Trizivir® (Trizivir®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAbacavir + Lamivudine + ZidovudineAbacavir + Lamivudine + Zidovudine
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  • Akimasol
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    FARMASINTEZ, JSC (Irkutsk)     Russia
  • Trizivir®
    pills inwards 
    VeeV Helsker United Kingdom Limited     United Kingdom
    • Dosage form: & nbspfilm coated tablets
    Composition:

    COMPOSITION on 1 tablet

    Name of components

    Amount, mg

    The core of the tablet

    Active substances

    Abacavir Sulfate

    351,00

    (in terms of abacavir)

    300,00

    Lamivudine

    150,00

    Zidovudine

    300,00

    Excipients

    Microcrystalline cellulose

    464,25

    Carboxymethyl starch of sodium, type A

    64,50

    Magnesium stearate

    20,25

    Film sheath

    Fall off the green

    21,0-35,0

    Composition of the film shell (Deficient green):

    Name of components

    Amount, mg

    Hypromellose

    22,05

    Titanium dioxide

    8,58

    Polyethylene glycol

    2,80

    Indigocarmine

    1,12

    Dye iron oxide yellow

    0,45
    Description:

    Tablets of the oval form, covered with a film shell of a greenish-blue color, with an engraved inscription "GX LL1"on one side of the pill.

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

    J.05.A.R.04   Abacavir + Lamivudine + Zidovudine

    Pharmacodynamics:

    Mechanism of action

    Lamivudine, zidovudine and abacavir - nucleoside analogs that inhibit HIV reverse transcriptase and selectively suppress the replication of HIV-1 and HIV-2.

    All three active components of Trizivir® pass consecutive stages of metabolism involving intracellular kinases and are converted into the corresponding 5'-triphosphates (TF). Lamivudine-TF, abacavir-TF and zidovudine-TF are substrates and competitive inhibitors of HIV reverse transcriptase. The main antiviral effect of the active ingredients of Trizivir® lies in their ability to be built in the form of monophosphate in the HIV DNA synthesizing, leading to a break of replication. The affinity of lamivudine, abacavir and zidovudine to DNA polymerases of the host cell is much lower.

    There was no antagonism in the antiviral activity of abacavir in cell culture when combined with neurotoxic reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine or a 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). There were no antagonistic effects in vitro with simultaneous use with zidovudine and other antiretroviral drugs (tested substances: abacavir, didanosine, lamivudine and interferon-alpha).

    In the obtained in vitro strains of HIV resistant to abacavir, mutations in several codons of the reverse transcriptase gene (RT) - M184V. K65R. L74V and Y115F.

    HIV resistance to abacavir in vitro and in vivo formed slowly. For a clinically significant increase in the inhibitory concentration IFROM5o (8 times the "wild" type virus) requires multiple mutations of the viral genome. Isolates resistant to abacavir may have reduced sensitivity to lamivudine, zalcitabine, and / or didanosine, but completely retain sensitivity to zidovudine and stavudine. The inefficiency of the combination of abacavir, lamivudine and zidovudine at the very beginning of treatment is usually due to only one mutation - M184V, so the use of this combination preserves the possibility of a wide choice of regimens for second-line therapy.

    Cross-resistance to abacavir, zidovudine, lamivudine, and HIV protease inhibitors or non-nucleoside reverse transcriptase inhibitors is unlikely. HIV isolates with reduced sensitivity to abacavir were isolated in patients with uncontrolled viral replication, in which previous therapy with other nucleoside reverse transcriptase inhibitors was ineffective.

    Pharmacokinetics:

    Studies in HIV-1-infected patients showed similar pharmacokinetic parameters of abacavir, lamivudine and zidovudine when administered as a fixed combination (Trizivir® preparation) or as a Combivir drug® (zidovudine + 3TC) in combination with the drug Ziagen® (abacavir). In addition, these parameters are close to those obtained in the study of the bioequivalence of the drug Trizivir® in healthy volunteers.

    A comparative study of the bioequivalence of Trizivir® and a combination of lamivudine 150 mg with zidovudine 300 mg and abacavir 300 mg taken together, as well as an assessment of the effect of food on the rate and degree of absorption.The results of the analysis of the area under the pharmacokinetic curve "concentration-time" (AUC∞) and the maximum concentration (CmOh) suggest that Trizivir® bioequivalent to lamivudine at a dose of 150 mg in combination with zidovudine at a dose of 300 mg and abacavir at a dose of 300 mg in the form of individual drugs, while taking Trisivir® with food did not lead to a clinically significant change in the pharmacokinetics of the drug.

    Suction

    Ingestion lamivudine, abacavir and zidovudine quickly and well absorbed in the gastrointestinal tract. Absolute bioavailability of lamivudine, abacavir and zidovudine after oral administration in adults is 80-85%, 83% and 60-70%, respectively.

    The intake of food reduces the rate of absorption of the active substances of Trizivir®, leading to a slight decrease in CmOh by 18-32% and an increase in the time to reach the maximum concentration (TmOh) for about 1 hour, but does not affect AUC∞. These changes in pharmacokinetic parameters are not of clinical significance, therefore the drug Trizivir® can be taken with or without food, and on an empty stomach.

    Distribution

    The volume distribution of lamivudine, abacavir and zidovudine for intravenous administration averages 1.3 l / kg, 0.8 l / kg and 1.6 l / kg, respectively. Lamivudine binding to the main protein of the blood plasma, albumin, insignificant (in vitro less than 36% of serum albumin), therefore the pharmacokinetics of lamivudine is linear. Zidovudine binds to blood plasma proteins by 34-38%. According to research in vitro, Abacavir in therapeutic doses is associated with serum proteins by approximately 49%. Interaction of active components of the drug Trizivir® with other drugs through their displacement from the compound with blood plasma proteins is unlikely. Thus, the drug Trizivir® also should not enter into such variant of interaction with medical products which is mediated by their displacement from communication with fibers of a plasma of blood.

    Lamivudine, abacavir and zidovudine penetrate the blood-brain barrier and are found in the cerebrospinal fluid (CSF). The ratio of the concentration of lamivudine and zidovudine in the serum to the corresponding concentrations of preparations in the CSF 2-4 hours after ingestion averages about 0.12 for lamivudine and 0.5 for zidovudine.The true extent of lamivudine penetration into the central nervous system (CNS), as well as the clinical significance of this phenomenon, have not been established to date.

    According to studies in HIV-infected patients, abacavir well penetrates into the CSF, while AUC Abacavir in CSF is 30-44% of AUC abacavir in the blood plasma. In the Phase I clinical study on the pharmacokinetics of abacavir, it was shown that 1.5 hours after the administration of abacavir 300 mg twice daily, its concentration in the CSF is 0.14 μg / ml. When using abacavir in a dose of 600 mg twice a day, its concentration in the CSF increases from 0.13 μg / ml 0.5-1 hour after its administration to 0.74 μg / ml after 3-4 hours. Thus, even if the concentration of abacavir in CSF after 4 hours after its administration at a dose of 600 mg twice a day does not reach its maximum, it exceeds IC50 (0.08 μg / ml, or 0.26 μmol / L) approximately 9-fold.

    Metabolism

    Since only a small fraction of lamivudine is metabolized in the liver (5-10%), and also due to insignificant binding to plasma proteins, metabolic interactions of lamivudine with other drugs are unlikely. Lamivudine is excreted unchanged by renal excretion.

    Zidovudine is mainly metabolized in the liver. The main metabolite of zidovudine in blood plasma and urine is 5'-glucuronide of zidovudine, which is excreted by the kidneys and is approximately 50-80% of the accepted dose of the drug. Another metabolite of zidovudine for parenteral administration is 3'-amino-3'-deoxythymidine (AMT).

    Abacavir is predominantly metabolized in the liver, only 2% of the accepted dose is excreted unchanged by the kidneys. In humans abacavir is metabolized mainly by the action of alcohol dehydrogenase to form a 5'-carboxylic acid and by conjugation with glucuronic acid to form 5'-glucuronide, which is about 66% of the total amount released through the kidneys of the drug.

    Excretion

    The half-life (T1/2) lamivudine is 5-7 hours. More than 70% lamivudine is excreted by the kidneys with the participation of the organic cation transport system, the total clearance is an average of about 0.32 l / h kg.

    According to studies with intravenous administration of zidovudine, its final T1/2 in blood plasma is an average of 1.1 hours, and the average systemic clearance is 1.6 l / h kg.The renal clearance of zidovudine is 0.34 l / h kg, indicating glomerular filtration and active tubular secretion of zidovudine. In patients with severe renal dysfunction, the concentration of zidovudine in the blood plasma increases.

    The mean value of T1/2 Abacavir is about 1.5 hours. Prolonged use of abacavir at a dose of 300 mg orally 2 times a day does not lead to significant cumulation of abacavir. Metabolized abacavir in the liver, its metabolites are excreted, mainly through the kidneys. About 83% of the drug in the form of metabolites and unchanged is excreted by the kidneys, the remaining amount - through the intestine.

    Special patient groups

    Elderly patients

    The pharmacokinetics of the drug in patients older than 65 years has not been studied.

    Patients with impaired renal function

    When examining patients with impaired renal function, it was shown that excretion of lamivudine is slowed by a decrease in renal clearance. If the creatinine clearance is less than 50 ml / min, an adequate correction of the dosing regimen is required.

    An increase in the concentration of zidovudine in blood plasma is observed only if there is a pronounced impairment of kidney function.Since less than 2% of abacavir is excreted by the kidneys unchanged, its pharmacokinetics in patients with terminal stage of renal failure does not differ from that in patients with normal renal function. Since patients with reduced renal function (creatinine clearance below 50 ml / min) may require a reduction in the dose of lamivudine and zidovudine, they are recommended to use monocomponent drugs lamivudine, zidovudine and abacavir.

    Patients with impaired hepatic function

    Data on the use of Trizivir® in patients with impaired liver function are not available. A few data obtained in patients with cirrhosis of the liver indicate a possible cumulation of zidovudine due to a decrease in the rate of formation of glucuronide. In studies in patients with violations of liver function of moderate and severe degree, no significant changes in the pharmacokinetics of lamivudine were detected.

    Abacavir is metabolized mainly in the liver. Results of a study of the pharmacokinetics of abacavir in patients with mild liver function disorders (Child-Pugh class A) indicate an increase AUC an average of 1.89 times and T1/2 - in 1,58 times. On the metric AUC metabolites of abacavir, liver function is not affected, but the rate of their formation and excretion is reduced. Therefore, the dose of abacavir should be reduced in patients with a mild liver function disorder. The pharmacokinetics of abacavir in patients with impaired liver function of medium and severe degree has not been studied, so the use of Trizivir® contraindicated in this group of patients.

    Indications:

    - HIV infection in adults and children over 12 years of age as part of antiretroviral therapy.

    Contraindications:

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

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

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

    - impaired renal function (creatinine clearance less than 50 ml / min);

    - marked decrease in the neutrophil count (less than 0.75 x 109/ l) or hemoglobin concentration (less than 7.5 g / dl or 4.65 mmol / L) due to the content of zidovudine;

    - age up to 12 years (due to the lack of possibility of dose adjustment);

    - body weight less than 40 kg (due to the lack of a recommended dosing regimen).

    Carefully:

    - Inhibition of bone marrow hematopoiesis (with a hemoglobin concentration of less than 9 g / dl (5.59 mmol / L) or a neutrophil count of less than 1.0 x 109/ l), a dose adjustment of zidovudine may be required, with the development of these unwanted reactions abacavir, zidovudine and lamivudine used as separate preparations;

    - pancreatitis (including in history);

    - hepatomegaly, hepatitis, any risk factors for liver disease;

    - presence of risk factors for the development of coronary heart disease;

    - elderly age.

    Pregnancy and lactation:

    Fertility

    The effects of abacavir, lamivudine and zidovudine on fertility in women have not been studied to date. With respect to zidovudine, it is shown that its use in men does not affect the number, morphology and motility of spermatozoa.

    Pregnancy

    Safety of Trisivir® in women during pregnancy has not been studied to date. There are research data on the effects of abacavir, lamivudine and zidovudine on fetal development in animals. Therefore, during pregnancy, Trizivir® is used only if the intended benefit to the mother exceeds the potential 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 were taking 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 causal relationship of these disorders to the effect of NRTIs during the intrauterine and perinatal periods has not been established. These data do not abolish existing recommendations for antiretroviral treatment during pregnancy to prevent vertical transmission of HIV.

    Breastfeeding period

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

    Dosing and Administration:

    The drug Trizivir® is intended for oral administration.

    Therapy should be carried out by a specialist with experience in the treatment of HIV infection.

    If it is necessary to cancel or reduce the dose of one of the active ingredients of the drug Trizivir®, they are used in the form of individual drugs of abacavir (Ziagen®), lamivudine (Epivir®) and zidovudine (Retrovir®).

    Adults and children over 12 years of age

    Recommended dose of Trizivir® for adults and children over 12 years - 1 tablet 2 times a day, regardless of food intake.

    If the body weight of a teenager or adult is less than 40 kg, the drug Trizivir® do not apply, since the dose of each active ingredient in the tablet is fixed, that is, it is not possible to reduce the dose for each active ingredient separately.

    Special patient groups

    Elderly patients

    Data on the pharmacokinetics of Trizivir® people over 65 are absent. Due to the possibility of age-related changes, including decreased renal function and hematologic disorders, the use of Trizivir® in persons of this age group requires special care.

    Patients with impaired renal function

    Impaired renal function may require a reduction in the dose of lamivudine or zidovudine.In this regard, patients with impaired renal function (creatinine clearance less than 50 ml / min) is recommended to use abacavir, lamivudine and zidovudine in the form of separate preparations.

    Patients with hepatic impairment

    Patients with mild liver function disorder (grade A on the Child-Pugh scale) may need a dose adjustment for abacavir and zidovudine. In connection with the impossibility of reducing the dose with Trizivir®, mono drugs of abacavir, lamivudine and zidovudine should be used, if necessary. The drug Trizivir® contraindicated in patients with impaired liver function.

    Correction of dose in the development of hematological adverse reactions

    With a hemoglobin concentration of less than 9 g / dL (5.59 mmol / L) or a neutrophil count of less than 1.0 x 109/ l, a dose adjustment of zidovudine may be required. When these unwanted reactions develop abacavir, zidovudine and lamivudine are used as separate preparations.

    Side effects:

    Since the preparation Trizivir® includes abacavir, lamivudine and zidovudine, it can cause the same undesirable reactions as these three active substances alone (Table 1).For a large number of the undesirable reactions listed below, it is not known whether they are related to the action of the active substance, as well as to the action of a wide range of commonly used drugs for the treatment of HIV infection, or the undesirable phenomena recorded are the result of pathological processes underlying the disease.

    The data necessary for a comprehensive assessment of the safety of Trisivir® is not sufficient to date.

    Hypersensitivity to abacavir

    According to clinical studies conducted prior to the screening for carriage of an allele HLA-B*5701, in about 5% of patients taking abacavir, a hypersensitivity reaction developed, in rare cases with a fatal outcome. This reaction is characterized by multiple organ failure.

    Most patients with hypersensitivity develop fever and / or a rash (usually maculopapular or urticaria), which are part of the manifestations of this syndrome, although in some cases these symptoms are absent.

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

    The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: Often (>1/10), often (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), rarely (> 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

    Table 1.

    Undesirable reactions of each of the active ingredients of Trizivir® (adverse reactions occurring in at least 5% of patients are isolated in bold)

    ATTENTION: information on hypersensitivity to abacavir see above

    Abacavir

    Lamivudine

    Zidovudine

    Violations from

    Rarely: cardiomyopathy.

    sides of the heart

    -

    -

    Violations from

    Often: nausea,

    Often: nausea, vomiting,

    Often: nausea.

    side of the gastrointestinal

    vomiting, diarrhea.

    diarrhea, pain in the

    Often: vomiting, diarrhea,

    Rarely: pancreatitis.

    upper abdomen.

    abdominal pain.

    Infrequent: flatulence.

    tract

    Rarely: increase

    Rarely: pigmentation

    serum amylase,

    mucous membrane

    pancreatitis.

    mouth, taste,

    dyspepsia, pancreatitis.

    Violations from

    -

    Infrequently: anemia and

    Often: anemia, neutropenia,

    sides of the blood

    neutropenia, thrombocytopenia.

    leukopenia.

    and lymphatic

    Infrequent: thrombocytopenia,

    systems

    Very rarely: true

    pancytopenia

    erythrocyte

    (due to hypoplasia

    aplasia.

    bone marrow).

    Rarely: true erythrocyte

    aplasia.

    Very rare: aplastic

    anemia.

    Immune system disorders

    Often: hypersensitivity.

    Disorders from the metabolism and nutrition

    Often: anorexia.

    Rarely: anorexia, lactic acidosis without hypoxemia.

    Disorders of the psyche

    Rarely: anxiety, depression.

    Disturbances from the liver and bile ducts

    Infrequently: transient increase in hepatic enzyme activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), increased serum amylase activity.

    Rarely: hepatitis.

    Often: increased bilirubin concentration and hepatic enzyme activity in the blood. Rarely: liver damage, including severe hepatomegaly with steatosis.

    Disorders from the kidneys and urinary tract

    Rarely: frequent urination.

    Violations of the genitals and mammary gland

    Rarely: gynecomastia.

    Disturbances from musculoskeletal and connective tissue

    Often: myopathy, arthralgia.

    Rarely: rhabdomyolysis.

    Often: myalgia. Infrequent: myopathy.

    Disturbances from the nervous system

    Often: headache.

    Often: headache, insomnia. Very rarely: peripheral neuropathy (paresthesia).

    Very often: headache, dizziness.

    Rarely: insomnia, paresthesia, dizziness, drowsiness, decreased mental abilities, convulsions, anxiety.

    Violations from

    side of the respiratory system, chest and mediastinal organs

    -

    Often: coughь,

    nasal symptoms.

    Infrequent: shortness of breath.

    Rarely: cough.

    Violations from

    side of the skin

    and subcutaneous

    fabrics

    Often: a rash without

    systemic manifestations.

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

    Often: rash, alopecia.

    Infrequent: rash, itching.

    Rarely: pigmentation

    nails and skin, hives, sweating.

    Other

    Often: fever,

    drowsiness, fatigue.

    Often: fever,

    malaise, fatigue.

    Often: malaise.

    Infrequently: fever,

    generalized pain, asthenia.

    Rarely: chills, chest pain, flu-like syndrome.

    Adverse reactions of abacavir

    Many of the above undesirable reactions associated with taking abacavir (nausea, vomiting, diarrhea, fever, fatigue, rash) can often be observed as part of a hypersensitivity reaction. Therefore, when any of these symptoms appear, a thorough examination of the patient is performed to confirm or exclude a hypersensitivity reaction. Trisivir® after interruption in connection with the appearance of the above symptoms can only be after the elimination of the hypersensitivity reaction and under direct medical supervision. Patients should be aware of the continued use of Trizivir®. Careful medical supervision is necessary during the first 2 months with consultations every 2 weeks.

    The hypersensitivity reactions are shown below. Symptoms that occur No less than the 10 % patients with hypersensitivity, highlighted in bold type.

    Disturbances from the skin and subcutaneous fat: rash (usually maculopapular or urticaria).

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

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

    Impaired nervous system: headache, paresthesia, retardation.

    Violations from the blood and lymphatic system: lymphopenia, lymphadenopathy.

    Disorders from the liver and bile ducts: increased activity of liver enzymes, 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 tract: an increase in the concentration of creatinine in the blood plasma, kidney failure.

    Immune system disorders: anaphylactic reactions.

    Disorders from the organs of vision: conjunctivitis.

    Vascular disorders: arterial hypotension.

    Other: fever, malaise, edema.

    Hematologic adverse reactions

    Treatment with zidovudine may lead to the development of anemia (blood transfusion may be required), neutropenia and leukopenia (usually secondary due to neutropenia). These complications are more common in the treatment of high doses of zidovudine (1200-1500 mg / day), as well as in cases when the patient is experiencing oppression of hematopoiesis before the start of treatment, particularly in the late stages of HIV infection with the number Cd4+- lymphocytes below 100 cells / mm2. Neutropenia is also more common in those patients whose neutrophil count, serum hemoglobin and vitamin B12 concentration were reduced even before the initiation of zidovudine therapy. In this regard, patients taking the drug Trizivir ®, it is necessary to carefully assess the hematological parameters (see section "Special instructions"). With the development of anemia, neutropenia and leukopenia, a dose reduction or discontinuation of Trisivir® therapy may be required. With the development of anemia, a blood transfusion may be required.

    Lactic acidosis

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

    Lipodystrophy and metabolic disorders

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

    Immunodeficiency Syndrome

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

    Osteonecrosis

    Osteonecrosis has been documented, especially in patients with well-known risk factors, advanced HIV infection, or long-term use of combined Apt. The frequency of this phenomenon is unknown.

    Overdose:

    Symptoms

    No cases of an overdose with Trizivir® were noted. Specific symptoms of an acute overdose of zidovudine or lamivudine, other than dose-dependent adverse reactions for these drugs, are not described. There were no cases of a lethal outcome with an overdose of zidovudine and lamivudine. Clinical studies of abacavir with single doses not exceeding 1200 mg and daily diets not exceeding 1800 mg did not reveal unforeseen undesirable reactions. The effects of abacavir in higher doses have not been studied to date.

    Treatment

    In the case of an overdose of Trizivir®, a patient is observed to detect symptoms of poisoning and, if necessary, conduct standard maintenance therapy. Because the lamivudine is withdrawn by dialysis, with an overdose of Trizivir® it is possible to resort to continuous hemodialysis, although its effectiveness in this situation has not been studied. Although hemodialysis and peritoneal dialysis are ineffective for the excretion of zidovudine, they accelerate the elimination of its metabolite - glucuronide. How effective are hemodialysis and peritoneal dialysis for abacavir removal to date unknown.

    For more information, the physician should read the instructions for the use of individual lamivudine preparations. abacavir and zidovudine.

    Interaction:

    Since the preparation Trizivir® includes abacavir, lamivudine and zidovudine, he can enter into the same drug interactions as each of them individually. Clinical studies have demonstrated the absence of pronounced drug interactions between abacavir, lamivudine and zidovudine.

    The following examples of drug interactions, although not exhaustive, are typical for drug groups, which should be used with extreme caution.

    Drug Interactions of Abacavir

    Research in vitro and analysis of the main metabolic pathways of abacavir indicate that its interaction with other drugs mediated by cytochrome P450 is unlikely. Abacavir does not suppress metabolic reactions involving isoenzyme 3A4 cytochrome P450. In studies in vitro shown, that abacavir does not reduce the activity of isoenzymes CYP3A4, CYP2C9 and CYP2D6. Clinical studies have not revealed induction of hepatic metabolism of exogenous substances under the influence of abacavir. Thus, the interaction of abacavir with HIV protease inhibitors and other drugs metabolized with the participation of the main cytochrome P450 isoenzymes is unlikely.

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

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

    Retinoids: retinoids, for example isotretinoin, are derived with the participation of alcohol dehydrogenase, so they can interact with abacavir, but to date no special studies have been conducted.

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

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

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

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

    Drug interactions of lamivudine

    Drug interactions of lamivudine are unlikely, since it is metabolized to a small extent, weakly binds to plasma proteins and is excreted almost exclusively by the kidneys. However, with the joint use of lamivudine with other drugs, it is necessary to consider the possibility of drug interactions, especially if these drugs are excreted, mainly by the kidneys.

    Trimethoprim: with simultaneous application of a combination of trimethoprim and sulfamethoxazole, 160 mg + 800 mg (co-trimoxazole), AUC lamivudine is increased by 40% due to trimethoprim. With normal renal function, such a change does not require correction of the dose of lamivudine. On the pharmacokinetics of trimethoprim and sulfamethoxazole lamivudine does not affect. Joint use of lamivudine with higher doses of co-trimoxazole used to treat pneumonia caused by Pneumocystis jiroveci and toxoplasmosis should be avoided.

    Zalcitabine: it is possible to suppress the intracellular phosphorylation of zalcitabine while using it with lamivudine, so Trizivir® it is not recommended to be used together with zalcitabine.

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

    Cladribine: the interaction has not been studied. In vitro lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a potential risk of loss of cladribine efficacy when combined in clinical practice. Some clinical data also confirm the interaction between lamivudine and cladribine. Thus, the simultaneous use of lamivudine and cladribine is not recommended.

    Rifampicin: the interaction is not studied. There is not enough data to recommend a dose adjustment.

    Phenobarbital: the interaction has not been studied. There is not enough data to recommend a dose adjustment.

    Phenytoin: the interaction has not been studied. There is not enough data to recommend a dose adjustment. It is necessary to monitor the concentration of phenytoin.

    Drug Interactions of Zidovudine

    Zidovudine is excreted mainly through the liver due to conjugation and the formation of an inactive glucuronide. In this regard, drugs that are metabolized primarily in the liver, especially with the formation of glucuronides, can inhibit zidovudine metabolism.

    Atovahon: zidovudine does not affect the pharmacokinetics of atovahona.However, pharmacokinetic analysis shows that atovahon can reduce the concentration of the zidovudine-glucuronide metabolite in the blood plasma (an increase in the exposure of zidovudine up to 33% and a decrease in the maximum concentration of glucuronide to 19%). It is unlikely that sharing zidovudine at a dosage of 500 or 600 mg per day and atovahona for 3 weeks to treat acute PCP may lead to an increase in the number of adverse reactions due to an increase in plasma concentrations of zidovudine. It requires careful monitoring of patients on prolonged treatment with atovahona.

    Clarithromycin: clarithromycin in a tablet dosage form can reduce zidovudine absorption. This can be avoided with the use of clarithromycin in tablets and preparations containing zidovudine, with at least a two-hour interval.

    Lamivudine: simultaneous use of zidovudine and lamivudine leads to an increase in the maximum concentration of zidovudine in blood plasma by 28% and an increase AUC zidovudine by 13%, assessed as clinically insignificant and does not change the safety profile of both components of the Trizivir® preparation, and therefore does not require correction of the dosing regimen. Zidovudine does not affect the pharmacokinetics of lamivudine.

    Phenytoin: in some patients who used phenytoin simultaneously with zidovudine, the concentration of phenytoin in the blood decreased, and one patient, on the contrary, noted its increase. These observations indicate the need for careful monitoring concentration of phenytoin in the blood in the case of its use together with the drug Trizivir®.

    Probenecid: according to a few data, probenecid, suppressing the conjugation of zidovudine with glucuronic acid, increases its T1/2 and AUC. Excretion of zidovudine in the form of glucuronide (and, possibly, in a free form) by kidneys under the influence of probenecid slows down.

    Rifampicin: according to a few data, rifampicin reduces the AUC zidovudine by 48 ± 34%. The clinical significance of this data is currently unclear.

    Stavudine: zidovudine can suppress intracellular phosphorylation of stavudine, so apply stavudine in combination with Trizivir® Not recommended. The concomitant use of valproic acid, fluconazole or methadone with zidovudine may lead to an increase in the area under the zidovudine pharmacokinetic curve and a corresponding decrease in its clearance.Despite the fact that the clinical significance of this phenomenon is unknown, it is necessary to provide close medical observation regarding possible manifestations of zidovudine toxicity.

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

    There are other drugs that can influence the metabolism of zidovudine by competitive binding to glucuronic acid or a direct inhibitory effect on microsomal enzymes of the liver, for example, acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam. cimetidine, clofibrate, dapsone and isoprinosine. Before using any of these drugs in combination with the drug Trizivir®, it is necessary to evaluate the possibility of their interactions, especially if long-term treatment is planned.

    Simultaneous use of zidovudine and drugs with nephrotoxic and myelosuppressive action (pentamidine for systemic use, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine,ganciclovir, interferon, vincristine, vinblastine and doxorubicin), especially in emergency treatment, increases the risk of developing unwanted zidovudine reactions. If you avoid using these drugs in combination with the drug Trizivir® it is impossible, then the treatment is carried out under careful control of kidney function and hematological parameters, and if necessary, the dose of one or more drugs is reduced.

    The concomitant use of ribavirin and zidovudine in some cases led to an increased risk of anemia, a fact that is especially important for patients who had an anemia of zidovudine-induced anemia.

    Since Trizivir® treatment does not exclude the risk of opportunistic infections, antimicrobial therapy with cotrimoxazole, penta- didine in the form of inhalations, pyrimethamine and acyclovir may be required for their prevention. According to a few clinical trials, these preparations do not cause a significant increase in the risk of developing adverse reactions of zidovudine.

    The drug Trizivir® should not be taken with other medicines containing lamivudine or medicinal products containing emtricitabine. The simultaneous use of stavudine with zidovudine should be avoided.

    Special instructions:

    Hypersensitivity to abacavir

    According to clinical studies conducted prior to the introduction of screening for carriers of allele HLA-B*5701, in about 5% of patients taking abacavir. developed a reaction of hypersensitivity, in rare cases with fatal outcome.

    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 an allele HLA-B*5701 abacavir preparations were not used, which allowed to significantly reduce the incidence of clinically suspected hypersensitivity reactions with 7.8% (66 of 847 patients) and 3.4% (27 of 803 patients) (p <0.0001), and the incidence of hypersensitivity reactions, confirmed kozhnoapplikatsionnoy sample with 2.7% (23 patients out of 842) to 0.0% (0 out of 802 patients) (p<0,0001). Thus, based on the results of this study, it was shown that a hypersensitivity reaction to abacavir develop in patients - carriers of the allele HLA-B*5701 with a frequency of 48-61% compared with patients in whom this allele is absent (frequency of occurrence of hypersensitivity reactions 0-4%).

    Before starting treatment, it is recommended to carry out screening for carriage of an allele HLA- B * 5701 in HIV-infected patients who had not previously used abacavir. Screening for carriage of an allele HLA-B*5701 It is recommended that before the repeated use of abacavir in patients with unknown HLA-B*5 701-status, previously well tolerated abacavir therapy. Treatment with abacavir is not recommended in carriers of the allele HLA-B*5701 and should be considered only in exceptional cases under close medical supervision, when the potential benefit exceeds the risk associated with the use of the drug.

    The clinical diagnosis of a suspected hypersensitivity reaction should remain the basis for deciding the use of abacavir in all patients. Even in the absence of an allele HLA-B*5701 Abacavir must be withdrawn and not restarted in all cases where the hypersensitivity reaction can not be ruled out, guided by clinical data, because of the potential risk of developing severe adverse reactions or even death.

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

    Clinical picture

    The reaction of hypersensitivity 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 the gastrointestinal tract (such as nausea, vomiting, diarrhea, abdominal pain), symptoms of respiratory damage (such as shortness of breath, sore throat, cough), as well as radiologic signs lesions of the chest (mainly, limited infiltrates). Symptoms of hypersensitivity reactions may occur at any time during treatment with abacavir, but, as a rule, appear during the first 6 weeks of taking the drug. 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.

    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, patients SHOULD immediately stop taking Trisivir®. NEVER RESUME TRIZIVIR TREATMENT® and other medicinal products containing abacavir (such as Ziagen®, Kivexa), after the emergence of a hypersensitivity reaction. This is due to the threat of appearance within a few hours after the resumption of taking the drug even more severe symptoms (including life-threatening arterial hypotension) that can lead to death.

    To prevent late detection and reduce the risk of life-threatening hypersensitivity reactions should completely stop taking Trisivir® if it is impossible to exclude hypersensitivity, even with the potential presence of other diagnoses (respiratory diseases, influenza-like diseases, gastroenteritis, reactions to taking other medications).Trizivir should not be resumed® and other medicinal products containing abacavir (such as Ziagen®, Kivexa), even in the case of hypersensitivity symptoms in the re-admission of alternative medications. A warning card with information for patients about the hypersensitivity reaction is in the package.

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

    In the event of discontinuation of treatment with any drug containing abacavir, regardless of the carriage of the allele HLA-B*5701 and before resumption of Trisivir® should carefully study the reason for refusing to use the drug and make sure that the patient does not have symptoms of a hypersensitivity reaction. Do not resume taking Trisivir® and other medications containing abacavir (such as Ziagen®, Kivexa), if it is impossible to exclude the hypersensitivity reaction.

    A few cases of the development of a hypersensitivity reaction during the resumption of treatment with abacavir after its withdrawal due to the appearance of any one of the typical symptoms of hypersensitivity (rash, fever, malaise, fatigue,gastrointestinal disturbances and disorders of the respiratory system). If a decision is made to resume therapy with Trizivir® in these patients, it is necessary to conduct treatment under direct medical supervision. A hypersensitivity reaction was noted, although extremely rare, even with the resumption of treatment with these drugs in patients who had not previously experienced symptoms of this reaction and a break in taking the drug containing abacavir, was associated with other causes. In this case, the resumption of taking the drug is possible, but requires the patient or people around him to have quick access to medical care.

    Screening for carriage of an allele HLA-B*5701 It is recommended to be performed before repeated use of abacavir in patients with unknown HLA-B*5701 status, previously well tolerated therapy with abacavir. Repeated use of abacavir in patients with allele carriers HLA-B*5701 is not recommended and can be considered only in exceptional cases under careful medical supervision, when the potential benefit from drug treatment exceeds all possible risks.

    Important information for patients

    The doctor prescribing the drug, should make sure, that the following information on 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;

    - patients should be warned that even in the absence of an allele HLA-B*5701 may develop a hypersensitivity reaction. Thus, with the appearance of symptoms that may be due to a hypersensitivity reaction, ALL patients MUST IMMEDIATELY contact your doctor;

    - patients with hypersensitivity to abacavir should never take Trizivir® and other abacavir-containing drugs (such as Ziagen®, Kivexa), 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 who prescribed the drug;

    - patients who discontinued Trizivir® for any reason (especially in connection with the development of adverse reactions) should consult their physician before recommencing the drug;

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

    Lactic acidosis and severe hepatomegaly with steatosis

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

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

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

    Mitochondrial dysfunction

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

    Redistribution of subcutaneous fat

    In some patients receiving combined Apt, there may be a redistribution and / or accumulation of subcutaneous fat, including obesity by the central type,dorsocervical fat deposition ("buffalo buffalo"), a reduction in the subcutaneous fat layer on the face and limbs, an increase in the mammary glands, an increase in serum lipid concentrations and a concentration of glucose in the blood.

    Lipodystrophy can develop when taking any medication from a class of HIV protease inhibitors or NRTIs. However, the available data indicate that the risk of developing these side effects when taking different preparations of these classes is not the same.

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

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

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

    Undesirable reactions from the hematopoiesis system

    In patients receiving zidovudine, anemia, neutropenia and leukopenia (usually secondary due to neutropenia) can be observed. Most often, these phenomena occur with the use of high doses of zidovudine (from 1200 to 1500 mg / day) and also in cases when the patient was oppressed with hematopoiesis before the start of treatment, in particular, in the late stages of HIV infection. Neutropenia is also more common in those patients whose neutrophil count, serum hemoglobin and vitamin B12 concentration were reduced even before the initiation of zidovudine therapy. Thus, in patients taking the drug Trizivir ®, it is necessary to carefully monitor hematologic indices.

    Hematological disorders usually occur no earlier than 4-6 weeks after the start of treatment. In the late stages of HIV infection during the first three months of treatment, a blood test is recommended at least every 2 weeks, then at least monthly. For therapy initiated in the early stages of HIV infection, hematologic side effects are rare. Depending on the general withThe total blood test can be performed less frequently, for example, every 1-3 months.

    With the development of severe anemia and severe myelosuppression under the influence of the drug Trizivira® also in the presence of hematologic disorders prior to treatment, for example. with a hemoglobin concentration below 9 g / dL (5.59 mmol / L) or a neutrophil content below 1.0 x Ю9/ l, a dose adjustment of zidovudine may be required. Since the dose of zidovudine in Trizivir® it is impossible, such patients should use separate preparations of zidovudine, abacavir and lamivudine.

    Pancreatitis

    On a background of treatment with abacavir, lamivudine and zidovudine, pancreatitis is rare in rare cases, although it is still unclear whether it is caused by the action of these drugs or is a consequence of HIV infection. When clinical or laboratory signs of pancreatitis appear, Trisivir® should be stopped immediately.

    Diseases of the liver

    Efficacy and safety of Trizivir® They were not established in patients with severe concomitant liver diseases. The drug Trizivir® contraindicated in patients with impaired liver function.

    In patients with an initially present impaired liver function,including an active form of chronic hepatitis, there is an increase in the frequency of violations of liver function in combination Apt. Such patients need to be monitored in accordance with standard clinical practice. If the liver function worsens in such patients, the possibility of suspending or canceling the drug should be considered.

    In patients with chronic hepatitis B or C receiving a combined Apt, increased risk of serious and deadly adverse reactions from the liver. In case of concomitant use of antiviral therapy for hepatitis B or C, the instructions for the use of these drugs should be consulted.

    When Trizivir® is withdrawn, patients with concomitant viral hepatitis B should monitor the performance of functional hepatic samples and regularly detect viral load, as a possible relapse of hepatitis after discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver damage.

    Co-infection of HIV and viral hepatitis B

    Clinical studies and post-registration data on the use of lamivudine show that in some patients with chronic hepatitis B, lamivudine reversal results in clinical and laboratory signs of recurrence of the disease that may have more severe consequences in patients with decompensated liver disease. In patients with concomitant hepatitis In the case of discontinuation of Trizivir® it is necessary to regularly assess liver function and determine the markers of hepatitis B virus replication.

    Co-infection of HIV and viral hepatitis C

    There have been reported cases of exacerbation of anemia in the presence of ribavirin with concomitant Apt zidovudine, the mechanisms of this phenomenon are not sufficiently studied. It is not recommended to combine preparations containing zidovudine, with ribavirin. If zidovudine already included in the combined Apt, such treatment regimen should be reviewed, especially for patients who had a history of anemia with zidovudine.

    Care should be taken when taking abacavir and ribavirin simultaneously.

    Immunodeficiency Syndrome

    In the presence of HIV-infected patients with severe immunodeficiency asymptomatic opportunistic infections or their residual effects at the time of onset Apt its conduct can activate the inflammatory process and lead to an increase in the symptoms of opportunistic infections or other severe consequences. Usually, these reactions occur within the first weeks or months after the onset Apt. As an example, cytomegalovirus retinitis, generalized or focal mycobacterial infection and pneumonia caused by Pneumocystis jiroveci. The appearance of any symptoms of inflammation requires an immediate examination and. if necessary, treatment.

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

    Opportunistic infections

    Use of Trizivir® 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.

    Osteonecrosis

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

    Transmission of HIV infection

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

    Myocardial infarction

    As a result of a prospective observational epidemiological study to study the incidence of myocardial infarction in patients receiving a combined Apt, The association of the previous administration of abacavir within 6 months with an increased risk of myocardial infarction was found.According to the generalized analysis of clinical studies, there was no increased risk of myocardial infarction associated with abacavir. Biological mechanisms that explain a potentially increased risk are unknown. In general, the available data obtained from observational cohort and controlled clinical trials do not allow one to unequivocally determine the relationship of abacavir therapy with the risk of myocardial infarction.

    Nevertheless, with caution should be applied Apt, including abacavir. patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize the modifiable risk factors (such as hypertension, hyperlipidemia, diabetes and smoking).

    Concomitant treatment

    Patients should be cautioned against self-medication with any form of medication.

    Selection of doses

    If individual dosing is necessary, separate preparations of abacavir, lamivudine and zidovudine are used. In this case, the physician should become familiar with the information on each of these drugs.

    Use with other antiretroviral drugs

    There is currently insufficient data on the efficacy and safety of simultaneous use of Trizivir® with NNRTIs and PIs.

    The drug Trizivir® Do not use with preparations containing lamivudine or emtricitabine.

    You should avoid the simultaneous use of stavudine and zidovudine.

    The use of lamivudine with cladribine is not recommended.

    Patient Warning Card

    Attention!

    Trizivir®, film-coated tablets abacavir + lamivudine + zidovudine

    Always carry this card with you

    Because Trizivir® contains abacavir. In some patients taking Trizivir®, a hypersensitivity reaction (a serious allergic reaction), often life-threatening, may occur if the drug is not withdrawn. IMMEDIATELY CONTACT YOUR DOCTOR'S DOCTOR for advice on the possibility of further administration of Trizivir® if:

    - you have a skin rash OR

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

    - fever;

    - shortness of breath, sore throat, or cough;

    - nausea or vomiting, abdominal pain, diarrhea;

    - increased fatigue, pain or general malaise.

    If you stop taking Trisivir® as a result of this reaction, DO NOT MAKE ANYTHING Trizivir® or any other preparation containing abacavir (Ziagen®, Kivexa), as this can immediately lead to a life-threatening drop in blood pressure or death.

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

    Studies of the effect of Trizivir® and its active ingredients (abacavir, lamivudine and zidovudine) on the ability to drive vehicles and work with mechanisms have not been conducted. Pharmacological properties of active substances do not allow to predict the effect of Trizivir® on these activities. When assessing a patient's ability to drive and work with machinery, consideration should be given to his clinical condition and the full range of unwanted reactions of Trizivir®.

    Form release / dosage:The tablets covered with a film cover, 300 mg + 150 mg + 300 mg.
    Packaging:

    10 tablets in a blister pack from PVC / Aklar® (PCTFE) / foil.

    For 6 blisters together with instructions for use in a cardboard bundle.

    For 12 tablets in a PVC / Aklar® blister (PCTFE) / foil.

    For 5 blisters together with instructions for use in a cardboard bundle.

    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:П N015795 / 01
    Date of registration:25.05.2009
    The owner of the registration certificate:VeeV Helsker United Kingdom LimitedVeeV Helsker United Kingdom Limited United Kingdom
    Manufacturer: & nbsp
    Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO
    Information update date: & nbsp22.12.2014
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