fever;

    - shortness of breath, sore throat, or cough;

    - nausea or vomiting or diarrhea or abdominal pain;

    - increased fatigue or pain or general malaise.

    If you stop taking Ziagen® as a result of this reaction, DO NOT NEVER take Ziagen® or any other preparation containing abacavir (Trizivir®, Kivexa), since within a few hours it can lead to a life-threatening drop in blood pressure or death.

    Effect on the ability to drive transp. cf. and fur:

    Data on the effects of abacavir on the ability to drive vehicles and handle mechanisms are not available.

    Form release / dosage:

    Film-coated tablets, 300 mg.

    Packaging:For 10 tablets in a blister of PVC / aluminum foil. For 6 blisters together with instructions for use in a cardboard bundle.
    Storage conditions:At a temperature of no higher than 30.
    Keep out of the reach of children.
    Shelf life:

    3 years.

    Do not use the drug after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:П N011612 / 01
    Date of registration:05.05.2010
    The owner of the registration certificate:VeeV Helsker United Kingdom LimitedVeeV Helsker United Kingdom Limited United Kingdom
    Manufacturer: & nbsp
    Representation: & nbspVIIV Chelskea UK Limited VIIV Chelskea UK Limited United Kingdom
    Information update date: & nbsp27.10.2014
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