Zidovudine + Lamivudine-Vial - instructions for use, dose, side effects, contraindications

Excipients: microcrystalline cellulose - 90,00 mg; sodium carboxymethyl starch - 36.00 mg; magnesium stearate - 6.00 mg; silicon dioxide colloid - 6,00 mg; povidone K-30 - 6.68 mg.

Sheath: hypromellose - 7,172 mg; Macrogol (polyethylene glycol) - 2.941 mg; titanium dioxide - 0.207 mg.

Description:Biconvex tablets capsular shaped, covered with a film coat of white or almost white; on the one hand tablets engraving: the logo of the manufacturer (the lettering "Sun", enclosed in an oval); On the fracture, the nucleus of the white or almost white color is visible.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.R.01 Zidovudine + Lamivudine

Pharmacodynamics:

Combined antiviral drug, in which includes zidovudine and lamivudine, which are potent selective inhibitors of HIV-1 and HIV-2 reverse transcriptase.

Lamivudine is a synergist of zidovudine against the suppression of HIV replication in cell culture. Both substances are sequentially metabolized by intracellular kinases to 5'-triphosphate (TF). Lamivudine-TF and zidovudine-TF are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme.

However, the antiviral activity of the preparations is mainly due to the inclusion of their monophosphate form in the viral DNA chain, as a result of which a chain break occurs.Triphosphates of lamivudine and zidovudine have a much lower affinity for DNA polymerases of human cells. 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 when using zidovudine and other antiretroviral drugs (tested substances: abacavir, didanosine, lamivudine and interferon-alpha).

In vitro shows low cytotoxicity of lamivudine against lymphocytic and monocyte-macrophage colonies and a number of precursor cells of the red bone marrow. In this way, in vitro lamivudine has a wide therapeutic index.

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

Resistance to thymidine analogues (such as zidovudine) is well described and correlates with sequential accumulation up to 6 specific mutations of HIV reverse transcriptase in codons 41, 67, 70, 210, 215 and 219. Viruses acquire phenotypic resistance to thymidine analogues by combining mutations in codons 41 and 215 or by accumulation of at least four or six. These mutations against the background of thymidine analogs alone do not cause high cross-resistance to other nucleosides, which subsequently allows the use of other approved NRTIs.

There are two types of development of mutations leading to multidrug resistance, the first type - mutations of viral reverse transcriptase in codons 62, 75, 77, 116 and 151, the second type - T69S mutations with insertion into position 6th pair of nitrogenous bases corresponding to this position, which is accompanied by the appearance of phenotypic resistance to zidovudine and other NRTIs. Any of these types of mutations leading to the development of multidrug resistance severely limits the possibilities of treatment.

In clinical trials, the combination of lamivudine and zidovudine led to a decrease in HIV-1 load and an increase CD4 + cells. Clinical evidence suggests that the use of a combination of lamivudine and zidovudine or a combination of lamivudine and zidovudine-containing regimens leads to a significant reduction in the risk of disease progression and mortality.

Separately, monotherapy with lamivudine or zidovudine resulted in the appearance of HIV isolates with reduced sensitivity to these drugs in vitro. Clinical evidence suggests that patients who have not previously received APT, combined therapy with lamivudine and zidovudine slows the emergence of resistant to zidovudine HIV strains.

The clinical significance of the in vitro viral sensitivity to zidovudine and lamivudine is investigated.

Combination therapy with lamivudine and zidovudine is widely used as a component Apt together with other antiretroviral drugs of the same class (NRTIs) or other classes (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors [NNRTIs]).

Combined regimens of antiretroviral therapy, including lamivudine are effective in the treatment of patients who have not previously received antiretroviral drugs and patients who have isolated HIV strains with M184V a mutation.

Pharmacokinetics:

Suction

Lamivudine and zidovudine well absorbed from the intestine. In adults after oral administration, the bioavailability of lamivudine is 80-85%, and of zidovudine 60-70%.

After taking the drug inside the maximum concentration (FROM_max) lamivudine and zidovudine are detected through 0.75 (0.5-2) h and 0.5 (0.25-2) h and is 1.5 (1.3-1.8) mg / ml and 1.8 (1.5-2.2) mg / ml, respectively.

The degree of absorption of lamivudine and zidovudine (based on the area under the pharmacokinetic curve "concentration-time" (AUC)) and half-life (T₁_/2) after intake from food were similar to those after fasting, although the rate of absorption was somewhat slowed.

Distribution

When administered intravenously, the average volume of distribution (Vd) for lamivudine and zidovudine is 1.3 and 1.6 l / kg, respectively. Lamivudine has linear pharmacokinetics when used in therapeutic doses and is bound to bound to blood plasma albumin (less than 36% of serum albumin in vitro). Zidovudine binds to plasma proteins by 34-36%. Thus, the interaction of lamivudine and zidovudine with other drugs through the replacement of protein bonds is unlikely.

Determined that lamivudine and zidovudine penetrate into the central nervous system and cerebrospinal fluid. 2-4 hours after oral administration, the ratio between the concentration of lamivudine and zidovudine in the cerebrospinal fluid and in serum is on average 0.12 and 0.5, respectively.

Metabolism

Lamivudine is excreted from the body mainly by the kidneys in unchanged form. Metabolic interactions of lamivudine are unlikely because of a slight metabolism in the liver (from 5 to 10%) and low binding to plasma proteins. Zidovudine 5'-glucuronide is the main metabolite in plasma and urine, with approximately 50-80% of the administered dose of zidovudine excreted by renal excretion.3'-amino-3'deoxythymidine is detected in the urine after intravenous administration.

Excretion

T₁_/2lamivudine is 5-7 hours. The systemic clearance of lamivudine is approximately 0.32 l / h / kg, with renal clearance through active tubular secretion (organic cation transport system) of more than 70%.

With intravenous administration of zidovudine, the mean T₁_/2was 1.1 hours, and the average system clearance was 1.6 l / h / kg. The renal clearance of zidovudine is 0.34 l / h / kg by glomerular filtration and active tubular secretion in the kidneys.

Pharmacokinetics in special clinical cases

The pharmacokinetics of lamivudine and zidovudine has not been studied in patients older than 65 years. In children older than 5-6 months, the pharmacokinetic parameters of zidovudine are similar to those in adults. Zidovudine Well absorbed from the intestine after administration in all studied doses in adults and children; its bioavailability is 60-74%, an average of 65%. Maximum concentration in equilibrium state (C_ssmax) is 4.45 μmol (1.19 μg / ml) after taking zidovudine at a dose of 120 mg / m² in the form of a solution and 7.7 μmol (2.06 μg / ml) after taking in a dose of 180 mg / m². The dose of 180 mg / m² 4 times / day leads to the same systemic exposure in children (AUC₂₄ is 10.7 h x mcg / ml), as is the dose 200 mg 6 times / day in adults (AUC₂₄ is 10.9 h x μg / ml).

In general, the pharmacokinetics of lamivudine in children is similar to the pharmacokinetics in adult patients. However, absolute bioavailability (approximately 55-65%) was reduced in children younger than 12 years. Systemic clearance in children is higher than in adults, and is prone to decline as it grows up, reaching levels as in adults, to 12 years. Taking into account these differences, the recommended dose of lamivudine in children (aged 3 months to 12 years with a body weight of 6 kg to 40 kg) is 8 mg / kg / day. After taking this dose AUC_0-12 reaches 3800-5300 ng x h / ml. Recent data indicate that exposure in children aged 2 to 6 years can be reduced by 30% compared with other age groups.

Due to reduced renal clearance, excretion of lamivudine is impaired in patients with renal insufficiency. Reduction of the dose of lamivudine is recommended in patients with creatinine clearance (CC) less than 50 ml / min. The concentration of zidovudine in plasma also increases in patients with severe renal insufficiency.

Decreased glucuronuclease due to cirrhosis of the liver may result in the cumulation of zidovudine.Correction of doses is required in patients with severe hepatic insufficiency.

Pregnancy does not affect the pharmacokinetics of lamivudine and zidovudine. Lamivudine and zidovudine are found in the serum of the child at birth in the same concentrations as in the mother's serum and cord blood during labor, which confirms the theory of passive penetration through the hematoplacental barrier.

Indications:

Treatment of HIV-1 infection in combination antiretroviral therapy in adults and children weighing at least 30 kg.

Contraindications:

Lamivudine + Zidovudine-Vial and zidovudine is contraindicated in patients with severe neutropenia (neutrophil count less than 0.75x109 / L) or anemia (hemoglobin level less than 7.5 g / dl or 4.65 mmol / l). Violation of kidney function with creatinine clearance less than 50 ml / min (for this dosage form), severe degree of impaired liver function (for this dosage form). Lactation period. Children weighing up to 30 kg.

Hypersensitivity to the components of the drug.

Carefully:

Application for violations of liver function

With hepatic insufficiency, cumulation of zidovudine may be noted as a result of a delay in binding it to glucuronic acid.In patients with severe liver function impairment, it is recommended that lamivudine and zidovudine in the form of individual drugs to be able to individually select the dose of zidovudine. Use with caution in patients with mild to moderate severity of liver function disorders.

Application for violations of kidney function

In patients with renal insufficiency, concentrations of lamivudine and zidovudine in the blood are increased due to a slowing of their elimination. Since patients with impaired renal function (CC less than 50 ml / min) in a number of cases, it is necessary to individually select the dose of lamivudine and zidovudine, it is recommended that they be given separate preparations of lamivudine and zidovudine.

Application in elderly patients

Specific data on the use of the drug in elderly patients is not available. However, in the treatment of elderly patients, special care should be taken, taking into account age-related changes, for example, changes in hematological parameters and impaired renal function.

Patients with hematologic side effects

With severe anemia (hemoglobin content less than 9 g / dL or 5.59 mmol / L) or neutropenia(the number of neutrophils is less than 1.0x10⁹/ l), a dose adjustment of zidovudine may be required. When using the drug Zidovudine + Lamivudine-Vial it is impossible to individually select the dose of lamivudine and zidovudine, it is recommended to use separate preparations of lamivudine and zidovudine.

Pregnancy and lactation:

It is not recommended to use the drug in the first 3 months of pregnancy, except when the expected benefit of therapy for the mother does not exceed the likely risk to the fetus.

It was shown that zidovudine treatment of pregnant women and the subsequent introduction of this drug to newborns reduces the frequency of HIV transmission from mother to fetus. There is no such data regarding lamivudine. Consequently, the drug can be given to pregnant women only in cases where the expected benefit to 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 took NRTIs during pregnancy and in the perinatal period. 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. However, the cause-and-effect 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 carrying out APT during pregnancy to prevent vertical transmission of HIV.

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

Dosing and Administration:

Treatment with the drug should be carried out by doctors with experience in HIV therapy. The drug can be taken regardless of food intake. To ensure the accuracy of dosing, the tablets must be swallowed whole.

Adults and adolescents with a body weight of at least 30 kg the recommended dose of the drug - 1 tablet 2 times / day.

In those cases when it is necessary to reduce the dose of the drug Lamivudine + Zidovudine-Vial or cancel one of its components (lamivudine or zidovudine), it is possible to use separate preparations of lamivudine and zidovudine in dosage forms of a tablet / capsule and a solution for oral administration.

Side effects:

Treatment of HIV infection with lamivudine and zidovudine in the form of monotherapy or as a combination of these drugs can cause side effects. For many side effects, it is not known whether they are caused by lamivudine, zidovudine, a wide range of other drugs used to treat HIV infection, or are a consequence of the underlying disease. The composition of the drug includes lamivudine and zidovudine, and therefore it can cause side effects, characteristic of each of these ingredients. At present, there is no evidence that the combination of lamivudine and zidovudine has additive toxicity.

Determination of the frequency of side effects: very often (≥1 / 10); often (≥1 / 100 and <1/10); infrequently (≥1 / 1000 and <1/100); rarely (≥1 / 10,000 and <1/1000); very rarely (<1/10 000).

Lamivudine

On the part of the hematopoiesis system: infrequently - neutropenia, anemia, thrombocytopenia; very rarely - true erythrocytic aplasia.

From the side of metabolism: often - hyperlactatemia; rarely - lactic acidosis; redistribution / accumulation of adipose tissue (the frequency of this side effect depends on many factors, incl.from a specific combination of antiretroviral drugs).

From the respiratory system: often - cough, rhinitis.

Dermatological reactions: often - a rash, alopecia, rarely - angioedema.

From the nervous system: often - headache, insomnia; very rarely - paresthesia, there are reports of peripheral neuropathy, but its association with lamivudine therapy is not clear.

From the digestive system: often - nausea, vomiting, epigastric pain, diarrhea; infrequently, a transient increase in hepatic enzyme activity (ACT, ALT); rarely - pancreatitis (association with lamivudine is not established), an increase in serum amylase, hepatitis.

Disturbances from the musculoskeletal system: often - arthralgia, muscle disorders; rarely rhabdomyolysis.

Other: often - fatigue, general malaise, fever.

Zidovudine

On the part of the hematopoiesis system: often anemia (blood transfusion may be required), neutropenia and leukopenia. These side effects are more likely to occur with zidovudine at high doses (1200-1500 mg / day), in patients with advanced HIV infection (especially with a reduced bone marrow reserve before treatment) and in particular in patients with CD4 + cell counts less 100 μl.In some patients it is necessary to reduce the dose of zidovudine up to cancellation. Neutropenia occurs more often in those patients whose neutrophil count, hemoglobin level and serum vitamin B12 levels are lower at the time of zidovudine treatment. Infrequent - thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rarely - true erythrocyte aplasia; very rarely - aplastic anemia.

From the side of metabolism: often - hyperlactatemia; rarely - lactic acidosis, anorexia; redistribution / accumulation of adipose tissue (the frequency of this side effect depends on many factors, including the specific combination of antiretroviral drugs).

Mental disorders: rarely - anxiety and depression.

From the nervous system: very often - headache; often - dizziness; rarely - insomnia, paresthesia, drowsiness, decreased mental activity, convulsions.

From the cardiovascular system: rarely - cardiomyopathy.

From the respiratory system: infrequently - shortness of breath; rarely - a cough.

From the digestive system: very often - nausea; often - vomiting, abdominal pain and diarrhea,increased activity of hepatic enzymes and bilirubin; infrequently - flatulence; rarely - pigmentation of the oral mucosa, taste perversion (dysgeusia) and dyspepsia, pancreatitis, liver damage such as severe hepatomegaly with steatosis.

Dermatological reactions: infrequent - rash, itching; rarely - pigmentation of nails and skin, hives and sweating.

From the musculoskeletal system: often - myalgia; infrequently - myopathy.

From the urinary system: rarely - frequent urination.

On the part of the reproductive system: rarely - gynecomastia.

Other: often - a general malaise; infrequently - fever, generalized pain syndrome and asthenia; rarely - chills, chest pain and flu-like syndrome.

Overdose:

Information on cases of overdose with a combination zidovudine + 3TC no. However, there are limited data on the consequences of an acute overdose of lamivudine and zidovudine. None of these cases ended in a fatal outcome, and the condition of all patients returned to normal. No specific signs or symptoms were described.

Treatment: it is recommended to monitor the patient's condition for the timely detection of symptoms of intoxication and to conduct standard maintenance therapy. Because the lamivudine is derived by dialysis, continuous hemodialysis can be used for overdose, however, there is no relevant clinical experience yet. Apparently, hemodialysis and peritoneal dialysis are ineffective when removing zidovudine from the body, but accelerate the elimination of its metabolite (glucuronide).

Interaction:

Interaction with lamivudine

Lamivudine is mainly excreted by active tubular secretion (the transport system of organic cations), respectively, remember the possibility of drug interaction Zidovudine + Lamivudine-Vial with the same drugs that have the same pathway.

Simultaneous reception of lamivudine and trimethoprim (one of the components of the drug co-trimoxazole) leads to an increase in the concentration of lamivudine in plasma by 40% when taking this drug in therapeutic doses. However, patients with normal renal function are not required to individually select a dose of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole.

Care should be taken when using co-trimoxazole and zidovudine + 3TC in patients with renal insufficiency. The concomitant use of lamivudine and co-trimoxazole in high doses for the treatment of pneumocystis pneumonia and toplasmoplasmosis has not been studied and should be avoided.

Lamivudine may inhibit intracellular phosphorylation of zalcitabine when taken concomitantly. Therefore, it is not recommended to use the drug Zidovudine + Lamivudine-Vial in combination with zalcitabine.

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

In vitro lamivudine inhibits intracellular phosphorylation of cladribine, thus leading to a potential risk of a decrease in cladribine efficacy when combined with lamivudine in clinical practice.The results of some clinical studies confirm the possibility of interaction between lamivudine and cladribine. Therefore, it is not recommended to use the drug Zidovudine + Lamivudine-Vial in combination with cladribine.

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

Interaction with fluconazole has not been studied. Since limited data are available, the clinical significance is unknown.

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

Interaction with valproic acid has not been studied. Since limited data are available, the clinical significance is unknown.

Interaction with ranitidine has not been studied. Clinically significant effect is unlikely. Ranitidine partially excreted by active tubular secretion (organic cation transport system). No dose adjustment is required.

Interaction with zidovudine

Zidovudine has no effect on the pharmacokinetics of atovahona. However, pharmacokinetic data indicate that atovahon reduces the degree of metabolism of zidovudine to its glucuronide (in the equilibrium state, the zidovudine AUC is increased by 33%, C_max in the plasma, glucuronide is reduced by 19%).When zidovudine is prescribed in doses of 500-600 mg / day and the concomitant course of treatment of acute pneumocystis pneumonia with atovahona, an increase in the incidence of adverse reactions associated with elevated zidovudine concentrations in plasma is unlikely. If a longer combined use is required, careful monitoring of the clinical condition of the patient is recommended.

Absorption of zidovudine decreases with the simultaneous administration of clarithromycin in the form of tablets. Observe the interval between clarithromycin and zidovudine at least 2 hours.

Simultaneous reception of zidovudine and lamivudine leads to an increase of 13% of the time of exposure to zidovudine and an increase of 28% in its C_maxin the plasma. However, the overall exposure of zidovudine (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

In some patients who received zidovudine in combination with phenytoin, a decrease in the concentration of phenytoin in the blood was detected, and in one case an increase in the concentration of phenytoin was noted. These observations indicate the need to monitor the concentration of phenytoin in the blood in patients who simultaneously take zidovudine + 3TC and phenytoin.

According to some data, probenecid increases the mean T_1/2zidovudine and AUC as a result of inhibition of the formation of glucuronide. In the presence of probenecid, renal excretion of glucuronide and, possibly, zidovudine itself decreases.

Limited data show that when zidovudine and rifampicin are combined, the AZUC of zidovudine is reduced by 48% +/- 34%. However, the clinical significance of this observation is unknown.

Zidovudine can inhibit the intracellular phosphorylation of stavudine during their simultaneous administration. Thus, concomitant use of a combination of stavudine and the drug is not recommended Zidovudine + Lamivudine-Vial. Acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, inosine pranobex can alter the metabolism of zidovudine as a result of competitive inhibition of the glucuronization process or direct suppression of zidovudine metabolism by microsomal liver enzymes. Before prescribing these drugs in combination with zidovudine + 3TC, especially for long-term treatment, it is necessary to evaluate the possible drug interaction.

Simultaneous use, especially for the treatment of acute conditions, zidovudine and potentially nephrotoxic or myelosuppressive drugs (eg, systemic administration of pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin B, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk side effects of zidovudine. With simultaneous appointment zidovudine + 3TC and any of these drugs should closely monitor kidney function and hematological parameters and, if necessary, reduce the dose of one or more drugs.

Because in some patients, despite taking the drug Zidovudine + Lamivudine-Vial, opportunistic infections may develop, additional therapy may be required to prevent infections. For such prophylaxis, co-trimoxazole, pentamidine in the form of an aerosol, pyrimethamine and acyclovir. Limited data from clinical trials indicate that there is no significant increase in the incidence of side effects of zidovudine when used concomitantly with these drugs.

Nucleoside analogues that disrupt DNA replication, such as ribavirin, can in vitro reduce the antiviral activity of zidovudine. Simultaneous use of such drugs with zidovudine is not recommended. Simultaneous use of zidovudine and doxorubicin is not recommended due to mutual weakening of activity of each of the drugs in vitro.

Interaction with didanosine has not been studied. No dose adjustment is required.

With simultaneous application with fluconazole at a dosage of 400 mg once a day and zidovudine at a dosage of 200 mg 3 times a day, an increase in AUC zidovudine by 74% due to inhibition of UDP-glucuronosyltransferase (UDF-HT) is observed. Given the limited data, clinical significance is unknown. It is necessary to monitor the toxic effects of zidovudine.

Interaction with phenobarbital has not been studied. Potentially reduces the concentration of zidovudine in blood plasma by induction of UDF-HT. There is insufficient data for dose adjustment recommendations.

With the simultaneous use of valproic acid in a dosage of 250 mg or 500 mg 3 times a day and zidovudine at a dosage of 100 mg 3 times a day, an increase in zidovudine AUC is observed by 80% due to inhibition of UDP-HT.Given the limited data, clinical significance is unknown. It is necessary to monitor the toxic effects of zidovudine.

Interaction with ranitidine has not been studied. No dose adjustment is required.

There have been reports of increased anemia with ribavirin, when zidovudine was used as part of the HIV treatment regimen, but the exact mechanism remains unexplained. The combined use of ribavirin and zidovudine is not recommended because of the increased risk of developing anemia.

Special instructions:

If it is necessary to individually select the dose, it is recommended to use separate preparations of lamivudine and zidovudine. Doctors should be guided by information on the use of these drugs.

Despite taking the drug Zidovudine + Lamivudine-Vial or any other antiretroviral drug, patients may develop opportunistic infections and other complications of HIV infection. Therefore, patients should be under constant supervision of physicians with experience in the treatment of HIV infection.

Patients should be informed that treatment with antiretroviral drugs, such as Zidovudine + Lamivudine-Vial does not prevent the risk of HIV transmission to other people during sexual intercourse or transfusion of infected blood, so patients should take appropriate precautions. It is necessary to warn patients about possible interaction of the drug Zidovudine + Lamivudine-Vial with other drugs at their concomitant reception.

Hematologic disorders

Possible development of anemia, neutropenia and leukopenia (the latter is usually secondary to neutropenia) in patients receiving zidovudine. These phenomena are more often observed with zidovudine in high doses (1200-1500 mg / day) in patients with advanced HIV infection with a reduced bone marrow reserve before treatment. Therefore, during the treatment with the drug, it is necessary to carefully monitor hematological parameters. These hematologic changes usually appear no earlier than 4-6 weeks after the start of therapy. In patients with late stage of clinically expressed HIV infection, blood tests should be performed at least once every 2 weeks during the first 3 months of therapy, and then at least once a month.

In patients with early stage of HIV infection, side effects from the blood system are rare. Blood tests can be done less often, focusing on the general condition of patients, for example, 1 time in 1-3 months. It may require special selection of zidovudine dose in the case of severe anemia or myelosuppression during drug treatment, as well as in patients with prior bone marrow suppression, such as hemoglobin 9 g / dL (5.59 mmol / L) or less neutrophil count 1.0x10⁹/ l. Because the individual dose of the drug Zidovudine + Lamivudine-Vial is not possible, it is recommended to use separate preparations of lamivudine and zidovudine.

Pancreatitis

In patients who took lamivudine and zidovudine, rare cases of development of pancreatitis are described. However, it is not established whether this complication is caused by medications or the underlying disease - HIV infection. Drug treatment should be immediately discontinued in case of appearance of clinical symptoms or laboratory evidence of pancreatitis development (abdominal pain, nausea, vomiting or elevated levels of biochemical markers).You should stop taking the drug Zidovudine + Lamivudine-Vial before the diagnosis of pancreatitis.

Lactic acidosis / severe hepatomegaly with steatosis

In patients taking antiretroviral drugs - analogues of nucleosides, in the form of monotherapy or in combination, including, lamivudine and zidovudine, rare cases of lactic acidosis and severe hepatomegaly with fatty liver dystrophy are described, but with a possible fatal outcome. The majority of cases were recorded in women.

Clinical symptoms of lactic acidosis include general weakness, loss of appetite, sudden, unexplained weight loss, symptoms of gastrointestinal tract damage (nausea, vomiting, abdominal pain), respiratory disorders (shortness of breath and increased breathing), neurologic symptoms (including motor weakness).

Caution should be exercised when using nucleoside analogues to treat any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and liver steatosis (including the use of certain drugs and alcohol use).Treatment with nucleoside analogues should be discontinued if symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis develop, progressive hepatomegaly, or a rapid increase in aminotransferase levels.

Redistribution of subcutaneous fat

In some patients receiving combination antiretroviral therapy, there is a redistribution / accumulation of adipose tissue, including the central type of obesity, dorsovissorial 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 lipids and blood glucose . The listed symptoms in patients can be observed together or separately.

Although one or more of the above side effects associated with a common syndrome, often attributed to lipodystrophy, can cause all drugs related to protease inhibitors and NRTIs, the data suggest that there are differences between individual representatives of these classes of drugs with respect to the ability to cause these side effects effects.

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 play an important, perhaps synergistic role.

The long-term effects of these side effects are currently unknown. Clinical examination of patients should include an assessment of the physical signs of redistribution of adipose tissue. The content of serum lipids and blood glucose should be determined. Disorders of lipid metabolism should be treated, guided by their clinical manifestations.

Immunodeficiency Syndrome

At the beginning of antiretroviral treatment of HIV-infected patients with severe immunodeficiency, inflammatory reactions and residual opportunistic infections can develop, which sometimes leads to serious clinical consequences or increased symptoms. Typically, such reactions are observed during the first weeks or months after the onset of antiretroviral therapy. The most significant examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumocystis pneumonia.Any symptoms of inflammation should be immediately identified and if necessary begin 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.

Osteonecrosis

Despite the fact that the etiology of this disease is multifactorial (including taking glucocorticosteroids, drinking alcohol, severe immunosuppression, high body mass index), cases of osteonecrosis were most often found in patients at a late stage of HIV infection and / or who took long-term combined antiretroviral therapy. Patients should consult a doctor if they experience pain and joint stiffness or difficulty in moving.

Mitochondrial dysfunction

In vitro and in vivo studies have shown that analogues of nucleosides and nucleotides are capable of causing a different degree of damage to 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 hypertension, convulsions, impaired behavior). Whether neurological disorders are transient or persistent is currently unknown. Any child, even HIV-negative, who has undergone intrauterine exposure to nucleoside and nucleotide analogues, must undergo a clinical and laboratory examination in order to exclude mitochondrial dysfunction in case of revealing the relevant signs or symptoms. The data described do not affect the current national recommendations on the use of antiretroviral therapy in pregnant women, for the prevention of vertical transmission of HIV infection.

Co-infection of HIV and viral hepatitis B

Clinical studies and post-registration data on the use of lamivudine suggest that,that in some patients with concomitant viral hepatitis B there may be clinical or laboratory signs of hepatitis relapse after stopping lamivudine, which may have more severe consequences in patients with decompensated liver damage. Therefore, in patients with concomitant viral hepatitis B, when the drug is withdrawn, it is necessary to monitor the performance of functional hepatic samples and regularly determine the level of replication of viral hepatitis B for 4 months.

Co-infection of HIV and viral hepatitis C

The aggravation of anemia was observed with the combined administration of ribavirin and zidovudine, although the mechanism of development of this phenomenon remains unclear. Thus, simultaneous use of ribavirin and zidovudine is not recommended, especially in patients with a history of zidovudine-induced anemia. In these cases, it is recommended to consider the possibility of changing the regimen of antiretroviral therapy with the aim of reversing zidovudine. Patients with co-infection with hepatitis C who receive therapy with interferon alfa and ribavirin form a special risk group.

Diseases of the liver

The safety and effectiveness of zidovudine have not been established in patients with severe concomitant liver disease. In patients with chronic hepatitis B and C receiving combined antiretroviral therapy, the risk of developing serious and potentially leading to death adverse reactions from the liver increases. In case of concomitant antiviral therapy for the treatment of hepatitis B and C, also refer to the appropriate instructions for use for the medications used.

Patients with a history of liver dysfunction, including chronic hepatitis, have an increased frequency of adverse reactions in the liver during treatment with combination antiretroviral therapy and should be examined. In these cases, it is recommended to consider the possibility of interrupting or discontinuing treatment.

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

There was no special study of the effects of lamivudine and zidovudine on the ability to drive and work with machinery. Pharmacological properties of these drugs indicate a low probability of such an effect.The clinical state of the patient, as well as the nature of the side effects, should be taken into account lamivudine and zidovudine.

Form release / dosage:

Film-coated tablets containing 300 mg of zidovudine and 150 mg of lamivudine.

Packaging:

For 60 tablets in a polymer container with a screw cap, which prevents accidental opening, and control the first opening. One container, together with instructions for use, is placed in a cardboard package (pack) of cardboard.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years. Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002779

Date of registration:19.12.2014 / 02.02.2016

Expiration Date:19.12.2019

The owner of the registration certificate:VIAL, LLC VIAL, LLC Russia

Representation: & nbspKIROVSKAYA PHARMACEUTICAL FACTORY, OJSCKIROVSKAYA PHARMACEUTICAL FACTORY, OJSC

Information update date: & nbsp13.10.2017

Illustrated instructions

Instructions

Zidovudine + Lamivudine-Vial (Zidovudine + Lamivudine-Vial)