Abacavir / Lamivudine-Teva - instructions for use, dose, side effects, contraindications

active substances: 600,00 mg of abacavir, lamivudine 300.00 mg;
Excipients: 270.00 mg microcrystalline cellulose, giproloza 39.00 mg sodium carboxymethylstarch (type A) 78.00 mg 13.00 mg magnesium stearate;
film sheath: Reward orange 13B230005 39.00 mg (24.375 mg of Hypromellose, 4000 makrogol- 2,438 mg, titanium dioxide (E171) 9.906 mg, Polysorbate 80 0.390 mg Iron oxide yellow dye (E172) 1.697 mg iron oxide red dye (E172) 0.195 mg).

Description:

Biconvex oblong tablets covered with a film coat from light orange with a brownish tinge to orange, with an embossed "300" on one side and "600" on the other side.

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 and are potent selective inhibitors of human immunodeficiency viruses (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) are a substrate and competitive inhibitors of reverse transcriptase (RT) of HIV. However, the main antiviral effect of drugs is due to the insertion of monophosphate into the DNA chain, which in The result is torn. Triphosphates of abacavir and lamivudine have a much lower affinity for DNA polymerases of host cells.

Lamivudine enhances the action of zidovudine, suppressing the replication of HIV in cell culture. In conditions in vitro Abacavir shows synergism in combination with amprenavir, nevirapine and zidovudine. It is shown that the action of the drug is enhanced in combination with didanosine, zalcitabine, stavudine and lamivudine.

Resistance of HIV-1 to lamivudine is due to a mutation in the codon M184V, located close to the active center of viral OT. This mutation is observed both in conditions in vitro, gak and in HIV-1-infected patients who underwent combined therapy, including lamivudine. In case of mutation in the codon MI84V the susceptibility to lamivudine is significantly reduced and the virus's ability to replicate in vitro. In studies in vitro It is shown that zidovudine-resistant isolates of the virus can become susceptible to the action of the drug in the event of resistance to lamivudine. However, the clinical significance of such changes has not been determined to date. Abacavir-resistant HIV-1 isolates were selected under conditions in vitro. They are characterized by specific genotypic changes in codons close to OT (codons M184V, K.65R, L74V and Y115F). Resistance of the virus to abacavir in vitro and in vivo is formed relatively slowly, multiple mutations are necessary to achieve 8-fold, in comparison with the "wild" virus, an increase in the inhibitory concentration against 50% of the strains (IC₅₀), which can be of clinical importance.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 and non-nucleoside reverse transcriptase inhibitors, is unlikely. There was a decrease in the susceptibility to abacavir of clinical isolates obtained from patients with uncontrolled viral replication, who had previously taken other nucleoside inhibitors and who had been shown to be resistant to this class of drugs. The susceptibility to abacavir of clinical isolates with three or more mutations associated with non-nucleoside reverse transcriptase inhibitors is unlikely. Cross-resistance, due to M184V OT, is limited to nucleoside inhibitors. Zidovudine, stavudine, abacavir and tenofovir preserve its antiretroviral activity against lamivudine-resistant HIV-1, which carries only the M184V mutation.

Pharmacokinetics:

When administered intramuscularly, there was no significant difference in the degree of absorption (area under the concentration-time curve, (AUC) and the maximum concentration (C_m_Oh)) of each of the components. Also, there were no clinically significant changes in pharmacokinetic parameters due to the use of the drug Abacavir / Lamivudine-Teva 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 ingestion. Absolute bioavailability of abacavir and lamivudine in adults with oral administration is 83% and 80-85%, respectively. The average time to reach C_m_Oh (T_m_Oh) in the serum is about 1.5 h and 1 h for abacavir and lamivudine, respectively. After a single oral administration of abacavir in a dose of 600 mg, the average C_m_Oh in blood plasma is 4.26 μg / ml, and the average AUC ∞ - 11.95 μg x h / ml. After repeated administration of lamivudine 300 mg once a day, within 7 days, the average maximum equilibrium concentration is 2.04 μg / ml, and the average AUC - 8.87 μg h / ml.

Distribution. Studies have shown that for intravenous (IV) administration, the average apparent volume of distribution of abacavir and lamivudine is 0.8 and 1.3 l / kg, respectively. In studies in vitro It was shown that in therapeutic concentrations abacavir poorly or moderately (about 49%) binds to human plasma proteins. Lamivudine demonstrates a linear change in pharmacokinetic parameters when used in therapeutic doses and poorly binds to plasma proteins (less than 36%). This indicates a low probability of interaction with other drugs due to the displacement of plasma from the bond with proteins.

The available data indicate that abacavir and lamivudine penetrate into the central nervous system (CNS) and into the cerebrospinal fluid (CSF). Studies have shown that AUC for CSF is between 30% and 44% of AUC for blood plasma. When ingestion of the drug in a dose of 600 mg 2 times a day C_m_Oh abacavir in CSF is 9 times higher IC₅₀ abacavir, which is 0.08 μg / ml or 0.26 μmol / l. The average ratio of lamivudine concentration in CSF and plasma after 2 hours and 4 hours after ingestion is approximately 12%. The true extent of lamivudine penetration into the CNS and the clinical significance of this property are not known.

After repeated intake of abacavir in a dose of 300 mg 2 times a day, there is no significant accumulation of abacavir.

Metabolism. Abacavir it is metabolized mainly in the liver. 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 interaction with lamivudine is low, because in the liver, a small portion (less than 10%) of the accepted dose of the drug is metabolized.

Excretion. Mean half-life (T_1/2) of abacavir is approximately 1.5 h.

T_1/2 lamivudine is 5-7 hours. The average total clearance for lamivudine is approximately 0.32 L / h / kg, most of which is renal clearance (> 70%) by the organic cationic transport system.

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 found in unchanged form and in the form of metabolites. Less than 2% of the accepted dose of the drug is excreted by the kidneys unchanged.The rest is removed through the intestine.

Pharmacokinetics in special clinical cases. 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 points on the Child-Pugh scale). The study found that AUC Abacavir increased by an average of 1.89 times, and T_1/2 - in 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 may require a reduction in the daily dose of abacavir. To treat such patients, a drug containing only abacavir. Studies of the pharmacokinetics of abacavir in patients with violations of liver function of medium and severe degree have not been conducted. It is assumed that in such patients the concentration of abacavir in the blood plasma is variable and in most cases increased. In this regard, the use of the drug Abacavir / Lamivudine-Teva is contraindicated in patients with violations of the liver function of medium and severe degree.

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

Abacavir 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 to patients with creatinine clearance (CK) less than 50 ml / min, lamivudine mono drug should be used.

Indications:

Treatment of HIV infection in the combination of antiretroviral therapy for adults and children over 12 years of age and body weight of more than 40 kg.

Contraindications:

Hypersensitivity to lamivudine, abacavir and other components of the drug; hepatic insufficiency of moderate and severe degree (class B and C on the Child-Pugh scale (in connection withlack of clinical data and recommended dosing regimen)); hepatic insufficiency of mild degree (class A on the Child-Pugh scale (due to the lack of a recommended dosing regimen)); chronic renal failure (CC less than 50 ml / min); children under 12 years of age (no possibility of dose adjustment); body weight less than 40 kg; simultaneous reception with zalcitabine.

Carefully:

Caution should be exercised in patients with hepatomegaly, hepatitis, or other known risk factors for developing liver disease and steatosis of the liver (including certain drugs and alcohol).

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

Pregnancy and lactation:

The safety of the drug Abacavir / Lamivudine-Teva in pregnant women is not established. The question of the use of the drug in pregnancy can be considered only if the expected benefit of therapy for the mother exceeds the possible risk to the fetus.

There is evidence of a slight transient increase in lactate concentration in the blood plasma,possibly due to mitochondrial disorders, in newborns and infants whose mothers during pregnancy and in the perinatal period received nucleoside reverse transcriptase inhibitors (NRTIs). The clinical significance of this enhancement is not currently established. In addition, there are some reports of developmental delay, convulsive seizures and other neurological disorders, such as increased muscle tone. However, the cause-and-effect relationship of these disorders to the effect of NRTIs during the intrauterine and perinatal periods has not been established.

The drug should be used in accordance with the current recommendations for antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

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. Animal studies have shown that neither abacavir, nor lamivudine do not have any effect on fertility.

Dosing and Administration:

Inside.Regardless of food intake.

Combined drugs with fixed doses of active substances should not be used when there may be a need for dose adjustment, for example, with SC less than 50 ml / min, as well as with liver failure. If Abacavir / Lamivudine-Teva is discontinued or if a dose adjustment is necessary, mono drugs of abacavir and lamivudine should be used. In such situations, the doctor should become familiar with the instructions for the use of these medications.

Adults and children aged 12 years and over the drug is prescribed 1 tablet once a day daily.

While the patients with impaired renal function correction of the dose of abacavir is not required, the dose of lamivudine should be reduced in proportion to the decrease in QC. In this regard, the use of the drug Abacavir / Lamivudine-Teva is contraindicated with SC less than 50 ml / min in this category of patients.

Patients with mild liver function disorder a decrease in the daily dose of abacavir may be required. In connection with the absence of the possibility of dose reduction with the use of the drug Abacavir / Lamivudine-Teva, a drug containing only abacavir. The drug Abacavir / Lamivudine-Teva is contraindicated patients with violations of the liver function of medium and severe degree.

In the treatment elderly patients should take into account the increased incidence of violations of the liver, kidneys, heart, other related diseases, as well as the use of other medications. The pharmacokinetics of abacavir and lamivudine in patients older than 65 years have not been studied. Special care must be taken when using the drug in elderly patients due to changes associated with age, such as decreased renal function and changes in blood parameters.

In connection with the impossibility of dose adjustment when using tablets containing a combination of active substances with fixed dosages, the drug Abacavir / Lamivudine-Teva is contraindicated for use in children under 12 years. For the selection of therapy should refer to the instructions for the use of lamivudine and abacavir.

Side effects:

Since the drug Abacavir / Lamivudine-Teva is a combined drug, 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 associated with the action of the active substances of the drug, the simultaneous use of other drugs (for the treatment of HIV infection), or they are manifestations of the underlying disease.

Hypersensitivity to abacavir (see section "Special instructions")

In clinical studies conducted before the screening for the presence of an allele HLA- B * 5701, approximately 5% of patients taking abacavir, a hypersensitivity reaction developed, which in rare cases led to a fatal outcome. This reaction is characterized by the appearance of symptoms that indicate a multiple organ failure. Almost in all cases, there is an increase in body temperature and / or the appearance of rash (usually maculopapular or urticaria). However, cases of a hypersensitivity reaction not accompanied by the appearance of a rash and an increase in body temperature were noted. Symptoms of hypersensitivity reactions can occur at any time during treatment with abacavir, but usually they appear within the first 6 weeks from the start of the drug (mean 11 days).

Symptoms and symptoms that occur in patients with hypersensitivity reactions:

Body System	Not less than 10%	Less than 10%
From the skin and subcutaneous fat	rash (usually spotty-papular or urticaria)
From the digestive system	nausea, vomiting, diarrhea, abdominal pain, increased performance functional liver tests, liver failure	ulceration of the oral mucosa, hepatitis
From the respiratory system	dyspnoea, cough	sore throat, respiratory distress syndrome, respiratory failure
From the nervous system	headache	paresthesia
On the part of the hematopoiesis system		lymphopenia
From the musculoskeletal system	myalgia	myolysis, arthralgia, increased activity of creatine phosphokinase
From the side urinary system		increased creatinine concentration, renal failure
Other	fever, tiredness, malaise	edema, lymphadenopathy, lowering of arterial pressure, conjunctivitis, anaphylaxis

Patients with a hypersensitivity reaction at first can take it for a respiratory disease (pneumonia, bronchitis, pharyngitis,respiratory viral infection), gastroenteritis, or for unwanted reactions associated with taking other drugs. Continuation of the drug Abacavir / Lamivudine-Teva in the development of hypersensitivity, as well as the resumption of its administration after the symptoms subsided, is fraught with serious consequences, even fatal. Therefore, if any of these symptoms appear, a thorough examination of the patient is necessary to exclude the hypersensitivity reaction. If you can not exclude hypersensitivity reaction, then repeated use of the drug Abacavir / Lamivudine-Teva or other abacavir-containing drugs is strictly contraindicated.

If patients continue to take Abacavir / Lamivudine-Teva when developing a hypersensitivity reaction, the clinical manifestations become more pronounced, and if they are withdrawn, they usually undergo a reverse development. Renewal of Abacavir / Lamivudine-Teva with patients with a history of hypersensitivity reaction leads to the development of a second reaction within a few hours.

Repeated hypersensitivity reactions can occur more severely than the first, and manifest life-threatening arterial hypotension, up to a lethal outcome. When a hypersensitivity reaction develops, the patient, regardless of the carrier of the allele HLA-B*5701, must permanently abandon the use of the drug Abacavir / Lamivudine-Teva and other preparations containing abacavir.

Sometimes a hypersensitivity reaction develops when the drug is resumed after its withdrawal, caused by the appearance of just one of the main symptoms of this reaction (rash, fever, malaise, fatigue, gastrointestinal (GI) or respiratory system). In rare cases, this reaction occurs when the Abacavir / Lamivudine-Teva drug is resumed in patients who had no symptoms of hypersensitivity before the drug was discontinued.

Side effects of abacavir or lamivudine

The side effects of abacavir or lamivudine, presented below in the tables, are classified with the following frequency: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely (including isolated cases) - less than 0.01%.

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 abacavir / lamivudine-Teva was discontinued due to one of these symptoms, and then a decision was made to resume taking abacavir, it should be started only under the direct supervision of the doctor.

Clinical research data and post-registration data

System organism	Abacavir	Lamivudine
From the side systems hematopoiesis		Infrequent - neutropenia, anemia, thrombocytopenia Very often - true red blood cell aplasia
From the immune system	Often - hypersensitivity to the drug
From the side of metabolism	Often - anorexia, hyperlactatemia Rarely, lactic acidosis	Often - hyperlactatemia Rarely, lactic acidosis
From the nervous system	Often - a headache	Often - a headache Very rarely - paresthesia, peripheral neuropathy is described (although a causal relationship with treatment is not established)
From the side digestive systems	Often - nausea, vomiting, diarrhea Rarely - pancreatitis, but a causal relationship with abacavir ns established	Often - nausea, vomiting, pain in the upper abdomen, diarrhea Rarely - increased serum amylase activity, pancreatitis (although a causal relationship with lamivudine is not established)
Hepatobiliary violations		Infrequently - a temporary increase in the activity of "hepatic" transaminase (aspartate aminotransferase, alanine aminotransferase) Rarely - hepatitis
From the skin and subcutaneous tissues	Often - a rash (without systemic symptoms); very rarely - exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis	Often - a rash, alopecia
From the body as a whole	Often - an increase in body temperature, apathy, a feeling of fatigue	Often - a feeling of fatigue, malaise, fever
From the side musculoskeletal systems		Often - arthralgia, muscle damage rarely - rhabdomyolysis

In some patients who underwent combined antiretroviral therapy, there was a redistribution / accumulation of fat in the body. The frequency of this phenomenon depends on many factors, includingfrom a combination of antiretroviral drugs.

Lactate acidosis, sometimes with a fatal outcome, usually associated with severe hepatomegaly and with steatosis of the liver, with the use of nucleoside analogues, has been reported.

Combined antiretroviral therapy (Apt) is associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia.

In HIV-infected patients with severe immunodeficiency at the time of the onset of combined Apt, can develop an inflammatory response in asymptomatic or resedual opportunistic infections. Autoimmune disorders have been reported (eg, Graves' disease). However, the time of receiving these messages is quite diverse, and these phenomena can occur many months after treatment.

Osteonecrosis has been reported, especially in patients with recognized risk factors, HIV disease or prolonged use of combined Apt. The frequency is unknown.

Overdose:

Symptoms Acute overdoses of abacavir and lamivudine correspond to adverse reactions of these active substances associated with their pharmacological action.

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

Interaction:

The drug interaction spectrum of the drug Abacavir / Lamivudine-Teva is due to the nature of the interaction of abacavir and lamivudine; At present, there is no clinically significant interaction of these active substances.

Abacavir and lamivudine are slightly metabolized by cytochrome P450 isoenzymes (for example, CYP3A4, CYP2C9 or CYP2D6) and do not have an inhibitory or inductive effect on this enzyme system. Therefore, the probability of drug interaction with antiretroviral non-nucleoside protease inhibitors and other drugs, the metabolism of which occurs with the participation of the basic isoenzymes of this system, is small.

The probability of metabolic interaction with lamivudine is low, because it is little metabolized, poorly bound to plasma proteins and excreted almost exclusively by the kidneys. Lamivudine is derived mainly through active organic cationic secretion. Consideration should be given to the possibility of interaction with other drugs, especially in cases where the kidneys are the main way of excretion.

Drug interactions caused by lamivudine

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

With simultaneous application lamivudine is able to suppress intracellular phosphorylation of zalcitabine, therefore this combination is not recommended.

With simultaneous application lamivudine can slow the intracellular phosphorylation of emtricitabine. In addition, the mechanism of development of resistance to both lamivudine and emtricitabine is associated with a mutation in the same codon of the reverse transcriptase gene (M184V), and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. The use of lamivudine in combination with emtricitabine or fixed dose combinations containing emtricitabine, Not recommended.

The interaction of lamivudine with didanosine has not been studied. Correction of the dose is not required.

With the simultaneous use of zidovudine in a dose of 300 mg once and lamivudine in a dose of 150 mg once AUC lamivudine without changes, AUC zidovudine without changes. Correction of the dose is not required.

Interaction with rifampicin has not been studied. There is not enough data to recommend a dose adjustment.

Interaction with cimetidine 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.

Interaction with cladribine has not been studied. In vitro lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a potential risk of loss of cladribine efficacy in the case of combined use 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.

Interaction with retinoids (for example, isotretinoin) has not been studied. There is not enough data to recommend a dose adjustment.

Interaction with methadone has not been studied. Correction of the dose of the drug Abacavir / Lamivudine-Teva is not required. For most patients, methadone dose adjustment is not required, in rare cases, it may be necessary to repurpose.

Drug Interactions Due to Abacavir

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.

Simultaneous application with such powerful inducers of cytochrome P450 as rifampicin, phenobarbital, phenytoin reduces the concentration of abacavir in the blood plasma induction of uridine diphosphate (UDF).

Theoretically, simultaneous use with ribavirin can lead to a decrease in intracellular phosphorylated metabolites. Care is required when using these medicines together.

In a study of pharmacokinetics of drugs with concurrent administration of abacavir (at a dose of 600 mg 2 per day) and methadone, there was a decrease in C_m_Oh abacavir by 35% and a decrease in T_m_Oh for 1 hour, however AUC remained unchanged. Changes in the pharmacokinetics of abacavir have not been clinically significant. In this study abacavir increased the average total methadone clearance by 22%. This change was not clinically significant in most patients, but there may sometimes be a need for a methadone dose adjustment.

Interaction with didanosine has not been studied. Correction of the dose is not required.

Interaction with zidovudine has not been studied. Correction of the dose is not required.

The interaction of cimetidine has not been studied. Correction of the dose is not required.

Interaction with retinoids (for example, isotretinoin) 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.

Special instructions:

Hypersensitivity reaction to abacavir. According to clinical studies conducted before the screening for the presence of an allele HLA-B*5701, in about 5% of patients taking abacavir, hypersensitivity to the drug develops, in rare cases with a fatal outcome (see section "Side effect").

Risk factors. In clinical studies, it has been shown that the carriage of an allele HLA-B*5701 significantly increases the risk of developing a hypersensitivity reaction to abacavir. In a prospective clinical study CNA106030 (PREDICT-1) in patients with the presence of an allele HLA-B*5701 drugs abakavira not used, which allowed to significantly reduce the incidence of clinically suspected hypersensitivity reactions from 7.8% (66 patients out of 847) to 3.4% (27 patients from 803) (p <0.0001), as well as the incidence of hypersensitivity reaction, confirmed by the skin-application test with 2.7% (23 patients from 842) to 0.0% (0 patients from 802) (p <0.0001). Thus, based on the results of this study, it was shown that the hypersensitivity reaction to abacavir develops in patients carrying the allele HLA-B*5701 with a frequency of 48-61% compared with patients who do not have this allele (the frequency of occurrence of a hypersensitivity reaction is 0-4%).

It is recommended that clinicians carry out screening for carriage of an allele HLA-B*5701 in HIV-infected patients who have not previously used drugs containing abacavir.

Screening for carriage of an allele HLA-B*5701 it is recommended that the product containing abacavir, patients with unknown HLA-B*5701-Status, previously well tolerated therapy with a drug containing abacavir.

The use of abacavir drugs is not recommended in patients with allele carriers HLA- B * 5701 and should be considered only in exceptional cases with careful medical supervision, when the potential benefit exceeds the risk of using the drug. The clinical diagnosis of suspected hypersensitivity reactions should remain the basis for deciding on the use of drugs containing abacavir, in all patients. Even in the absence of an allele HLA-B*5701 Abacavir must be withdrawn and not resumed in all cases,when the hypersensitivity reaction can not be ruled out, guided by clinical data, due to the potential risk of serious adverse effects or even death.

Clinical picture. The reaction of hypersensitivity is characterized by the appearance of symptoms of multiple organ failure. Most patients have fever and / or rash. Other possible symptoms of hypersensitivity include weakness, malaise, symptoms of gastrointestinal disorders (nausea, vomiting, diarrhea, abdominal pain), respiratory symptoms (dyspnea, sore throat, cough), and x-ray signs of chest damage limited infiltrates). Symptoms of hypersensitivity reactions in the treatment of abacavir can be observed at any time, however, usually appear during the first 6 weeks of taking the drug. When The continuation of treatment increases the severity of the symptoms, and they can take a life-threatening character. In most cases, these symptoms disappear when discontinuing abacavir.

Some patients with hypersensitivity initially believed,that suffer from respiratory (pneumonia, bronchitis, pharyngitis) or influenza-like diseases, gastroenteritis or reactions to other medications. In this regard, the hypersensitivity reaction was not diagnosed immediately, and patients continued (or resumed) the drug. This entailed the development of a more severe hypersensitivity reaction (up to a lethal outcome). Taking this into account, it is necessary to take into account the possibility of developing such a reaction and to exclude it in patients who have symptoms of these diseases. If it is impossible to exclude the presence of a hypersensitivity reaction, then resume the use of the drug Abacavir / Lamivudine-Teva or any other medication containing abacavir, do not do it.

Symptoms caused by hypersensitivity reactions increased with continued treatment and usually disappeared after discontinuation of abacavir. The resumption of abacavir after a hypersensitivity reaction for several hours leads to a rapid return of symptoms. Recurrence of hypersensitivity reactions may be more severe, compared with the first reaction, and accompanied by life-threatening lowering of blood pressure (up to a lethal outcome).Patients who experience this hypersensitivity reaction should stop and never resume taking the drug Abacavir / Lamivudine-Teva, as well as any other medications containing abacavir.

There are isolated reports of the development of a hypersensitivity reaction after resuming admission of abacavir, which was canceled when certain key symptoms of hypersensitivity appear (rash, fever, weakness / malaise, gastrointestinal disorders or respiratory symptoms). In very rare cases, the development of a hypersensitivity reaction has been reported after resumption of treatment with patients who have not previously experienced hypersensitivity symptoms.

Treatment. Patients, regardless of HLA-B * 5701-status, who have signs and symptoms of hypersensitivity, should immediately contact their doctor for advice. When making a diagnosis of hypersensitivity, immediately stop taking Abacavir / Lamivudine-Teva. Never the treatment with Abacavir / Lamivudine-Teva and other medications containing abacavir, after the occurrence of a hypersensitivity reaction.This is due to the threat of appearance within a few hours after the resumption of the drug of the expressed symptoms (including life-threatening arterial hypotension), which can lead to death.

To prevent delayed identify and reduce the risk of development

hypersensitivity, life-threatening, Abacavir / Lamivudine-Teva should be completely discontinued if it is impossible to exclude hypersensitivity, even with the potential for other diseases (respiratory diseases, flu-like diseases, gastroenteritis, reactions to other medications). Do not resume treatment with Abacavir / Lamivudine-Teva and other medications containing abacavir, even in the case of the appearance of symptoms of hypersensitivity in the re-admission of other medications.

Warning card with information for patients about the hypersensitivity reaction is in the package and corresponds to the instructions for the medical use of the drug.

Special instructions for treatment after a break in therapy with the drug Abacavir / Lamivudine-Teva. In the event of discontinuation of treatment, regardless of the carriage of the allele HLA- B * 5701, with the drug Abacavir / Lamivudine-Teva, before resumption of the drug should carefully study the reason for refusing the drug and make sure the patient has no symptoms of a hypersensitivity reaction. Do not resume taking Abacavir / Lamivudine-Teva and other medications containing abacavir, if it is impossible to exclude the hypersensitivity reaction.

A few cases of development of a hypersensitivity reaction during the resumption of treatment with abacavir after its withdrawal due to the appearance of any one of the typical symptoms of hypersensitivity (rash, fever, malaise, fatigue, gastrointestinal disturbances and respiratory system disorders) are described. Since in all such cases it is impossible to exclude the hypersensitivity reaction, then, taking into account the data on its more severe course with repeated use of abacavir, the resumption of therapy with the drug Abacavir / Lamivudine-Teva or other drug containing abacavir, these patients are not recommended.

The hypersensitivity reaction was noted, although extremely rare, even with the resumption of treatment with this drug for patients who had not previously experienced symptoms of this reaction, and a break in receiving the abacavir drug was associated with other causes. In this case, the resumption of taking the drug is possible, but the patient needs to provide quick access to medical care.

Screening for the carriage of the HLA-B * 5701 allele is recommended before re-use of abacavir-containing drugs in patients with an unknown HLA-B * 5701-status who had previously tolerated abacavir-containing drug therapy.

The repeated use of an abacavir-containing drug in patients carrying an allele HLA-B*5701 is not recommended and can only be considered in exceptional cases under close supervision, when the expected benefit of the drug treatment exceeds all possible risks.

Important information for patients

Before using the drug, the physician should make sure that the following information about the hypersensitivity reaction has been brought to the attention of the patient in full.Patients should be cautioned about the risk of developing a hypersensitivity reaction to abacavir, which can lead to life-threatening complications or death, as well as an increased risk of hypersensitivity reactions in the carriers of the allele HLA-B*5701.

If symptoms or symptoms, possibly due to a hypersensitivity reaction, appear, patients MUST contact their physician immediately.

The patient should be warned that even in the absence of the HLA-B * 5701 allele, a hypersensitivity reaction may develop; Therefore, when symptoms appear that may be due to a hypersensitivity reaction, all patients should immediately consult their physician.

Patients with hypersensitivity to abacavir should never take the drug Abacavir / Lamivudine-Teva and other medications containing abacavir, regardless of HLA-B * 5701-status.

To avoid the risk of resumption of the drug, patients who have a hypersensitivity reaction should return the remaining pills to the doctor.

Patients,who stopped taking Abacavir / Lamivudine-Teva for any reason (for example, due to the development of side effects), should consult with their doctor before resumption of the drug.

Each patient should read The warning card, attached to the drug. Patients should be reminded that they should always carry Warning card, attached to the drug.

Lactate acidosis, hepatomegaly and fatty liver. When using antiretroviral nucleoside analogues (including abacavir and lamivudine), taken both separately and in combination, development of lactic acidosis, hepatomegaly and severe fatty liver disease, including cases that ended in a fatal outcome, was noted. Similar reactions were noted, mainly, in women.

The clinical signs of developing lactic acidosis are symptoms from the gastrointestinal tract (nausea, vomiting and abdominal pain), general weakness, anorexia, loss of appetite, sudden causeless weight loss, symptoms of gastrointestinal tract and respiratory organs (shortness of breath, rapid breathing) or neurologic symptoms (including motor weakness).

Caution should be exercised when using Abacavir / Lamivudine-Teva in all patients (particularly obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and steatosis (including 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 drug should be discontinued if clinical or laboratory signs of lactic acidosis with or without hepatitis appear (including hepatomegaly and steatosis, even in the absence of a significant increase in aminotransferase activity) in conditions of symptomatic hyperlactatemia and metabolic acidosis / lactate 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 decrease in the number of peripheral fat deposits,emaciation of the face, enlargement of the mammary glands, increase in the concentration of glucose and lipids in the blood serum.

Lipodystrophy can develop when taking any drugs 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. The presence of HIV infection, the elderly age and the duration of antiretroviral therapy play an important and possibly counterproductive role.

During the clinical examination, attention should be paid to the signs of fat redistribution in the body. It is necessary to closely monitor the concentration of lipids in blood serum and the concentration of blood glucose. If necessary, appropriate treatment for violations of fat metabolism.

Patients with concomitant viral hepatitis B. Clinical studies and post-marketing data on the use of lamivudine suggest that in some patients with concomitant viral hepatitis B, clinical or laboratory signs of hepatitis relapse may occur after discontinuation of lamivudine.

Discontinuation of lamivudine may have more severe consequences in patients with decompensated liver damage. Therefore, in patients with concomitant viral hepatitis B, when Abacavir / Lamivudine-Teva is withdrawn, indicators of functional hepatic samples should be monitored and viral load regularly determined.

Syndrome of restoration of immunity. If HIV-infected patients with severe immunodeficiency are asymptomatic or asymptomatic opportunistic infections at the time of initiation of antiretroviral therapy, such therapy may lead to an increase in 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 (Pneumocystis carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

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

Opportunistic infections. The use of the drug Abacavir / Lamivudine-Teva 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 infection. Modern antiretroviral therapy, including the drug Abacavir / Lamivudine-Teva, does not prevent the transmission of HIV 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 to study the incidence of myocardial infarction in patients receiving combined antiretroviral therapy, a connection was found between the previous, within 6 months, administration of abacavir with an increased risk of myocardial infarction. According to the generalized analysis of clinical studies, there was no increase in the risk of myocardial infarction, associated with 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 studies do not allow one to unequivocally determine the relationship between abacavir therapy and the risk of myocardial infarction. Nevertheless, caution should be exercised 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, dyslipidemia, diabetes and smoking).

Abacavir and ribavirin have the same pathways of phosphorylation, which is why the intracellular interaction of these preparations is possible, which can lead to a decrease in intracellular phosphorylation of ribavirin metabolites and, as a result, a decrease in the response to treatment with pegylated interferon in combination with bocuprovir / peginterferon / ribosterin in co-infected patients with hepatitis C. According to the literature data, co-infected with HIV / hepatitis C patients receiving abacavir-containing combination APT, leads to a risk of delayed response to treatment with pigylated interferon / ribavirin. Care should be taken when using these drugs at the same time.

Mitochondrial dysfunction: In conditions in vitro and in vivo the ability of nucleotide and nucleoside analogs to cause damage to mitochondria of different degrees was revealed. There are reports of mitochondrial dysfunction in HIV-negative children who have been exposed to nucleoside analogues in utero or immediately after birth. The main manifestations of mitochondrial dysfunction were anemia, neutropenia, hyperlactatemia, hyperlipazemia. These reactions are often transient. There were also more recent neurologic manifestations (increased blood pressure, convulsions, behavioral disorders). The duration of neurological disorders is unknown. In utero, children can be exposed to nucleosides and their analogues, even in HIV-negative, and therefore a complete laboratory examination is needed for possible mitochondrial dysfunction with the corresponding signs or symptoms.The occurrence of these cases does not affect the current national recommendations but the use of a combined Apt in pregnant women for the prevention of vertical transmission of HIV infection.

Cases of pancreatitis have been reported, but a causal relationship between lamivudine and abacavir has not been established.

Osteonecrosis. Although the etiology of osteonecrosis is multifactorial (treatment with corticosteroids, alcohol consumption, severe immunodeficiency, high body mass index), cases of osteonecrosis have been reported in patients at the late stage of HIV and / or long-term combined Apt. If there is pain in the joints and difficulty in moving, you need to see a doctor.

Patients with chronic hepatitis B or C. Patients with chronic hepatitis B or C who received a combined Apt, are at risk of serious, sometimes fatal, liver problems. In the case of combined Apt for hepatitis B or C, see also the relevant information for these medicines.

In cases where lamivudine is used concomitantly with the treatment of HIV and hepatitis B. see the instructions for the medical use of the mono drug.

In the case of abolition of Abacavir / Lamivudine-Teva in co-infected with hepatitis B, periodic laboratory monitoring of liver function and hepatitis B markers is necessary, because of the possible exacerbation of hepatitis.

Liver disease. Efficacy and safety is not available in patients with severe liver disease. Abacavir / Lamivudine-Teva is contraindicated in patients with impaired hepatic function.

Patients who previously have liver dysfunction, including chronic / acute hepatitis, have an increased incidence of liver dysfunction when combined Apt, therefore, careful monitoring of patients should be ensured; If signs of worsening liver function appear, consider reversing treatment.

While the patients with impaired renal function correction of the dose of abacavir is not required, the dose of lamivudine should be reduced in proportion to the decrease in QC. In this regard, it is contraindicated to use the drug Abacavir / Lamivudine-Teva with SC less than 50 ml / min in this category of patients.

Risk of virological failure. In connection with the risk of virological failure should not take the drug Abacavir / Lamivudine-Tevasimultaneously with other medicinal products containing lamivudine or emtricitabine, it is not recommended to use simultaneously with cladribine.

Patient Warning Card for Hypersensitivity Reactions

Hypersensitivity reaction to abacavir. According to clinical studies conducted before the screening for the presence of an allele HLA-B*5701, in about 5% of patients taking abacavir. develops a hypersensitivity to the drug, in rare cases with a fatal outcome.

Symptoms of hypersensitivity reactions in the treatment of abacavir can be observed at any time, however, as a rule, appear during the first 6 weeks of taking the drug.With the continuation of treatment, the severity of the symptoms increases, and they can take a life-threatening character. In most cases, these symptoms disappear when discontinuing abacavir.

Treatment. Patients, regardless of HLA-B*5701 -Status, which have signs and symptoms of hypersensitivity, MUST immediately contact their doctor for advice. When making a diagnosis of hypersensitivity, SHOULD immediately stop taking preparation Abacavir / Lamivudine-Teva. NEVER SHOULD renew treatment with Abacavir / Lamivudine-Teva and other medications containing abacavir, after the occurrence of a hypersensitivity reaction. Ego is associated with the threat of appearance within a few hours after the resumption of taking the drug of severe symptoms (including life-threatening arterial hypotension), which can lead to death.

Do not resume treatment with Abacavir / Lamivudine-Teva and other medications containing abacavir. even in the case of the appearance of symptoms of hypersensitivity when re-taking other medications.

A warning card with patient information on hypersensitivity reactions is found in the package and follows the instructions for the medical use of the drug.

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, as well as the nature of the side effects that may occur when taking the drug Abacavir / Lamivudine-Teva, should be considered.

Form release / dosage:

Film-coated tablets, 600 mg + 300 mg.

Packaging:

For 10 tablets in a blister of PVC / PVDC / aluminum foil. 3 blisters together with instructions for use and a patient's warning card with information on hypersensitivity reactions in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002987

Date of registration:07.05.2015

Expiration Date:07.05.2020

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

PLIVA HRVATSKA, d.o.o. Croatia

Representation: & nbspTeva Teva Israel

Information update date: & nbsp16.01.2017

Illustrated instructions

Instructions

Abacavir / Lamivudine-Teva (Abacavir / Lamivudine-Teva)