Alaget (Alaget)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbsptfilm-covered laths
Composition:

Each film-coated tablet contains:

Active substance:

Abacavir Sulfate

702 mg

in terms of abacavir

600 mg

Lamivudine

300 mg

Excipients:

Core: giprolose low-substituted - 150.0 mg; hypromellose E15 - 3.0 mg: carboxymethyl starch sodium (sodium starch glycolate) - 56.0 mg; sodium stearyl fumarate 9.0 mg; cellulose microcrystalline - 150.0 mg.

Composition of film water-soluble shell: hypromellose E5 - 28.0 mg, macrogol 6000 (polyethylene glycol 6000) - 3.6 mg, polysorbate 80 - 0.4 mg, titanium dioxide - 8.0 mg.
Description:The tablets covered with a film shell of white color, biconvex, oval. On a cross-section of a tablet of white or almost white color.
Pharmacotherapeutic group:Antiviral [HIV] agent
ATX: & nbsp
  • Abacavir + Lamivudine
    • Pharmacodynamics:

    Abacavir and lamivudine belong to the group of nucleoside reverse transcriptase inhibitors and are potent selective inhibitors of HIV-1 and HIV-2.

    Abacavir and lamivudine are subsequently metabolized under the action of intracellular kinases to the corresponding triphosphates (TF), which act as active metabolites. Lamivudine-TF and carbovir-TF (active triphosphate abacavir) act as a substrate and are competitive inhibitors of reverse transcriptase (RT) of HIV.However, the main antiviral effect of the drugs is due to the insertion of monophosphate into the DNA chain, which leads to the termination of replication. Triphosphates of abacavir and lamivudine have a much lower affinity for DNA polymerases of host cells.

    A study in which 20 HIV-infected patients took abacavir (300 mg twice daily daily and once 24 hours prior to taking the material for analysis) showed that the geometric mean of the terminal intracellular half-life of carbovir-TF at an equilibrium state was 20.6 hours. The mean geometric half-life of abacavir from plasma in this study was 2,6 hr. The equilibrium pharmacokinetic parameters for the administration of abacavir 600 mg once a day were similar to those with abacavir 300 mg twice daily in a cross-sectional clinical trial of 27 HIV-infected patients. The intracellular content of carbovir-triphosphate in peripheral blood mononuclear cells was higher when taking abacavir in a dosage of 600 mg 1 once a day compared to taking abacavir 300 mg twice daily (an increase in the area under the concentration-time curve in a state of equilibrium in 24 hours (AUC24,ss) by 32%, the maximum daily concentration in the equilibrium state (CmOh 24, ss) - by 99% and the residual concentration - by 18%). In patients who took lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TF increased from 16 to 19 hours, and the half-life of lamivudine from plasma increased from 5 to 7 hours. A study of the pharmacokinetics of lamivudine taken at a dose of 300 mg once daily in for 7 days compared with the administration of lamivudine 150 mg twice daily for 7 days in 60 healthy volunteers, the AUC24, ss and Cmax 24, ss for the intracellular concentration of lamivudine-TF in peripheral blood mononuclear cells were similar, but the minimum values ​​for lamivudine 300 mg once a day were lower than with lamivudine 150 mg twice daily. Intersubject variability of lamivudine-TF concentration inside the cell was higher than in plasma. These results are confirmed by the data obtained with the administration of 300 mg lamivudine and 600 mg abacavir once daily (efficacy and safety of this combination once daily was also confirmed in the baseline clinical study CNA30021).

    Pharmacodynamic effects

    There was no antagonism of the antiviral activity of abacavir in cell culture when the latter was combined with nucleoside reverse transcriptase inhibitors (NRTIs) with HIV didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, a non-neuronosine reverse transcriptase (NNRTI) inhibitor of HIV nevirapine or a protease inhibitor (PI) HIV with amprenavir.

    There were no antagonistic effects in vitro with the simultaneous use of lamivudine and other antiretroviral drugs (tested substances: abacavir, didanosine, nevirapine, zalcitabine and zidovudine).

    Resistance of HIV-1 to lamivudine is due to a mutation in the codon M184Vlocated close to the active center of the virus OT. This mutation is observed both in conditions in vitro, and in HIV-1-infected patients who underwent combined therapy, including lamivudine. In case of mutation in the codon M184V significantly reduces the sensitivity to lamivudine and significantly reduces the ability of the virus to replicate according to research data in vitro. In studies in vitro it is established that zidovudine-resistant isolates of the virus can become susceptible to its action if these isolates develop resistance to lamivudine simultaneously. However, the clinical significance of such changes has not been determined to date.

    Abacavir-resistant isolates of HIV-1 were isolated under conditions in vitro. These isolates are characterized by certain genotypic changes in the OT codons (codons M184V, K65R, L74V and Y115F).

    HIV resistance to abacavir in vitro and in vivo formed slowly. For a clinically significant increase IC50 (inhibitory concentration in the ratio of 50 % strains) in 8 times with respect to the "wild" strain of the virus), multiple mutations of the viral genome are required. Resistant to abacavir isolates may also have a decreased sensitivity to lamivudine, zalcitabine, tenofovir, emtricitabine and / or didanosine, but remain sensitive to zidovudine and stavudine.

    The development of cross-resistance between abacavir and lamivudine and antiretroviral drugs of other classes (eg: HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors) is unlikely. HIV isolates with reduced susceptibility to abacavir were isolated in patients with uncontrolled replication of the virus, in which previous treatment with other NRTIs was ineffective.

    It is unlikely that clinical isolates of the virus that have three or more mutations associated with resistance to NRTIs will be sensitive to abacavir. Cross-resistance, due to M184V mutation of OT, is limited to a class of nucleoside inhibitors of antiretroviral drugs. Zidovudine, stavudine, abacavir and tenofovir retain their antiretroviral activity against HIV-1 lamivudine-resistant isolates that carry only M184V mutation.

    Pharmacokinetics:

    Suction

    Abacavir and lamivudine quickly and well absorbed after oral administration. Absolute bioavailability of abacavir and lamivudine in adults with oral administration is 83% and 80-85%, respectively. Mean time to maximum serum concentration (tmax) is about 1.5 hours and 1,0 h for abacavir and lamivudine, respectively. After a single oral intake of 600 mg of abacavir, the average CmOh is 4.26 μg / ml, and the mean AUC∞ - 11.95 μg / ml. After repeated oral administration of lamivudine 300 mg once a day for seven days, the average equilibrium CmOh is 2.04 μg / ml, and the mean AUC24 - 8.87 μg h / ml.

    Distribution

    Studies have shown that with intravenous administration, the average apparent volume of distribution of abacavir and lamivudine is 0.8 and 1.3 l / kg, respectively. In conditions in vitro the study found that when administered at therapeutic concentrations abacavir poorly or moderately (~ 49%) binds to human plasma proteins. Lamivudine demonstrates a linear change in pharmacokinetic parameters when using therapeutic doses and poorly binds to blood plasma proteins (less than 36%). This indicates a low probability of a variant of interaction with other drugs, in which the drug is displaced from the connection with plasma proteins. The available data indicate that abacavir and lamivudine penetrate into the central nervous system (CNS) and enter the cerebrospinal fluid (CSF). It was found that AUC for CSF is 30 to 44% of the value AUC for plasma. The peak concentration of abacavir in CSF when taken at a dose of 600 mg twice daily is 9 times that IC50 abacavir, which is 0.08 μg / ml or 0.26 μmol / l. The average ratio of the concentration of lamivudine in CSF to its serum concentration after 2 and 4 hours after oral administration of the drug is approximately 0.12.The true extent of lamivudine penetration into the central nervous system, as well as the clinical significance of this phenomenon, have not been established to date.

    Metabolism

    Abacavir is metabolized, mainly in the liver, in an unchanged form is released by the kidneys of less than 2% of the accepted dose of the drug. In humans 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 constituting about 66% of the total administered dose of the drug. These metabolites are excreted by the kidneys.

    Lamivudine is almost not metabolized and is mainly excreted unchanged by the kidneys. The likelihood of metabolic interactions with lamivudine is low, since a small proportion of the liver is metabolized (less 10%) of the accepted dose of the drug.

    Excretion

    The mean half-life of abacavir is approximately 1.5 hours. After repeated oral administration of abacavir (300 mg twice daily), there is no significant accumulation of abacavir. Abacavir is excreted by metabolism in the liver with subsequent excretion of metabolites mainly through the kidneys.In urine, approximately 83% of the accepted dose of abacavir is detected in the form of metabolites and unchanged. The rest is removed through the intestine.

    The half-life of lamivudine is from 5 to 7 hours. The average total clearance for lamivudine is approximately 0.32 L / h / kg, most of which is renal clearance (> 70%) by the organic cationic transport system.

    Special patient groups

    Children

    Abacavir is well and quickly absorbed in the form of a solution for oral administration and tablets when ingested in children. It was demonstrated that the exposure of abacavir in blood plasma is the same for both dosage forms at the same dosage. In children receiving abacavir in the form of a solution for oral administration in accordance with the recommended dosing regimen, the same exposure in blood plasma as in adults is achieved. In children receiving abacavir in the form of tablets in accordance with the recommended dosing regimen, exposure in the blood plasma is higher than in children receiving abacavir in the form of a solution for oral administration, in connection with the administration of higher doses in mg / kg with the administration of tablets.Pharmacokinetic studies in children showed that taking the drug 1 time per day is equivalent in terms of AUC24 Receive the same dose of the drug in the form of a solution for oral administration or tablets, divided into 2 doses.

    The absolute bioavailability of lamivudine (approximately 58-66%) was lower and more variable in children under 12 years of age. At children at reception of tablets of value AUC∞ and CmOh lamivudine in the blood plasma were higher than when taking a solution for oral administration. In children receiving lamivudine in the form of a solution for oral administration in accordance with the recommended dosing regimen, the exposure of lamivudine in blood plasma is in the range of values ​​noted in adults. In children receiving lamivudine in the form of tablets in accordance with the recommended dosing regimen, lamivudine exposure in the blood plasma is higher than in children receiving oral solution, due to higher doses in mg / kg and higher bioavailability when taking tablets (see section "Method application and dose "). Pharmacokinetic studies of lamivudine in children have shown that taking the drug 1 once a day is equivalent in terms of AUC24 taking the drug 2 once a day at the same daily dose for both the oral solution and the tablets.

    Dysfunction of the liver

    There are data on the pharmacokinetics of abacavir and lamivudine, obtained with separate use of drugs. The pharmacokinetics of abacavir has been studied in patients with mild liver function disorders (5-6 on the Child-Pugh scale). The study found that AUC Abacavir increased by an average of 1.89-fold, and half-life increased 1.58 times. With liver diseases AUC the individual metabolites of the drug did not change. However, the rate of formation and excretion of these metabolites decreased. Patients with mild liver function disorders need to reduce the daily dose of abacavir. To treat such patients, a drug containing only abacavir. Studies of the pharmacokinetics of abacavir in patients with violations of liver function of medium and severe degree have not been conducted. It is assumed that in such patients the concentration of abacavir in plasma will be characterized by considerable variability and will be significantly increased.In this regard, the use of drugs containing abacavir, is contraindicated in patients with impaired liver function of medium and severe degree.

    The data obtained with the use of lamivudine in patients with violations of the liver function of moderate and severe degree, indicate that significant changes in the pharmacokinetic parameters of the drug in the violation of liver function does not occur.

    Renal impairment

    There are data on the pharmacokinetics of abacavir and lamivudine, obtained with separate use of drugs. Abacavir it is metabolized mainly in the liver. Approximately 2% of abacavir is excreted unchanged by the kidneys. The pharmacokinetic indices of abacavir in patients with terminal stage of renal insufficiency and normal renal function are practically unchanged. Studies have shown that in patients with impaired renal function, the concentration (AUC) of lamivudine in plasma increases due to lower clearance. In connection with the need to reduce the dose of lamivudine in patients with creatinine clearance less than 50 ml / min, such patients should be prescribed a lamivudine mono drug.

    Indications:

    Treatment of HIV infection in combination antiretroviral therapy for adults and children weighing at least 25 kg.

    Contraindications:

    - Hypersensitivity to abacavir or lamivudine, or any other component of the drug;

    - hepatic failure secondary to severe (grade B and C Child-Pugh (in the absence of clinical data and the recommended dosing regimen));

    - hepatic insufficiency of mild degree (class A on the Child-Pugh scale (due to the lack of a recommended dosing regimen));

    - impaired renal function (with creatinine clearance less than 50 ml / min (due to lack of recommended dosing regimen));

    - body weight less than 25 kg (due to the lack of a recommended dosing regimen).

    Carefully:

    Care must be taken when applying Alaget drug, especially in patients with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain drugs and alcohol).

    When prescribing antiretroviral therapy, including abacavir, it is necessary to take into account the existing risk of coronary heart disease.

    Pregnancy and lactation:

    Fertility

    Animal studies have shown that neither abacavir, nor lamivudine do not affect fertility.

    Pregnancy

    There are no adequate and strictly controlled studies involving pregnant women, the safety of using abacavir, lamivudine or a combination of abacavir / lamivudine in pregnancy in humans has not been established to date. Therefore, during pregnancy, Alaget should be used only if the intended benefit to the mother exceeds the potential risk to the fetus.

    The impact of abacavir was assessed based on the Registry of Antiretroviral Drugs in Pregnant Women, which was obtained from more than 2000 women during pregnancy and the postpartum period. Available data from the Registry of Antiretroviral Drugs in Pregnant women do not indicate an increased risk of significant birth defects when abacavir is used compared to their background frequency.

    The impact of lamivudine has been evaluated on the basis of the Registry of Antiretroviral Drugs in Pregnant Women who received more than 11000 women during pregnancy and in the postpartum period. The available data for a person from the Registry on the use of antiretroviral drugs in pregnant women does not indicate an increased risk of significant birth defects when using lamivudine compared to their baseline frequency.

    There are no data on the use of the combined drug during pregnancy.

    A small amount of data in pregnant women taking a combination of mono drugs abacavir and lamivudine, do not indicate malformative toxicity (more than 400 outcomes in the first trimester of pregnancy). A large amount of data for lamivudine (more than 3000 outcomes in the first trimester of pregnancy) does not indicate malformative toxicity. A small amount of data (more than 600 outcomes in the first trimester of pregnancy) do not indicate malformative toxicity of abacavir. Based on the data volume mentioned, malformational risk in humans is unlikely. Lamivudine and abacavir penetrate the placenta. Lamivudine did not show teratogenicity, but increased early embryonic mortality in rabbits, but not in rats, with systemic exposure comparable to that achieved in humans. Abacavir showed embryophototoxicity in rats, but not in rabbits (reduced fetal mass, embryonic edema and an increase in the number of cases of skeletal changes / malformation, early intrauterine mortality and stillbirth).

    There is evidence of a slight transient increase in lactate concentration in the blood plasma, possibly due to mitochondrial disorders in newborns and infants whose mothers took NRTIs during pregnancy and in the perinatal period. The clinical significance of this enhancement is not currently established. In addition, there are very few reports of developmental delay, convulsive seizures and other neurological disorders, such as increased muscle tone. However, the causal relationship of these disorders to the effect of NRTIs during the intrauterine and perinatal periods has not been established. These data do not abolish existing recommendations for antiretroviral therapy (Apt) during pregnancy to prevent vertical transmission of HIV.

    Breastfeeding period

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

    In the study, after repeated oral administration of 150 mg of lamivudine 2 times a day (in combination with zidovudine 300 mg twice a day) or 300 mg of lamivudine 2 times a day, lamivudine was excreted in breast milk (0.5 to 8.2 μg / ml), in similar concentrations lamivudine was found in the serum. In other studies, after repeated oral administration of 150 mg lamivudine 2 (as in combination with zidovudine 300 mg, as well as in Combivir® or Trizivir®), the ratio of lamivudine concentration in breast milk and maternal blood plasma was between 0.6 and 3.3. In studies after repeated oral administration of 300 mg of abacavir 2 times a day (taken in the form of Trizivir®), the concentration ratio in breast milk and maternal plasma was 0.9. For oral administration of abacavir 1 once a day, pharmacokinetic studies were not conducted. The median of lamivudine concentration in the serum in infants was between 18 and 28 ng / ml and was not determined in one of the studies (sensitivity of the assay was 7 ng / ml). Most babies (8 of 9) had undetectable levels of abacavir (sensitivity analysis - 16 ng / ml). The content of intracellular lamivudine-TF and carbovir-TF (active metabolites of lamivudine and abacavir) in infants with breastfeeding has not been measured, therefore the clinical significance of measurements of the serum concentration of the parent compound is unknown.

    Dosing and Administration:

    Therapy should be performed by a physician with experience in the treatment of HIV infection.

    Due to the impossibility of dose adjustment when using combined tablets with fixed dosages of components, the drug should not be administered to adults and adolescents whose weight is less than 25 kg.

    Tablets can be taken regardless of food intake.

    Combined drugs with fixed doses of components are contraindicated when it may be necessary to adjust the dose, for example, when creatinine clearance is less than 50 ml / min, as well as in liver failure.

    In case of discontinuation of Alaget or if necessary dose adjustment abacavir or lamivudine should be given as mono drugs.In such situations, the doctor should become familiar with the instructions for the use of these medications.

    Patient groups

    Adults and children with a body weight of at least 25 kg

    The recommended dose is 1 tablet once a day daily.

    Children with body weight up to 25 kg

    It is not recommended to use the drug to treat children weighing less than 25 kg due to the lack of a recommended dosing regimen. For the selection of therapy, physicians are advised to consult the instructions for the use of lamivudine and abacavir.

    Elderly patients

    The pharmacokinetics of abacavir and lamivudine in patients older than 65 years have not been studied. In treating elderly patients, the increased incidence of liver, kidney, heart, and other comorbid conditions, as well as the use of other medications, should be considered. Special care must be taken when using the drug in this age group because of age-related changes such as decreased kidney function and changes in blood parameters.

    Patients with impaired renal function

    While patients with impaired renal function do not need a dose adjustment for abacavir, the dose of lamivudine should be reduced in proportion to the decrease in creatinine clearance.In this regard, it is contraindicated to use Alaget in the clearance of creatinine less than 50 ml / min.

    Patients with impaired hepatic function

    Patients with impaired liver function mild (Class A scale Chayld- Pugh), may require a reduction in the dose of abacavir. In connection with the inability to reduce the dose when using the combination preparation, should use separate preparations of abacavir and lamivudine. Alaget is contraindicated in patients with impaired liver function.

    Side effects:

    Since Alaget is a combined preparation, it may be a manifestation of adverse reactions typical of abacavir and lamivudine. For many of the following adverse reactions remains unclear whether their appearance due to the action of the active substances of the drug, while the use of other drugs (used to treat HIV infection), or they are a manifestation of the underlying disease.

    Characteristic for the administration of abacavir or lamivudine, the adverse reactions listed below are listed in accordance with organ and organ damage and frequency of occurrence.Frequency of occurrence is defined as follows: 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 and post-registration surveillance.

    Many of the unwanted reactions (nausea, vomiting, diarrhea, fever, apathy, rash) often occur in patients with hypersensitivity to abacavir. Therefore, patients with any of these symptoms should be carefully screened to exclude the hypersensitivity reaction (MRI). If the combination was stopped due to one of these symptoms, and then a decision was made to resume taking abacavir, it should be started only under the direct supervision of the doctor.

    In addition to the undesirable reactions described in the clinical studies, the table below shows the undesirable reactions found in the post-marketing application of abacavir and lamivudine. These reactions were selected for inclusion in the table due to a possible causal relationship with abacavir and / or lamivudine.

    Clinical research data and post-registration data

    Body System

    Abacavir

    Lamivudine

    Violations of the blood and lymphatic system


    Infrequently: neutropenia, anemia, thrombocytopenia

    Rarely: true erythrocyte aplasia *

    Immune system disorders

    Often: hypersensitivity to the drug


    Disorders from the metabolism and nutrition

    Often: anorexia, hyperlactatemia *

    Rarely: lactic acidosis *

    Often: hyperlactatemia

    Rarely: lactic acidosis *

    Disturbances from the nervous system

    Often: headache

    Often: headache

    Rarely: paresthesia, peripheral neuropathy is described (cause-and-effect relationship with treatment not established) *

    Infringements from gastrointestinal tract

    Often: nausea, vomiting, diarrhea

    Rarely: pancreatitis, but the cause-effect relationship with the reception of abacavir is not established *

    Often: nausea, vomiting, pain in the upper abdomen, diarrhea

    Rarely: increased activity of serum amylase, pancreatitis (cause-effect relationship with lamivudine not established) *

    Disorders from the liver and bile ducts


    Infrequently: temporary increase in biochemical parameters of liver function (ACT, ALT)

    Disturbances from the skin and subcutaneous tissues

    Often: rash (without systemic symptoms) *Rarely: exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis *

    Often: rash, alopecia *

    General disorders and disorders at the site of administration

    Often: fever, apathy, fatigue

    Often: feeling tired, malaise, fever

    Disturbances from musculoskeletal and connective tissue *


    Often: arthralgia, muscle damage *

    Rarely: rhabdomyolysis *

    * adverse reactions described in clinical trials

    Children

    Safety data confirming single dosing of the combined preparation in children were obtained in the study ARROW (COL 105677), in which 699 children infected with HIV-1 received abacavir and lamivudine 1 or 2 times a day. In this group, 104 infants infected with HIV-1 with a body weight of at least 25 kg received abacavir and lamivudine in a combination preparation 1 or 2 times a day. There were no additional safety signals for children taking the drug 1 or 2 times a day, compared with adults.

    Description of individual adverse reactions

    Hypersensitivity

    The hGH to abacavir was defined as a general undesirable reaction in the treatment with drugs containing abacavir. The signs and symptoms of MRI are listed below.

    These signs and symptoms were identified during clinical trials or post-marketing follow-up. Symptoms and symptoms that occur in at least 10% of patients with MRI are highlighted in bold.

    Disturbances from the skin and subcutaneous tissues: rash (usually maculopapular or urticarum).

    Disorders from the gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain, ulceration of the oral mucosa.

    Disturbances from the respiratory system, organs of the thorax and mediastinum: shortness of breath, cough, sore throat, adult respiratory distress syndrome, respiratory failure.

    Impaired nervous system: headache, paresthesia.

    Violations from the blood and lymphatic system: lymphopenia.

    Disorders from the liver and bile ducts: increase of biochemical parameters of liver function, hepatitis, hepatic insufficiency.

    Disturbances from the musculoskeletal and connective tissue: myalgia, rarely - myolysis, arthralgia, increased activity of creatine phosphokinase.

    Disorders from the kidneys and urinary tract: increased serum creatinine concentration, renal failure.

    General disorders and disorders at the site of administration: fever, fatigue, malaise, edema, lymphadenopathy, arterial hypotension, conjunctivitis, anaphylaxis.

    Renewal of abacavir / lamivudine combination in patients after WGH on abacavir leads to a rapid return of symptoms within a few hours. Repeated MRI usually proceeds more severely than the first, and may include life-threatening arterial hypotension and death. In rare cases, the reaction also occurs when the abacavir is resumed after its withdrawal, caused by the appearance of just one of the main symptoms (see above), and in very rare cases this reaction occurs when the abacavir is resumed in patients who had no symptoms prior to withdrawal hypersensitivity (i.e.in patients previously thought to be abacavir-treated).

    Detailed information on the clinical management of a suspected MRSV case abacavir see "Special instructions".

    There are reports of the development of lactic acidosis, including fatal, usually accompanied by severe hepatomegaly with steatosis, due to Apt analogues of nucleosides.

    Application of combined Apt was associated with the redistribution of adipose tissue (lipodystrophy) in patients with HIV, including a reduction in the subcutaneous fat layer on the face and extremities, an increase in intra-abdominal and visceral fat, an increase in mammary glands and dorsocervical fat deposition (buffalo hump). Application of combined Apt was associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

    In HIV-infected patients with severe immunodeficiency during the onset of combined Apt there may be inflammatory responses to asymptomatic or residual opportunistic infections. There have also been cases of autoimmune diseases (eg, Graves' disease) occurring under conditions of immune reactivation,However, the presented terms of manifestation of the disease are more diverse, and these phenomena can occur many months after the initiation of therapy.

    Cases of osteonecrosis have been reported, especially in patients with recognized risk factors, late HIV infection or long-term combined Apt. The frequency of occurrence of this phenomenon is unknown.

    Overdose:

    Symptoms

    There were no specific symptoms or signs of acute overdose of abacavir and lamivudine other than those listed in the "Side effect" section.

    Treatment

    In case of an overdose, the patient should be under the supervision of a doctor (in order to identify signs of toxic effects of the drug). If necessary, conduct a standard maintenance therapy. Due to lamivudine can be removed from the body by dialysis, treatment of an overdose should include continuous hemodialysis (although studies to study the possibility of hemodialysis during drug overdose have not been performed). At present, it is not known whether peritoneal dialysis and hemodialysis contribute to the excretion of abacavir from the body.

    Interaction:

    The spectrum of interactions of the drug is determined by the nature of the interactions of abacavir and lamivudine, among which, to date, there are no clinically significant.

    Abacavir and lamivudine are slightly metabolized by enzymes of the cytochrome P450 system (for example: CYP 3A4, CYP 2C9 or CYP 2D6) and do not have an inhibitory or inductive effect on this enzyme system. Therefore, the probability of drug interaction with antiretroviral non-nucleoside protease inhibitors and other drugs, the metabolism of which occurs with the participation of the main enzymes of the cytochrome P system450, is small. The likelihood of metabolic interactions with lamivudine is low, since it is not metabolized very much. slightly binds to plasma proteins and is excreted almost exclusively by the kidneys. Lamivudine is excreted mainly through active tubular secretion through the transport system of organic cations. Consideration should be given to the possibility of interacting with other medicinal products, especially in cases where the kidneys are the main way of excretion.

    Drug interactions due to the presence of abacavir

    Ethanol

    The metabolism of abacavir is disturbed by simultaneous administration with ethanol, which leads to an increase AUC abacavir by approximately 41%. Given the safety profile of abacavir, these data are not considered clinically relevant. Abacavir does not affect the metabolism of ethanol.

    Methadone

    In a study of the pharmacokinetics of drugs with simultaneous administration of abacavir (at a dose of 600 mg once, then 600 mg twice a day) and methadone (40 mg to 90 mg once a day), a decrease in CmOh abacavir at 35% and a decrease in TmOh for 1 hour, however AUC remained unchanged. Changes in the pharmacokinetics of abacavir have not been clinically significant. In this study abacavir increased the average total methadone clearance by 22%. This change was not clinically significant in most patients, but there may sometimes be a need for a methadone dose adjustment. There is no need to adjust the dose of Alaget.

    Didanosine

    The interaction has not been studied. No dose adjustment is required.

    Zidovudine

    The interaction has not been studied.No dose adjustment is required.

    Rifampicin

    The interaction has not been studied. It may slightly increase the concentration of abacavir in the blood plasma by the induction of UDP-glucuronyl transferase (UDF-HT). There is not enough data to recommend a dose adjustment.

    Cimetidine

    The interaction has not been studied. No dose adjustment is required.

    Retinoid compounds (eg, isotretinoin)

    The interaction has not been studied. Perhaps interaction, given the general pathway of elimination under the influence of alcohol dehydrogenase. There is not enough data to recommend a dose adjustment.

    Ribavirin

    The interaction has not been studied. Theoretically, a decrease in the intracellular concentration of phosphorylated metabolites is possible. Care is required when using these medicines together.

    Phenobarbital

    The interaction has not been studied. It may slightly increase the concentration of abacavir in the plasma by induction of UDF-HT. There is not enough data to recommend a dose adjustment.

    Phenytoin

    The interaction has not been studied. It may slightly increase the concentration of abacavir in the plasma by induction of UDF-HT. There is not enough data to recommend a dose adjustment.It is necessary to monitor the concentration of phenytoin.

    Drug Interactions, caused by the presence of lamivudine

    Trimethoprim

    Acceptance of trimethoprim / sulfamethoxazole 160 mg / 800 mg (co-trimoxazole) causes an increase in lamivudine exposure by 40%, which is due to the presence of trimethoprim. However, except for patients with renal failure, a dose adjustment of lamivudine is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. Joint use of lamivudine with higher doses of co-trimoxazole used to treat pneumonia (caused by Pneumocystis carinii) and toxoplasmosis, has not been studied.

    Zalcitabine

    Lamivudine can suppress intracellular phosphorylation of zalcitabine while simultaneously taking these drugs. In this regard, the simultaneous use of the drug Alaget and with zalcitabine is contraindicated.

    Emtricitabine

    With simultaneous application lamivudine can inhibit intracellular phosphorylation of emtricitabine. In addition, the mechanism of development of resistance to both lamivudine and emtricitabine is associated with a mutation in the same codon of the reverse transcriptase gene (M184V), and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. The use of lamivudine in combination with emtricitabine or fixed dose combinations containing emtricitabine, is contraindicated.

    Didanosine

    The interaction has not been studied. No dose adjustment is required.

    Zidovudine

    Zidovudine in a dose of 300 mg once, lamivudine in a dose of 150 mg once. Lamivudine: AUC without changes. Zidovudine: AUC without changes. No dose adjustment is required.

    Rifampicin

    The interaction has not been studied. There is not enough data to recommend a dose adjustment.

    Cimetidine

    The interaction has not been studied. Clinically significant interaction is not expected. Cimetidine is partially excreted by the renal organic cationic transport system. No dose adjustment is required.

    Cladribine

    The interaction has not been studied.

    In vitro lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a potential risk of loss of cladribine efficacy when combined in clinical practice. Some clinical data also confirm the interaction between lamivudine and cladribine.

    Thus, the simultaneous use of lamivudine and cladribine is contraindicated.

    Retinoid compounds (for example, isotretinoin)

    The interaction has not been studied. There is not enough data to recommend a dose adjustment.

    Methadone

    The interaction has not been studied. No dose adjustment is required for Alaget. For most patients, methadone dose adjustment is not required, in rare cases, it may be necessary to repurpose.

    Special instructions:

    This section contains guidelines for abacavir and lamivudine. There are no additional specific indications relating to a fixed combination of doses of abacavir and lamivudine.

    Hypersensitivity to abacavir

    The use of abacavir is associated with the risk of HSR, characterized by the appearance of temperature increase and / or rash and other symptoms suggestive of multiple organ lesions. The MRI may be life threatening and, in rare cases, when no appropriate treatment is prescribed, death can result. The risk of developing MRI with abacavir is significantly increased in patients with a positive test for the presence of an allele HLA-B* 5701. However, abacavir with a lower frequency observed in patients who are not carriers of this allele.

    The following rules should be observed:

    - A study should be conducted for the presence of an allele HLA-B* 5701 before initiation of therapy with Alaget and also before resumption of therapy with Alaget in patients with unknown status for the allele HLA-B* 5701, previously well tolerated with abacavir therapy.

    - It is not recommended to use Alaget in patients with an allele HLA-B * 5701 or in patients who were suspected of having an MRI during the administration of any other drug containing abacavir (eg, drugs Ziagen®, Trizivir®) regardless of status in relation to HLA- B * 5701.

    - Each patient should be reminded that it is necessary to read the instructions for use, enclosed in the package of the drug. Also, patients should be reminded that they should always carry a warning card attached to the drug.

    - In all patients receiving Alaget, the clinical diagnosis of a suspected hypersensitivity reaction should remain the basis for making a clinical decision.

    - If MRI is suspected, therapy with Alaget should be stopped immediately, even if there is no allele HLA-B* 5701. The delay in discontinuing therapy with Alaget with the emergence of MRI may lead to a life-threatening reaction.

    - Patients who developed MRLT should be informed about the need to transfer the remaining tablets of the drug Alaget to the treating doctor in order to avoid the resumption of taking abacavir.

    - Renewal of the use of drugs containing abacavir, after the suspected MRI on abacavir can lead to a rapid return of MHV symptoms within a few hours, which may include life-threatening arterial hypotension and death.

    - When considering the resumption of therapy with abacavir after discontinuation of treatment with any containing abacavir the drug for any reason should be determined the reason for discontinuing therapy, regardless of the patient's carriage of the allele HLA-B* 5701. If the MRI can not be ruled out, it is not possible to resume therapy with Alaget or any medications containing abacavir (for example, Ziagen®, Trizivir®).

    - If the MRI is excluded, it is possible to resume therapy with Alaget. In rare cases, patients who discontinued abacavir use for reasons other than MRS symptoms also reported the development of life-threatening reactions within a few hours after resumption of abacavir therapy (see section "Description of individual adverse reactions"). Patients should be informed of the possibility of developing an MRI in the resumption of therapy with Alaget or other medications containing abacavir (for example, Ziagen®, Trizivir®), and that when resuming therapy with Alaget or other medications containing abacavir (eg, drugs Ziagen®, Trizivir®) should only be carried out with quick access to medical care.

    Clinical picture of MRI on abacavir

    MIRVs on abacavir were well studied in clinical trials and during post-registration follow-up. The reaction of hypersensitivity is characterized by the appearance of symptoms of multiple organ failure. The symptoms of MRI usually appear within the first six weeks (the median time of the onset of this reaction - 11 days) after the start of the drug, however, these reactions can develop at any time during the therapy.

    Virtually all of the MRI reactions include increased body temperature and / or rash as part of the syndrome. Other signs and symptoms that are noted as a manifestation of WGS on abacavir, include symptoms on the part of the respiratory and gastrointestinal tract, which can lead to incorrect diagnosis of MRI as a respiratory disease (pneumonia, bronchitis, pharyngitis) or gastroenteritis (see "Side effects", "Description of individual adverse reactions"). When continuing therapy with drugs containing abacavir, the severity of symptoms associated with MRIs is increasing, and they can be life threatening character. In most cases, these symptoms disappear after discontinuation of abacavir therapy.

    Lactic acidosis and severe hepatomegaly with steatosis

    There are reports of the development of lactic acidosis, severe hepatomegaly with steatosis, including fatal Apt analogues of nucleosides in the form of individual preparations, including abacavir, lamivudine or a combination thereof.Similar phenomena were observed, mainly, in women.

    The clinical signs of developing lactic acidosis are gastrointestinal symptoms (nausea, vomiting and abdominal pain), general weakness, anorexia, loss of appetite, rapid unexplained weight loss, symptoms of gastrointestinal and respiratory damage (dyspnea and tachypnea), or neurological symptoms (including motor weakness).

    Caution should be exercised when prescribing Alaget, especially in patients with hepatomegaly, hepatitis, or other risk factors for liver damage and liver steatosis (including certain drugs and alcohol). Patients with co-infection with hepatitis C and patients who receive treatment with alpha interferon and ribavirin may constitute a special risk group. The use of the drug should be discontinued when clinical or laboratory signs of lactic acidosis occur with or without hepatitis (which include hepatomegaly and steatosis, even in the absence of a significant increase in aminotransferase activity) in symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis,progressive hepatomegaly or with a rapid increase in aminotransferase activity.

    Lipodystrophy

    In some patients receiving combined Apt, redistribution and / or accumulation of subcutaneous fat can be observed, including obesity in the central type, 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 concentration glucose in the blood, either individually or together.

    Although all drugs from PI and NRTI classes can cause one or more of the above unwanted reactions associated with a general syndrome, often called lipodystrophy, the accumulated evidence suggests 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 duration Apt play an important, possibly synergistic role in the development of this complication.

    The long-term consequences of these undesirable phenomena are still unknown.

    During the clinical examination, attention should be paid to the signs of redistribution of subcutaneous fat. It is necessary to closely monitor the serum lipids concentration and blood glucose concentration. If the lipid metabolism is disturbed, an appropriate treatment is prescribed.

    Immunodeficiency Syndrome

    In the presence of HIV-infected patients with severe immunodeficiency asymptomatic opportunistic infections or their residual effects at the time of onset Apt, 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 the onset of ART. Typical examples are cytomegalovirus retinitis, generalized or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (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.

    Opportunistic infections

    The use of the drug Alaget or other antiretroviral drugs does not exclude the possibility of developing opportunistic infections or other complications of HIV infection, so patients should remain under the supervision of a doctor who has experience in the treatment of HIV-associated diseases.

    Transmission of HIV infection

    Patients should be warned that treatment with antiretroviral drugs, including Alaget, does not prevent the risk of HIV transmission to other people during sexual intercourse or blood contamination. Therefore, patients should take appropriate precautions.

    Myocardial infarction

    As a result of a prospective observational epidemiological study to study the incidence of myocardial infarction in patients receiving a combined Apt, a link was found between the previous administration of abacavir for 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 myocardial infarction associated with abacavir. Biological mechanisms that explain a potentially increased risk are unknown. In general, the available data from observing cohorts and controlled clinical studies do not allow one to unequivocally determine the relationship of abacavir therapy with the risk of myocardial infarction. Nevertheless, caution should be given to Apt, including preparations containing abacavir. patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize risk factors (such as hypertension, hyperlipidemia, diabetes and smoking).

    Pancreatitis

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

    Kidney Diseases

    The use of Alaget is contraindicated in patients with creatinine clearance less than 50 ml / min.

    Diseases of the liver

    The efficacy and safety of the combination of abacavir / lamivudine have not been established in patients with severe concomitant liver disease.The use of Alaget is contraindicated in patients with impaired liver function.

    In patients with an initially present impaired liver function, including an active form of chronic hepatitis, there is an increase in the incidence of abnormalities on the part of the liver with combined Apt. Such patients need to be monitored in accordance with standard clinical practice.

    Patients with chronic hepatitis B or C

    Clinical studies and post-registration data on the use of lamivudine suggest that in some patients with concomitant viral hepatitis B (HBV), clinical or laboratory signs of hepatitis recurrence may appear after stopping lamivudine, which may have more severe consequences in patients with decompensated liver damage. As a result, in patients with concomitant viral hepatitis B, when Alaget is withdrawn, indicators of functional hepatic samples should be monitored and the markers for hepatitis B virus replication should be regularly determined.

    Due to abacavir and ribavirin have the same phosphorylation pathways, an interaction between these substances is suggested that 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 pegylated interferon and ribavirin. 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 should be taken when taking these medications at the same time.

    Mitochondrial dysfunction

    Research in vitro and in vivo showed that the analogues of nucleosides and nucleotides can cause a different degree of damage to the mitochondria. 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 (muscle tone increase, 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 affect the current national recommendations for use Apt in pregnant women for the prevention of vertical transmission of HIV infection.

    Osteonecrosis

    Despite the fact that 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 encountered in patients at a late stage of HIV infection and / or for a long time taking a combined Apt. Patients should consult a doctor if they experience pain and stiffness in the joints or difficulty moving.

    Risk of virological failure

    Triple Nucleoside Therapy: a high incidence of virological failure and early resistance was documented with the simultaneous administration of abacavir and lamivudine with tenofovir disoproxil fumarate under the dosing regimen 1 once a day.

    The risk of virological failure with Alaget may be higher than in other possible therapies.

    The drug Alaget should not be taken together with other medicines containing lamivudine, or medicinal products containing emtricitabine.

    The simultaneous use of lamivudine and cladribine is contraindicated.

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

    Special studies of the effects of abacavir or lamivudine on the ability to drive vehicles or mechanisms have not been conducted. In addition, the negative impact on such activities can not be predicted, based on the pharmacology of these drugs.When assessing a patient's ability to drive vehicles or mechanisms, his general condition, as well as the profile of unwanted reactions of Alaget, should be taken into account.

    Form release / dosage:

    Film-coated tablets, 600 mg + 300 mg.

    Packaging:

    Primary packaging of medicinal product

    For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

    To 30, 60, 90, 120 tablets in a polymer jar of low-pressure polyethylene with a lid of a high-pressure polyethylene pulled from the first opening under control.

    Free space is filled with cotton wool. Labels are applied to cans from paper label or writing or from polymeric materials, self-adhesive.

    Secondary packaging of medicinal product

    By 3, 6, 9 contour mesh packages together with the instruction for use are placed in a pack of cardboard for consumer containers. The packets are placed in a group package.

    On 1 bank together with instructions on application place in a pack from a cardboard. The packets are placed in a group package.

    Storage conditions:

    In the original packaging of the manufacturer, at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 of the year.

    Do not use after the expiration date indicated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003600
    Date of registration:04.05.2016
    Expiration Date:04.05.2021
    The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia
    Manufacturer: & nbsp
    Information update date: & nbsp28.06.2017
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