Abacavir + Lamivudine - instructions for use, dose, side effects, contraindications

Composition per 1 tablet
Active substances: abacavir sulfate 702.6 mg (equivalent to 600 mg of abacavir), lamivudine 300 mg.
Excipients: lactose monohydrate 40 mg, microcrystalline cellulose 44.4 mg, sodium carboxymethyl starch 7 mg, povidone-K 30 10 mg, talc 3 mg, magnesium stearate 3 mg.
The composition of the shell: povidone-K 30 1.5 mg, hypromellose 5 mg, talc 2 mg, titanium dioxide 1.44 mg, dye "sunset sun" yellow (E110) 0.06 mg.

Description:

Tablets are capsular-shaped, biconvex, film-coated, yellow. On the cross-section - the core is from white to almost white.

Pharmacotherapeutic group:Antiviral (HIV) agent

ATX: & nbsp

J.05.A.R.02 Abacavir + Lamivudine

Pharmacodynamics:

Abacavir and lamivudine belong to the group of nucleoside inhibitors of HIV reverse transcriptase 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 the blood plasma in this study was 2.6 h.Equilibrium pharmacokinetic indices when taking abacavir 600 mg once a day were similar to those with abacavir 300 mg twice daily in a cross-sectional clinical trial on 27 HIV-infected patients. The intracellular content of carbovir-triphosphate in peripheral blood mononuclear cells was higher when taking abacavir at a dosage of 600 mg 1 time per day compared with 300 mg twice a day for abacavir (an increase in the area under the concentration-time curve in equilibrium for 24 hoursAUC₂₄._ss) by 32%, the maximum daily concentration in a state of equilibrium (C_max_24,_ss) - by 99% and the residual concentration - by 18%). In patients who took lamivudine 300 mg once a day 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 a day for 7 days compared with taking lamivudine 150 mg twice daily for 7 days, conducted on 60 healthy volunteers, showed that the values AUC₂₄._ss and C_max₂₄,_ss for the intracellular concentration of lamivudine-TF in mononuclears of peripheral blood were identical,but the minimum values for taking lamivudine 300 mg once a day were lower than when taking lamivudine 150 mg twice daily.

The variability of the concentration of lamivudine metabolites inside the cell is 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 when taking the medications once a day was also confirmed daily in the baseline clinical trial CNA30021).

Pharmacodynamic effects

There was no antagonism of antiviral activity of abacavir in cell culture when the latter was combined with NDTI with HIV didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine or a protease inhibitor (HIV) 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. Also in studies in vitro it has been established that zidovudine-resistant isolates of the virus can become susceptible to the action of the drug if the resistance to lamivudine in these isolates develops subsequently. However, the clinical significance of such changes has not been determined to date.

Abacavir-resistant isolates of HIV-1 were obtained 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 in the inhibitory concentration with respect to 50% of strains 1C₅₀(1C increase₅₀ (inhibitory concentration in 50% of strains) is 8 times 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 [IP] and non-nucleoside reverse transcriptase inhibitors [NNRTI]) is unlikely. HIV isolates with reduced sensitivity to abacavir were isolated in patients with uncontrolled viral replication, in which previous treatment with other nucleoside reverse transcriptase inhibitors was ineffective. Clinical isolates of the virus with three or more mutations associated with resistance to nucleoside reverse transcriptase inhibitors (HIV) (NRTIs) are also likely to be resistant to abacavir. Cross-resistance, due to M184V mutation from HIV, is limited to a class of nucleoside inhibitors of HIV-1. Zidovudine, stavudine, abacavir and tenofovir retain their antiretroviral activity against HIV-1 lamivudine-resistant isolates that carry only M184V mutation.

Pharmacokinetics:

There were no clinically significant changes in pharmacokinetic parameters due to taking a combined preparation on an empty stomach or with food. it indicates that the drug Abacavir + Lamivudine can be taken regardless of food intake.

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 (T_ma_x) is about 1.5 h and 1.0 h for abacavir and lamivudine, respectively. After a single oral intake of 600 mg of abacavir, the mean peak concentration in plasma (C_m_Oh) is 4.26 μg / ml, and the area under the concentration-time curve (AUC_X) on the average - 11,95 mkg * h / ml. After repeated oral administration of lamivudine 300 mg once a day for seven days, the average equilibrium C_m_Oh is 2.04 μg / ml, and the mean AUC - 8.87 μg * h / ml.

Distribution

In conditions in vitro it was found that when administered at therapeutic concentrations abacavir slightly (about 49%) binds to human plasma proteins. Lamivudine demonstrates a linear change in pharmacokinetic parameters when using therapeutic doses and is slightly associated with blood plasma proteins (less than 36%). This indicates a low probability of interaction with other medicinal products due to the displacement of plasma from the connection with 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 blood plasma. The peak concentration of abacavir in CSF when taken at a dose of 600 mg twice daily is 9 times higher than the concentration of abacavir, in which binding is reduced by 50% (1C₅"), Which is 0.08 m kg / ml or 0.26 mcmol / 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 unchanged form it is secreted by the kidneys of less than 2 % the accepted dose of the drug. In humans abacavir is metabolized mainly by the action of alcohol dehydrogenase to form 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.

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

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 in the urine. 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%),carried out by active tubular secretion through the system of transport of organic cations.

Special patient groups

Children

Abacavir is quickly and well absorbed in the form of tablets when ingested in children. Pharmacokinetic studies in children showed that taking the drug 1 time per day is equivalent in terms of indices AUC₂₄ Reception of the same dose of the drug, divided into 2 times a day.

The absolute bioavailability of lamivudine (approximately 58-66%) was lower and more variable in children under 12 years of age. In studies of pharmacokinetics in children it was demonstrated that when taking the drug 1 time per day AUC₂₄ is equivalent to that when taking the drug 2 times a day at the same daily dose.

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 (Class A 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 (Class A on the Child-Pugh scale) should reduce the daily dose of abacavir. To treat such patients, a drug containing only abacavir. Studies of the pharmacokinetics of abacavir in patients with impaired liver function of moderate to severe severity (Class B and C on the Child-Pugh scale) were not 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 the drug Abacavir + Lamivudine is contraindicated in patients with impaired liver function of medium and severe degree (Class B and C on the Child-Pugh scale).

The data obtained with the use of lamivudine in patients with violations of the liver function of medium and severe degree (Class B and C on the Child-Pugh scale) indicate that there are no significant changes in the pharmacokinetic parameters of the drug in the case of liver dysfunction.

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 (AUC) 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 should be prescribed mono drug lamivudine.

Indications:

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

Contraindications:

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

- Lung insufficiency of mild severity (Class A on the Child-Pugh scale) (due to the lack of a recommended dosing regimen);

- Hepatic failure of moderate to severe severity (Class B and C on the Child-Pugh scale) (due to the lack of clinical data and the recommended dosing regimen).

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

- Body weight less than 25 kg (due to lack of recommended dosing regimen);

- Lactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Carefully:

- Care must be taken when using the drug Abacavir + Lamivudine, especially in patients with hepatomegaly, hepatitis, or other known risk factors for developing liver disease and steatosis of the liver (including certain drugs and alcohol);

- Care must be taken when using the drug Abacavir + Lamivudine in elderly patients (over 65 years);

- When administering 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, safety of the use of abacavir, lamivudine in pregnancy in humans is not established. Therefore, during pregnancy, the drug Abacavir + Lamivudine apply only if the intended benefit to the mother exceeds the potential risk to the fetus.

The impact of abacavir has been evaluated on the basis of the Registry of Antiretroviral Drugs in Pregnant Women, which were obtained from more than 2000 women during pregnancy and in the postpartum period. Available data for a person from the Antiretroviral pregnant women do not indicate an increased risk of significant birth defects when using abacavir compared with their background frequency.

The impact of lamivudine has been evaluated on the basis of the Registry of Antiretroviral Drug Use in Pregnant Women who were obtained from more than 11,000 women during pregnancy and the puerperium. Available data for a person from the Antiretroviral Registry drugs in pregnant women do not indicate an increased risk of significant birth defects when using lamivudine compared to their background frequency. There are no data on the use of the drug Abacavir + Lamivudine during pregnancy.A small amount of data in pregnant women taking a combination of monocomponents of abacavir and lamivudine does 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) does 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 in animals, but increased early embryonic mortality in rabbits, but not in rats, with systemic exposure comparable to that achieved in humans. When applying 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 are data on a slight transient increasethe concentration of lactate in the blood plasma, possibly due to mitochondrial disorders, in newborns and infants whose mothers during pregnancy and in the perinatal period were taking NRTIs. 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, for example, muscle tone increase. 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 treatment 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, lamivudine and HIV penetrate into breast milk, breastfeeding is contraindicated. In the study, after repeated oral administration of 150 mg lamivudine 2 times a day (in combination with zidovudine 300 mg twice a day) or 300 mg 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 lamivudine 150 mg 2 times a day (as in combination with zidovudine 300 mg, and in preparations containing zidovudine + 3TC or abacavir zidovudine + 3TC) the ratio of lamivudine concentration in breast milk and maternal blood plasma was between 0.6 and 3.3. In the study, after repeated oral administration of 300 mg of abacavir 2 times a day (taken as a preparation containing abacavir zidovudine + 3TC) the concentration ratio in breast milk and maternal blood plasma was 0.9. For oral administration of abacavir, pharmacokinetic studies were not performed once a day. Median serum concentration of lamivudine in infants is in a range between 18 and 28 ng / ml and ns was determined in one study (assay sensitivity - 7 ng / ml). Most infants (8 of 9) had undetectable levels of abacavir (sensitivity of the assay was 16 ng / ml). Intracellular lamivudine-TP and TF-carbovir (active metabolite of abacavir and lamivudine) in infants who are breastfed have not been measured, however clinical value of measurements of serum concentrations of the parent compound is unknown.

Dosing and Administration:

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

A drug Abacavir + Lamivudine should not be administered to patients with a body weight of less than 25 kg due to the impossibility of dose adjustment.

Patients weighing less than 25 kg should be prescribed individual drugs of abacavir and lamivudine.

A drug Abacavir + Lamivudine can be taken inside regardless of food intake. Combination preparations with fixed doses of components should not be used when there may be a need for dose adjustment, for example, when creatinine clearance is less than 50 ml / min, as well as in liver failure. In the event of discontinuation of the drug Abacavir + Lamivudine or, if necessary, dose adjustment should be given as mono drugs abacavir or lamivudine. In such situations, the doctor should become familiar with the instructions for the use of these medications.

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

The recommended dose of the drug Abacavir + Lamivudine adults and children with a body weight of 25 kg and more - 1 tablet once a day.

Special patient groups

Children weighing less than 25 kg

It is not recommended to apply the drug Abacavir + Lamivudine for the treatment of children weighing less than 25 kg due to the lack of possibility of dose adjustment. For selection therapy, it is recommended that physicians 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 the treatment of elderly patients, the increased incidence of liver, kidney, heart, and other comorbid conditions, as well as the use of other medications, should be considered.

Care should 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 function of night

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 apply the drug Abacavir + Lamivudine when the creatinine clearance is less than 50 ml / min.

Patients with impaired hepatic function

Patients with a mild liver function disorder (Class A on the Child-Pugh scale) require a reduction in the dose of abacavir. In connection with the impossibility of reducing the dose when using the drug Abacavir + Lamivudine It is necessary to use separate preparations of abacavir and lamivudine. The drug is contraindicated in patients with impaired liver function of medium and severe degree (Class B and C on the Child-Pugh scale).

Side effects:

Because the Abacavir + Lamivudine is a combined preparation, then undesirable reactions characteristic of abacavir and lamivudine are possible. For many of the undesirable reactions listed below, it remains unclear whether their appearance is related to the action of the active substances of the drug, the simultaneous use of other drugs (used to treat HIV), 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 (≥ 1/1000 and <1/100), rarely (≥ 1/10000 and <1/1000), rarely (<1/10000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug 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 confirm the development of a hypersensitivity reaction (MRI). If the drug is taken Abacavir + Lamivudine was stopped due to the onset of 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 *	Rarely: lactic acidosis *
Disturbances from the nervous system	Often: headache	Often: headache, insomnia Rarely: paresthesia, peripheral neuropathy is described (cause-and-effect relationship with treatment not established) *
Disturbances from the respiratory organs		Often: cough, nasal symptoms
Infringements from gastrointestinal tract	Often: nausea, vomiting, diarrhea Rarely: pancreatitis, but the cause-and-effect relationship with abacavir is not established *	Often: nausea, vomiting, pain in the upper abdomen, diarrhea Rarely: increased serum amylase activity, pancreatitis (although a cause-and-effect relationship with lamivudine has not been established) *
Disturbances from the liver and bile ducts		Infrequently: temporary increase in biochemical parameters of liver function (ACT, ALT) Rarely: hepatitis
Disturbances from the skin and subcutaneous tissue	Often: rash (without systemic symptoms) * Rarely: exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis *	Often: rash, alopecia * Rarely: angioedema
General disorders and disorders at the site of administration	Often: fever, drowsiness, fatigue	Often: feeling tired, malaise, fever
Disturbances from musculoskeletal and connective tissue*		Often: arthralgia, muscle damage * Rarely: rhabdomyolysis *

* adverse reactions described in clinical studies.

In very rare cases when the drug is used Abacavir + Lamivudine there may be erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis. When they occur, it is necessary to cancel the drug Abacavir + Lamivudine.

Children

Safety data confirming single dosing of the combined preparation in children were obtained in the study ARROW (COL 105677), in which 669 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. No additional safety signals were found in children taking the drug 1 or 2 times a day compared to 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 signs that occur in at least 10% of patients with MRI are highlighted in bold.

Practically all patients with hypertension develop a rise in body temperature and / or a rash (usually maculopapular or urticaria) as part of the syndrome, but reactions can proceed without a rash or an increase in body temperature. Other major symptoms include symptoms from the gastrointestinal tract, respiratory system, or constitutional symptoms, such as drowsiness or malaise.

Disorders from the rut 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, chest and mediastinal organs: shortness of breath, cough, sore throat, adult respiratory distress syndrome, respiratory failure.

Disturbances from the nervous system: headache, paresthesia.

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

Disorders from the kidneys and urinary tract: increasing the concentration of creatinine, kidney failure.

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

Renewal of the drug Abacavir + Lamivudine after the MIRV 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, reactions also occur with the resumption of abacavir treatment after withdrawal, due to the emergence of just one of the main symptoms of hypersensitivity (see above), and in very rare cases this reaction occurs when the abacavir is resumed in patients who did not before symptoms of MRI (ie, in patients previously thought to be abacavir-tolerant).

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, but the timing of the manifestation of the disease is 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

Symptoms of acute overdose of abacavir and lamivudine correspond to the symptoms listed in the "Side effect" section.

Treatment

In case of an overdose, the patient should be under the supervision of a physician (to identify signs of toxicaction 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:Spectrum of drug interactions Abacavir + Lamivudine is caused by the nature of the interactions of abacavir and lamivudine, among which there are no clinically significant ones to date. Abacavir and lamivudine are slightly metabolized by enzymes of the cytochrome P450 system (eg: isoenzymes CYP 3A4, CYP 2С9 or СУР 2D6) and do not have an inhibitory or inductive effect on this enzyme system. Therefore, the likelihood of drug interaction with antiretroviral drugs from classes NNRTI and PI, and other drug the metabolism of which occurs with the participation of the main enzymes of the cytochrome P450 system is small.

Abacavir is metabolized by UDP-glucuronyltransferase and alcohol dehydrogenase. The likelihood of metabolic interactions with lamivudine is low, as it is poorly metabolized, poorly bound to plasma proteins and excreted almost exclusively by the kidneys. Lamivudine is excreted mainly through active tubular secretion by means of organic cation transporters. 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

Trimethoprim / sulfamethoxazole

The interaction has not been studied. It is impossible to adjust the dose if the patient has renal failure.

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 (600 mg twice daily) and methadone (40 mg to 90 mg once a day), a decrease in C_m_Oh abacavir by 35% and a decrease in T_m_Oh for one 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 the drug Abacavir + Lamivudine.

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 of ribavirin 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 due to the presence of lamivudine

Trimethoprim / sulfamethoxazole

Acceptance of trimethoprim / sulfamethoxazole 160 mg / 800 mg (co-trimoxazole) once a day for 5 days and lamivudine 300 mg once a day causes an increase in lamivudine exposure by 40%, which is due to the presence of trimethoprim. However, except for patients with renal insufficiency, correction of the dose of lamivudine is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. Trimethoprim: AUC without changes; sulfamethoxazole: AUC without changes. Joint use of lamivudine with higher doses of co-trimoxazole used to treat pneumonia (caused by Pneumocystis carinii) and toxoplasmosis, has not been studied and should be avoided.

Zalcitabine

Lamivudine can suppress intracellular phosphorylation of zalcitabine while simultaneously taking these drugs. In this regard, it is not recommended to take the drug Abacavir + Lamivudine in combination with zalcitabine.

Emtricitabine

With simultaneous application lamivudine can inhibit intracellular phosphorylation of emtricitabine. In addition, the mechanism of development of resistance and lamivudine, and to 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, Not recommended.

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 not recommended.

Retinoid compounds (eg, 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 Abacavir + Lamivudine. For most patients, methadone dosage 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 (drug Abacavir + Lamivudine).

Hypersensitivity to abacavir

The use of abacavir is associated with the risk of developing an MRI that is characterized by a rise in body temperature and / or rash and other symptoms that indicate multiple organ failure. 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 were observed in patients who are not carriers of this allele.

The following rules should be observed:

- It is necessary to conduct a study for the presence of an allele HLA-B*5701 before starting therapy with the drug Abacavir + Lamivudine and also before resumption of therapy with the drug Abacavir + Lamivudine in patients with unknown status with respect to the allele HLA-B*5701, who had previously tolerated abacavir therapy.

- It is not recommended to use the drug Abacavir + Lamivudine 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 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 packaging of the drug Abacavir + Lamivudine.

- In all patients receiving drug therapy Abacavir + Lamivudine, the clinical diagnosis of a suspected MRI should remain the basis for making a clinical decision.

- In case of suspected MRI, therapy with the drug Abacavir + Lamivudine should be immediately discontinued even in the absence of an allele HLA-B*5701. Delayed discontinuation of drug therapy Abacavir + Lamivudine After the emergence of the MRI, it can lead to a life-threatening reaction.

- Patients who developed MRIs should be informed about the need to transfer the remaining tablets of the drug Abacavir + Lamivudine To the attending physician 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 symptoms within a few hours, which may include life-threatening arterial hypotension and death.

- When considering the resumption of therapy with abacavir after cessation of treatment by anyone 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, the use of the drug can not be resumed Abacavir + Lamivudine or any other medications containing abacavir.

- If the MRI is excluded, it is possible to resume therapy with the drug Abacavir + Lamivudine. 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 with the resumption of therapy with the drug Abacavir + Lamivudine or other medicinal products containing abacavir, and that the resumption of drug therapy Abacavir + Lamivudine or other medicinal products containing abacavir, should be carried out only with the availability of 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. Symptoms usually appear during the first weeks (the median time of the onset of this reaction is 11 days) after initiation of abacavir therapy, but these reactions can develop at any time during therapy.

Virtually all of the responses of the WGS to abacavir include a rise in body temperature and / or a 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"). With the continuation of treatment, the severity of the symptoms associated with MRIs increases, and they can take a life-threatening character.In most cases, these symptoms disappear when discontinuing abacavir.

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.

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 tract and respiratory (dyspnea and tachypnea), or neurological symptoms (including motor weakness).

Care should be taken when prescribing the drug Abacavir + Lamivudine, in particular to 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 if clinical or laboratory signs of lactic acidosis with or without hepatitis occur (including hepatomegaly and steatosis, even in the absence of a significant increase in aminotransferase activity) under conditions of symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis, progressive hepatomegaly or with a rapid increase in aminotransferase activity .

Lipodystrophy

In some patients receiving combined Apt, there may be a redistribution and / or accumulation of subcutaneous fat, including obesity but 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 glucose concentration in the blood, both individually and 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 serum lipid concentration and blood glucose concentration. If the lipid metabolism is disturbed, an appropriate treatment is prescribed.

Syndrome restoration of immunity

If HIV-infected patients with severe immunodeficiency have asymptomatic opportunistic infections or their residual effects at the time of initiation of ART, such therapy may lead to an increase in the symptoms of opportunistic infections or other severe consequences. Usually, these reactions occur within the first weeks or months after the onset Apt. 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 also observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after initiation of therapy and have an atypical course.

Opportunistic infections

Application of the drug Abacavir + Lamivudine 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 physician experienced in the treatment of these HIV-associated diseases.

Transmission of HIV infection

Patients should be warned that treatment with antiretroviral drugs, including the drug Abacavir + Lamivudine, 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 studyto study the incidence of myocardial infarction in patients receiving a combined Apt, The association of the previous administration of abacavir within 6 months with an increased risk of myocardial infarction was found. According to the generalized analysis of clinical studies, there was no increase risk of myocardial infarction associated with the use of abacavir. Biological mechanisms that explain a potentially increased risk are unknown. In general, the available data from observing cohorts and controlled clinical trials are not allow to unequivocally define or determine connection of therapy abakavirom with risk of a heart attack of a myocardium.

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

A drug Abacavir + Lamivudine should not be administered to patients with creatinine clearance less than 50 mL / min.

Diseases of the liver

Efficacy and safety of the drug Abacavir + Lamivudine It has not been established in patients with severe concomitant liver disease. A drug Abacavir + Lamivudine It is not recommended to appoint patients with a violation of 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 disease. As a consequence, in patients with concomitant viral hepatitis B when the drug is withdrawn Abacavir + Lamivudine should monitor the performance of functional liver samples and regularly determine the markers for the replication of the hepatitis B virus.

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 taking glucocorticosteroids, drinking alcohol,severe immunosuppression, high body mass index), cases of osteonecrosis were most often encountered in patients at a late stage of HIV infection and / or who took long-term 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-onset stability was noted with the simultaneous administration of abacavir and lamivudine with tenofovir dizoproxil fumarate under the dosing regimen once a day.

Risk of virological failure with drug use Abacavir + Lamivudine may be higher than in the case of other possible therapies.

A drug Abacavir + Lamivudine should not be taken with other medications containing lamivudine, or medicinal products containing emtricitabine.

The combination of lamivudine and cladribine is not recommended.

A drug Abacavir + Lamivudine contains a "sunset sun" yellow dye, which can cause allergic reactions.

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

Special studies of the effects of lamivudine on the ability to drive vehicles or mechanisms have not been carried out. 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 adverse drug reactions Abacavir + Lamivudine.

Form release / dosage:Film-coated tablets, 600 mg + 300 mg.

Packaging:

For 10 tablets in a blister of aluminum foil and PVC film amber. For 1, 3 or 10 blisters together with instructions for use in a cardboard box.

For 100, 500 or 1000 tablets in a plastic bag. 1 package in a can of HDPE with silica gel, sealed with aluminum foil with a polyethylene coating, with a screw cap. On the bank stick a label from paper label or writing or from polymer materials, self-adhesive. By 1,6, 12 or 24 banks, together with an equal number of instructions for use, are placed in a group box - a box of corrugated cardboard (for hospitals).

Storage conditions:

At a temperature of no higher than 25 ° C.

Shelf life:2 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004209

Date of registration:21.03.2017

Expiration Date:21.03.2022

The owner of the registration certificate:Lock-Beta Pharmaceuticals (I) Pvt.LtdLock-Beta Pharmaceuticals (I) Pvt.Ltd India

Manufacturer: & nbsp

LOK-BETA PHARMACEUTICALS (I), Pvt. Ltd. India

Representation: & nbspLock-Beta Pharmaceuticals (I) Pvt.LtdLock-Beta Pharmaceuticals (I) Pvt.Ltd

Information update date: & nbsp25.04.2017

Illustrated instructions

Instructions

Abacavir + Lamivudine (Abacavir + Lamivudine)