Abacavir + Lamivudine (Abacavir + Lamivudine)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAbacavir + LamivudineAbacavir + Lamivudine
Dosage form: & nbspfilm-coated tablets
Composition:

One tablet contains:

Active substances: abacavir sulfate 702.78 mg (in terms of abacavir 600.00 mg), lamivudine 300.00 mg.

Excipients: cellulose microcrystalline 296.42 mg, sodium carboxymethyl starch (type A) 70.00 mg, magnesium stearate 10.80 mg.

Film sheath: Reward orange YS-1-13065-A 34,50 mg: hypromellose 3 cps 32,17%, hypromellose 6 cps 32,17%, titanium dioxide 22,42%, polysorbate-80 1,00%, macrogol-400 8,00%, dye sunset yellow, 4,24%.

Description:

Capsule-shaped tablets covered with a film shell of orange color, with the squeezed out inscription "Н" on one side and "27" on the other side.

On the cross section, the core of the tablet is white or almost white in color.
Pharmacotherapeutic group:Antiviral [HIV] agent
ATX: & nbsp

J.05.A.R.02   Abacavir + Lamivudine

Pharmacodynamics:

Abacavir and lamivudine belong to the group of nucleoside reverse transcriptase inhibitors (NRTIs) 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 the equilibrium state was 20.6 hours.At the same time, the geometric mean of the half-life of abacavir from plasma in this study was 2.6 hours. Equilibrium pharmacokinetic parameters when taking abacavir 600 mg 1 once a day were the same with 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 the equilibrium state (CmOh 24,ss) - by 99%). 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 1 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 Cmoh 24,ss for the intracellular concentration of lamivudine-TF in peripheral blood mononuclears were identical, but the residual concentration with lamivudine 300 mg 1 once a day were lower than when taking lamivudine 150 mg twice daily. The variability of the concentration of lamivudine-TF within 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 for the treatment of HIV-infected patients (efficacy and safety of this combination once daily was also confirmed in the baseline clinical trial CNA30021).

There was no antagonism antiviral activity of abacavir in cell culture with a combination of the latter with a nucleoside reverse transcriptase inhibitor (NRTI), didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine or HIV protease inhibitor (PI) 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 research 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 inhibitory concentration against 50% of strains IC50 (increase IC50 (an inhibitory concentration of 50% cases) 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 (for example: protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs)) 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 (NRTIs) was ineffective. Clinical isolates of the virus that have three or more mutations associated with resistance to NRTIs are also likely to be resistant to abacavir. Cross-resistance, due to M184V mutation of OT, is limited to a class of nucleoside RT inhibitors.

Zidovudine, stavudine, abacavir and tenofovir retain their antiretroviral activity against HIV-1 lamivudine-resistant isolates that carry only M184V mutation.

Pharmacokinetics:

When taken on an empty stomach, there were no significant differences in the degree of absorption (area under the pharmacokinetic curve "concentration-time" (AUC)) and the maximum concentration (CmOh) of each of the components. Also, there were no clinically significant changes in pharmacokinetic parameters due to drug intake Abacavir + Lamivudine on an empty stomach or together with food. These data indicate that the drug 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 (TmOh) 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 average CmOh is 4.26 μg / ml, and the mean AUC∞ - 11.95 μg * h / ml. After repeated oral administration of lamivudine 300 mg once a day for seven days, the average equilibrium Cmax is 2.04 μg / ml, and the mean AUC24 - 8.87 μg * h / ml.

Distribution in the body

In conditions in vitro it was found that when administered at therapeutic concentrations abacavir slightly (~ 49%) binds to human plasma proteins.

Lamivudine demonstrates a linear change in pharmacokinetic parameters when therapeutic doses are used and poorly binds to blood plasma proteins (less than 36%). This indicates a low probability of interaction with other drugs, in which there is a replacement of drugs 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 lamivudine concentration in CSF to its serum concentration after 2 and 4 hours after oral administration of the drug is approximately 12%. The true degree of lamivudine penetration in the CNS, as well as the clinical significance of this phenomenon, have not been established to date.

Metabolism

Abacavir is metabolized mainly in the liver.In humans abacavir is metabolized mainly under the influence of alcohol dehydrogenase to form 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 from the body

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 excretion is carried out by metabolism in the liver with subsequent excretion of metabolites mainly by 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 of lamivudine is approximately 0.32 L / h / kg, most of which is renal clearance (> 70%), which is realized by active tubular secretion through the system of organic cation transport.

Special patient groups

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 violations of mild liver function should reduce the 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 expected that in such patients the concentration of abacavir in the plasma will be variable and, in most cases, increased. In this regard, the use of the drug Abacavir + Lamivudine contraindicated in patients with impaired liver function of mild, moderate and severe severity.

The data obtained with the use of lamivudine in patients with violations of liver function of moderate and severe severity indicate that significant changes in the pharmacokinetic parameters of the drug in the case of violations of the liver do 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 AUC lamivudine in plasma increases due to lower clearance. In connection with the need to reduce the dose of lamivudine, patients with a creatinine clearance less than 50 ml / min should be prescribed a lamivudine mono drug.

Children

Children abacavir quickly and well absorbed when taken in tablets. In children receiving abacavir in the form of tablets in accordance with the recommended dosing regimen, the exposure of abacavir in plasma is higher than in children receiving abacavir in the form of a solution for oral administration, due to the administration of higher doses in μ / kg when taking tablets. 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. 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 tablets in accordance with the recommended dosing regimen, a higher exposure to lamivudine in the blood plasma is achieved than in children receiving the oral solution, due to higher doses in μ / kg and higher bioavailability when taking tablets. In studies of pharmacokinetics in children, it was demonstrated that when taking the drug 1 once a day AUC24 is equivalent to that when taking the drug 2 times a day at the same daily dose.

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 other components of the drug;

- hepatic insufficiency (class A, 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 the lack of a recommended dosing regimen).

Carefully:

Patients who have risk factors for liver damage (due to lactic acidosis): hepatomegaly, hepatitis, or other known risk factors for liver disease and steatosis of the liver (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.

Patients over 65 years of age.

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 abacavir and 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. The available data for a person from the Registry of the Use of Antiretroviral Drugs in Pregnant Women does not indicate an increased risk of significant birth defects when abacavir is used compared to their baseline 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.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 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) 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 in animals, but increased early embryonic mortality in rabbits, but not in rats, with systemic exposure comparable to that achieved in humans.When applied, abacavir showed embryothetotoxicity in rats, but not in rabbits (reduced fetal mass, embryonic edema and an increase in the number of skeletal changes / malformations, early fetal deaths and stillbirths).

There is evidence of a slight transient increase in the concentration of lactic acid in the blood plasma of newborns and infants whose mothers during pregnancy and childbirth took nucleoside reverse transcriptase inhibitors. Perhaps this is due to mitochondrial disorders. The clinical significance of this phenomenon has not been established to date. In addition, there are extremely rare reports of developmental delay, convulsive seizures and other neurological disorders in newborns (eg, muscle tone increase). However, the causal relationship of these disorders with the intake of nucleoside reverse transcriptase inhibitors by mothers during pregnancy and in childbirth has not been established. These data do not cancel the existing recommendations on the use of antiretroviral drugs during pregnancy to prevent vertical transmission of HIV.

Lactation

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.

Dosing and Administration:

Therapy should be performed by a doctor with experience in HIV treatment.

In connection with the impossibility of dose adjustment when using combined tablets with fixed doses of components, the drug Abacavir + Lamivudine it is contraindicated to appoint adults and adolescents, whose weight is less than 25 kg. Pills Abacavir + Lamivudine 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 the event of discontinuation of the drug Abacavir + Lamivudine or, if necessary, dose adjustment should be administered as monopreparations abacavir or lamivudine. 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

1 tablet once a day every day.

Special patient groups

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

Patients with impaired hepatic function

Patients with impaired liver function of classes A, B and C on the Child-Pugh scale, this drug form of the drug Abacavir + Lamivudine contraindicated due to the impossibility of reducing the dose when used.

Side effects:

Because the Abacavir + Lamivudine is a combined drug, then there may be side effects, characteristic of abacavir and lamivudine. For many of the side effects 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 manifestations of the underlying disease.

The side effects of abacavir or lamivudine are presented below in the tables and grouped according to the body systems and frequency of occurrence. Side effects are divided into: Often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, < 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 abacavir and lamivudine and post-registration surveillance.

Many of the side effects (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 hypersensitivity reactions.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 *

Often: hyperlactatemia

Rarely: lactic acidosis *

Disturbances from the nervous system

Often: headache

Often: headache.

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

Violations from the side ofgastrointestinal 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: an increase in serum amylase activity, pancreatitis, (a causal 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)

Disturbances from the skin and subcutaneous tissues

Often: rash (without systemic symptoms) *

Very rare: exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis *

Often: rash, alopecia *

General disorders and disorders at the site of administration

Often: fever, drowsiness, fatigue

Often: feeling fatigue, malaise, fever

Disturbances from musculoskeletal and connective tissue


Often: arthralgia, muscle damage *

Rarely: rhabdomyolysis *

* adverse reactions described in clinical studies.

Children

Safety data confirming single dosing of abacavir and lamivudine in children were obtained in a clinical study with the participation of 669 children infected with HIV-1 receiving 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 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 hypersensitivity reaction to abacavir was defined as a general undesirable reaction in the treatment with drugs containing abacavir. Signs and symptoms of hypersensitivity reactions are listed below. Symptoms and symptoms noted in at least 10% of patients with hypersensitivity reactions are indicated in bold type.

In almost all patients who develop hypersensitivity reactions, there is an increase in body temperature and / or the appearance of rash (usually spottypopular or urticaria), however, there are cases of hypersensitivity reaction,not accompanied by the appearance of a rash and an increase in body temperature. Other major symptoms include symptoms from the gastrointestinal tract, respiratory system, or constitutional symptoms, such as drowsiness or malaise.

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

Disorders from the gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain, ulceration in the oral cavity.

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

Disorders from the kidneys and urinary system: 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 and lamivudine after hypersensitivity reaction to abacavir leads to a rapid return of symptoms within a few hours.

Repeated hypersensitivity reactions usually occur more severely than the first, and may include life-threatening arterial hypotension up to a lethal outcome. In rare cases, reactions also occur when the drug is resumed Abacavir + Lamivudine after its withdrawal caused by the appearance of just one of the main symptoms of hypersensitivity, and in very rare cases this reaction occurs when the abacavir is resumed in patients who had not had any symptoms of hypersensitivity reaction prior to its withdrawal (i.e., in patients previously thought to be transplanting therapy with abacavir).

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

Description of individual adverse reactions:

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 HIV patients, including a reduction in the subcutaneous fat layer on the face and extremities, an increase in intraperitoneal 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 inflammatory responses to asymptomatic or residual opportunistic infections (eg, Graves' disease) that occur under conditions of immune reactivity may occur and these phenomena can occur many months after initiation of therapy.

Osteonecrosis cases have been reported, especially in patients with recognized risk factors,at a late stage of HIV infection or with 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, except for the symptoms 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:

Spectrum of drug interactions Abacavir + Lamivudine is due to the nature of the interactions of abacavir and lamivudine. Clinical studies have shown that clinically significant interactions between abacavir and lamivudine are absent.

Abacavir and lamivudine slightly metabolized by isoenzymes of the cytochrome P system450 (for example: iso-fructose CYP 3A4, CYP 2C9 or CYP 206) 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 (NNRTIs) and HIV protease (PI) inhibitors and other drugs metabolized by the main enzymes of the cytochrome P system450, is small.

The likelihood of metabolic interactions with lamivudine is low, as it is poorly metabolized, has a low degree of binding 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 interaction with other drugs, especially in cases where the kidneys are the main way of excretion.

Preparations

Possible mechanism of interaction

Recommendations for joint application

Antiretroviral drugs

Didanosine / abacavir

The interaction has not been studied.

There is no need to adjust the dose.

Didanosine / 3TC

The interaction has not been studied.

Zidovudine / abacavir

The interaction has not been studied.

Zidovudine / 3TC

Zidovudine 300 mg once

Lamivudine 150 mg once

Lamivudine: AUC ↔

Zidovudine: AUC ↔

Emtricitabine / 3TC


The use of lamivudine in combination with emtricitabine or fixed dose combinations containing emtricitabine, Not recommended

Anti-infectives

trimethoprim / sulfamethoxazole / abacavir

The interaction has not been studied.

It is impossible to adjust the dose if the patient has renal failure.

trimethoprim / sulfamethoxazole / lamivudine

(160 mg / 800 mg once daily for 5 days / 300 mg once daily)

Trimethoprim: AUC ↔

Sulfamethoxazole: AUC ↔

(an inhibitor of the organic cation carrier)

Lamivudine: AUC ↑ 40%.

Lamivudine has no effect on 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 and should be avoided.

Antimycobacterial

Rifampicin / abacavir

The interaction has not been studied.

Potentially, a small decrease in the concentration of abacavir in plasma is possible.

There is not enough data to recommend a dose adjustment.

Rifampicin / 3TC

The interaction has not been studied.

Anticonvulsants

Phenobarbital / abacavir

The interaction has not been studied.

Potentially, a small decrease in the concentration of abacavir in plasma is possible.

There is not enough data to recommend a dose adjustment.

Phenobarbital / lamivudine

The interaction has not been studied.

Phenytoin / abacavir

Interaction is not studied

Potentially, a small decrease in the concentration of abacavir in plasma is possible.

There is not enough data to recommend a dose adjustment.

Monitor the concentration of phenytoin.

Phenytoin / lamivudine

The interaction has not been studied.

Blockers H2-gistaminovyh receptors

Ranitidine / abacavir

The interaction has not been studied.

There is no need to adjust the dose.

Ranitidine / 3TC

The interaction has not been studied.

Clinically significant interactions are unlikely.

Ranitidine is only partially excreted by the kidney transporter of organic cations.

Cimetidine / abacavir

The interaction has not been studied.

There is no need to adjust the dose.

Cimetidine / 3TC

The interaction has not been studied.

Clinically significant interactions are unlikely.

Cimetidine is only partially excreted by the kidney transporter of organic cations.

Cytotoxic drugs

Cladribine / 3TC

The interaction has not been studied.

In vitro lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a potential risk of a decrease in the effectiveness of cladribine.

Some clinical research data also confirm the possibility of interaction between lamivudine and cladribine.

Simultaneous application of lamivudine cladribine is not recommended

Opioids



Methadone / Abacavir

(40 to 90 mg once daily for 14 days / 600 mg once daily, then 600 mg twice daily for 14 days)

Abacavir: AUC↔

FROMmax ↓35%

Methadone: CL / F ↑ 22%

Not necessary adjust the dose.

Sometimes a methadone dose adjustment may be required.

Methadone / 3TC

Interaction is not studied

Retinoids

Retinoid compounds (eg, isotretinoin) / abacavir

The interaction has not been studied.

Possible interactions due to the common route of excretion with alcohol dehydrogenase.

There is not enough data to recommend a dose adjustment.

Retinoid compounds (eg, isotretinoin) / lamivudine

The interaction has not been studied.

Antiviral drugs

Ribavirin / abacavir

The interaction has not been studied.

The theoretical potential for reducing the intracellular phosphorylation of the metabolite.

Care must be taken when using together

Miscellaneous

Ethanol / abacavir

(0.7 g / kg once / 600 mg once)

Abacavir: AUC ↑ 41%

Ethanol: AUC ↔

Inhibition of alcohol dehydrogenase

There is no need to adjust the dose.

Ethanol / Lamivudine

Ribavirin / abacavir

Note: ↑ - increase; ↓- decrease; ↔ - no significant changes; AUC - area under the curve "concentration - time"; FROMmOh - maximum concentration; CL/F - an obvious verbal permission.

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 developing a hypersensitivity reaction characterized by the appearance of a rise in body temperature and / or rash with other symptoms indicative of multiple organ failure.Hypersensitivity reactions can threaten life and in rare cases, when no appropriate treatment is prescribed, can lead to death.

The risk of developing a hypersensitivity reaction with abacavir is significantly increased in patients with a positive test for the presence of an allele HLA-B* 5701. However, the hypersensitivity reaction to abacavir with a lower frequency were 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 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 previously tolerated abacavir well.

- It is not recommended to use the drug allele HLA-B* 5701 in patients with an allele HLA-B * 5701 or in patients who were suspected of a hypersensitivity reaction during the development 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.Patients should be reminded that they should always carry a Warning Card attached to the drug.

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

- If suspected of hypersensitivity reaction, drug therapy 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 appearance of a hypersensitivity reaction, it can lead to a life-threatening reaction.

- Patients who developed a hypersensitivity reaction 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 a suspected hypersensitivity reaction to 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 discontinuation of treatment with any containing abacavir the drug for any reason should be established the reason for discontinuing therapy, regardless of the carriage of the allele HLA-B* 5701. If the hypersensitivity reaction can not be ruled out, it is not possible to resume the use of the drug Abacavir + Lamivudine or any other medications containing abacavir.

- If a hypersensitivity reaction is excluded, it is possible to resume therapy with the drug Abacavir + Lamivudine. In rare cases, patients who discontinued abacavir for reasons other than hypersensitivity reactions also reported the development of life-threatening reactions within hours after the resumption of abacavir therapy. Patients should be informed of the possibility of developing a hypersensitivity reaction when resuming 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 hypersensitivity reactions to abacavir

Hypersensitivity reactions to abacavir were well studied in clinical trials and during post-registration follow-up. Symptoms usually appear within the first 6 weeks (median time of onset of this reaction is 11 days) after initiation of abacavir therapy, however these reactions can develop at any time during therapy.

Virtually all hypersensitivity reactions 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 a hypersensitivity reaction to abacavir, include symptoms on the part of the respiratory and gastrointestinal tract, which can lead to incorrect diagnosis of the hypersensitivity reaction as a respiratory disease (pneumonia, bronchitis, pharyngitis) or gastroenteritis (see section "Side effect"). With the continuation of treatment, the severity of symptoms increases,and they can take a life-threatening character. In most cases, these symptoms disappear when discontinuing abacavir.

Lactic acidosis, hepatomegaly and fatty liver disease

When using antiretroviral nucleoside analogues (including abacavir and lamivudine), taken either individually or in combination, development of lactic acidosis, hepatomegaly and severe fatty liver disease, including cases that ended in a fatal outcome, was noted. Similar phenomena were noted mainly among 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, respiratory symptoms (shortness of breath, rapid breathing), or neurologic 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-infected hepatitis C receiving interferon alfa and ribavirin therapy can be a particular risk group. Patients with an increased risk require careful monitoring. The drug should be discontinued if there are clinical or laboratory signs of lactic acidosis with or without hepatitis (including 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 who underwent combined antiretroviral therapy, there was a redistribution / accumulation of fat in the body, an increase in the amount of fat on the back of the neck and back ("buffalo buffalo"), a reduction in the amount of peripheral fat deposits, emaciation of the face, increased mammary glands, increased glucose concentration and lipids in the blood serum, either individually or together.

Lipodystrophy can develop when taking any medication from a class of protease inhibitors or nucleoside reverse transcriptase inhibitors.However, the available data indicate that the risk of developing these side effects when taking different preparations of these classes is not the same. In addition, many factors contribute to the development of lipodystrophy, for example, the stage of HIV infection, the elderly age and the duration of antiretroviral therapy 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 concentration of lipids and blood glucose. If necessary, appropriate treatment for violations of fat metabolism.

Immunodeficiency Syndrome

If HIV-infected patients with severe immunodeficiency have asymptomatic opportunistic infections or their residual effects at the time of initiation of antiretroviral therapy (APT), such therapy may lead to increased symptoms of opportunistic infections or other severe consequences.Typically, these reactions occur within the first weeks or months after the onset of 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 (for example, Graves' disease, polymyositis, and Guillain-Barre syndrome) can also manifest themselves against the background of the restoration of the immune system. However, the time of onset is more variable and can occur several months after the start of treatment 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 doctor who has experience in the treatment of these 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 during sexual intercourse or contact with infected blood. It is necessary to remember the need to comply with appropriate security measures.

Myocardial infarction

As a result of a prospective, observational, epidemiological study in order to study the incidence of myocardial infarction in patients receiving combined antiretroviral therapy, a previous connection, within 6 months, of abacavir with an increased risk of myocardial infarction was found. 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 between abacavir therapy and the risk of myocardial infarction.

Nevertheless, care should be taken to prescribe antiretroviral therapy, including drugs containing abacavir, patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize risk factors (such as arterialhypertension, dyslipidemia, diabetes mellitus and smoking).

Pancreatitis

Cases of pancreatitis have been documented. The causal relationship with the use of abacavir is not defined.

Kidney disease

A drug Abacavir + Lamivudine contraindicated in patients with creatinine clearance less than 50 ml / min.

Diseases of the liver

Abacavir +Lamivudine contraindicated in patients with a violation of liver function (this dosage form) class A, B and C on the Child-Pugh scale. Patients with pre-existing liver dysfunction, including active chronic hepatitis, have an increased incidence of liver dysfunction during combined antiretroviral therapy, and should be monitored in accordance with accepted practice.

Patients with concomitant viral hepatitis B or C

Clinical studies and post-marketing 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 discontinuation of lamivudine. Discontinuation of lamivudine may have more severe consequences in patients with decompensatedliver damage. 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.

Patients with chronic hepatitis B or C taking combination antiretroviral therapy are at increased risk of serious and potentially deadly adverse reactions from the liver. In the case of concomitant antiviral therapy for hepatitis B or C, it is also necessary to look at the relevant information for these drugs.

Due to abacavir and ribavirin have the same pathways of foforilirovaniya, it is assumed the interaction between these substances, which can lead to a decrease in intracellular phosphorylation of metabolites of ribavirin and potentially leads to a decrease in the likelihood of achieving a stable virologic response in HIV-infected patients infected with hepatitis C who received pegylated interferon and ribavirin therapy. Caution should be exercised in the combined use of abacavir and ribavirin.

Mitochondrial dysfunction

Ataxes of nucleosides and nucleotides in vitro and in vivo demonstrated a different degree of damage to the mitochondria. Mitochondrial dysfunction in HIV-negative children who received intrauterine and / or nucleoside analogues of nucleosides was documented.

The main manifestations are hematologic disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipazemia). These events are often temporary.

Later neurological disorders (muscle tone, convulsions, behavioral disorders) were recorded. Whether these neurological disorders are transient or persistent is currently unknown.

Any child, even HIV-negative, exposed to prenatal exposure to nucleoside and nucleotide analogues, must undergo a clinical and laboratory examination in order to exclude mitochondrial dysfunction in case of revealing the corresponding signs or symptoms.

These data do not influence the current national recommendations on the use of antiretroviral therapy in pregnant women for the prevention of vertical transmission of HIV infection.

Osteonecrosis

Despite the fact that the etiology of osteonecrosis is considered multifactorial (including the use of glucocorticosteroids, alcohol consumption, severe immunodeficiency, high body mass index), cases of osteonecrosis have been reported in patients with advanced HIV infection and / or long-term exposure to combined antiretroviral therapy.

Patients should be advised to see a doctor if they have experienced joint pain, joint stiffness, or difficulty in moving.

Risk of virological failure

Triple therapy with nucleoside analogues (combination of abacavir, lamivudine and zidovudine), a high incidence of virological failure and early resistance was recorded when abacavir and lamivudine were combined with tenofovir with disoproxil fumarate once daily. Abacavir + Lamivudine it is contraindicated to take with other medicinal products containing lamivudine or medicinal products containing emtricitabine.

The combination of lamivudine and cladribine is not recommended.

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

Special studies of the influence of lamivudine on the ability of concentration of attention when driving vehicles / mechanisms were not carried out. It is unlikely that the drug will adversely affect the ability to perform tasks that require concentration, motor or cognitive skills. Nevertheless, when evaluating a patient's ability to concentrate attention, his general condition should be taken into account, as well as the nature of side effects that may appear against the background of the drug Abacavir + Lamivudine.

Form release / dosage:

Film-coated tablets, 600 mg + 300 mg.

Packaging:

For 30 tablets in bottles of high-density polyethylene of white color, sealed with a screw cap polypropylene cover with protection from opening by children, and sealed with aluminum foil.

One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription
Registration number:LP-003451
Date of registration:09.02.2016
Expiration Date:09.02.2021
The owner of the registration certificate:Bright Pharmaceuticals Operation SenteBright Pharmaceuticals Operation Sente China
Manufacturer: & nbsp
Representation: & nbspAurobindo Pharma, ZAOAurobindo Pharma, ZAO
Information update date: & nbsp16.01.2017
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