Lazevun - instructions for use, dose, side effects, contraindications

Excipients: Microcrystalline cellulose - 169.2 mg Corn starch - 21.6 mg Croscarmellose sodium - 21.6 mg Sodium carboxymethyl starch - 43.2 mg Sodium stearyl fumarate - 14.4 mg;

shell composition: ready mix "Opadrai pink" (hypromellose 62.5%, macrogol 24.0%, titanium dioxide 12.5%, ferric oxide red oxide E172 1.0%) - 14.4 mg.

Description:

The tablets covered with a film cover, from pink to pink with a brownish shade of color, round, biconcave, with risk on one side.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

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

Pharmacodynamics:

Combined antiviral agent.

Lamivudine and zidovudine are potent selective inhibitors of human immunodeficiency virus reverse transcriptase (HIV-1 and HIV-2). 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 lamivudine and zidovudine is mainly due to the inclusion of their monophosphate form in the viral DNA chain, resulting in a chain break. 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 studies in vitro lamivudine has a weak cytotoxic effect on peripheral blood lymphocytes, as well as on lymphocytic and monocyte-macrophage cell lines and a number of other bone marrow stem cells. 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 M184Vlocated 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, 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 studied and occurs as a result of gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. The viruses acquire phenotypic resistance to thymidine analogues as a result of combined mutations in codons 41 and 215 or by the accumulation of at least four of six mutations. These mutations to thymidine analogs do not in themselves cause high cross-resistance to other nucleoside analogues, which subsequently allows the use of other approved reverse transcriptase inhibitors.

Two kinds of mutations lead to the development of multiple drug resistance.

In one case, mutations occur in 62, 75, 77, 116 and 151 HIV reverse transcriptase positions, and in the second case T69S mutations with the insertion of 6 pairs of nitrogenous bases in this position, which is accompanied by the appearance of phenotypic resistance to zidovudine, as well as to other nucleoside reverse transcriptase inhibitors (NRTIs). Both types of these mutations significantly limit the therapeutic possibilities for HIV infection.

In clinical trials, the combination of lamivudine and zidovudine resulted in a reduction in HIV-1 viral load and an increase in the content CD4⁺cells.

Clinical evidence suggests that using a combination of lamivudine and zidovudine or a combination of lamivudine and zidovudine-containing regimens results in a significant reduction in the risk of disease progression and mortality.

Separately, monotherapy with lamivudine or zidovudine led to the appearance of HIV isolates with reduced sensitivity to these drugs in vitro. Clinical evidence suggests that combination therapy with lamivudine and zidovudine slows the emergence of zidovudine-resistant HIV strains in patients who have not previously received antiretroviral therapy. At present, the association between sensitivity to lamivudine and / or zidovudine in vitro and the clinical effect of therapy has not been studied.

Lamivudine and zidovudine are widely used as components of combined antiretroviral therapy in conjunction with other antiretroviral drugs of the same class of NRTIs or other classes (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors and fusion inhibitors).

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 strains of HIV with a mutation M184V.

Pharmacokinetics:

Suction

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

After taking Lazevun®, the maximum concentrations in the blood plasma of lamivudine and zidovudine (C_mOh) are noted through 0.75 (0.5-2.0) h and 0.5 (0.25-2.0) h and are 1.5 (1.3-1.8) μg / ml and 1, 8 (1.5-2.2) μg / ml, respectively.

The degree of absorption of lamivudine and zidovudine (based on the area under the pharmacokinetic curve "concentration-time" (AUC)) and the half-life after taking with food are similar to those after taking fasting, although the rate of absorption is somewhat slowed down.

Distribution

With intravenous administration, the average volume of distribution for lamivudine and zidovudine is 1.3 and 1.6 l / kg, respectively.

Lamivudine has a linear pharmacokinetics when used in therapeutic doses and bounds boundly to blood plasma albumin (less than 36% of serum albumin in vitro). Zidovudine binds to blood plasma proteins by 34-38%. Thus, the interaction of lamivudine and zidovudine with other drugs through their replacement at binding sites on proteins is unlikely.

Determined that lamivudine and zidovudine penetrate into the central nervous system (CNS) and cerebrospinal fluid. After 2-4 hours after oral administration, the ratio between the concentration of lamivudine and zidovudine in CSF and 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 blood plasma and urine, with approximately 50-80% of the accepted dose of zidovudine excreted by renal excretion.

Excretion

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

With intravenous administration of zidovudine, the mean half-life of blood plasma (T_1/2) is 1.1 hours, the average systemic clearance is 1.6 l / h / kg. The renal clearance of zidovudine is 0.34 l / h / kg by glomerular filtration and active tubular secretion.

Special patient groups

Elderly patients

The pharmacokinetics of lamivudine and zidovudine has not been studied in patients older than 65 years.

Children

In children older than 5-6 months pharmacokinetic parameters of zudovudine are similar to those in adults.

Zidovudine Well absorbed from the intestine after ingestion in adults and children. Its bioavailability is 60-74%, on average 65%.

The pharmacokinetics of lamivudine in children, in general, 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 indicators as in adults by the age of 12.Recent data indicate that exposure in children aged 2 to 6 years can be reduced by 30% compared with other age groups.

Patients with impaired renal function

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 less than 50 ml / min. The concentration of zidovudine in blood plasma is also increased in patients with severe renal failure.

Patients with impaired hepatic function

Decreased glucuronization in patients with impaired hepatic function due to liver cirrhosis may lead to cumulation of zidovudine. Correction of doses is required in patients with severe hepatic insufficiency.

Pregnancy

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

Indications:

Treatment of HIV infection in adults and children with a body weight of at least 14 kg.

Contraindications:

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

- severe neutropenia (neutrophil count less than 0.75x10⁹/ l) or anemia (hemoglobin level less than 7.5 g / dl or 4.65 mmol / l);

- impaired renal function with creatinine clearance less than 50 ml / min (for a given dosage form);

- severe degree of impaired liver function (for a given dosage form);

- the period of breastfeeding;

- body weight less than 14 kg.

Pregnancy and lactation:

Fertility

There are no data on the effect of lamivudine and zidovudine on fertility in women. Zidovudine does not affect the number, morphology and motility of spermatozoa in men.

Pregnancy

The safety of lamivudine in women during pregnancy has not been studied to date. It is not recommended to use Lazevun® in the first 3 months of pregnancy, unless the expected benefit for the mother does not exceed the probable 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.Therefore, Lazevun® can be given to pregnant women only when 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 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 therapy 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 lamivudine, zidovudine and HIV penetrate into breast milk, breastfeeding is contraindicated.

Dosing and Administration:

The drug Lazevun® is taken orally, regardless of food intake.

Treatment with Lazevun® should be performed by doctors with experience in HIV therapy.

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 Lazevun® is 1 tablet 2 times a day.

Children with body weight from 21 to 30 kg

The recommended dose of Lazevun® is 1/2tablets in the morning plus 1 tablet in the evening.

Children with body weight from 14 to 21 kg

The recommended dose of Lazevun® is 1/2 pills 2 times a day.

Children weighing less than 14 kg

It is necessary to use separate preparations of lamivudine and zidovudine.

In cases where it is necessary to reduce the dose of Lazevun®, reduce the dose or cancel one of its components (lamivudine or zidovudine), it is possible to use separate preparations of lamivudine and zidovudine.

Use in selected patient groups

Elderly patients

There are no specific data on the use of Lazevun® in elderly people.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 impaired renal function

Since patients with impaired renal function (creatinine clearance less than 50 ml / min) should individually choose a dose of lamivudine and zidovudine, it is recommended to prescribe individual preparations of lamivudine and zidovudine.

Patients with impaired hepatic function

In patients with a severe degree of impaired liver function, it is recommended to use separate preparations of lamivudine and zidovudine.

Patients with hematologic side effects

When the hemoglobin content is lower than 9 g / dL (5.59 mmol / L) or neutropenia (the number of neutrophils is less than 1.0х10⁹/ l), a dose adjustment of zidovudine may be required.

When using Lazevun®, it is impossible to select individual doses of lamivudine and zidovudine individually, it is recommended to use separate preparations of lamivudine and zidovudine.

Side effects:

Adverse reactions have been described in the treatment of patients with HIV with lamivudine and zidovudine in the form of monotherapy or as a combination of these drugs.For many adverse reactions, it is not known whether they are caused by lamivudine, zidovudine, or a wide range of other drugs used to treat HIV infection, or are a consequence of the underlying disease.

The composition of the drug Lazevun® includes lamivudine and zidovudine, so it can cause the side reactions described below, which are characteristic of each of these components. At present, there is no evidence that the combination of lamivudine and zidovudine has additive toxicity.

Cases of lactic acidosis, sometimes fatal, associated, as a rule, with severe hepatomegaly and steatosis of the liver, were recorded with the use of nucleoside analogues.

Combined antiretroviral therapy can induce the redistribution / accumulation of fatty tissue (lipodystrophy), in particular, central obesity, the accumulation of fatty tissue in the dorsocervical (buffalo hump) and thoracic areas, thinning of fat in the limb or face area. The use of combination antiretroviral therapy has been associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

In HIV-infected patients with severe immunodeficiency during the onset of combined antiretroviral therapy, inflammation may worsen with asymptomatic or residual opportunistic infection. There have also been cases of autoimmune diseases (for example, Graves' disease) developing against the background of restoration of immunity, however, the time of primary manifestations varied and the disease could occur many months after initiation of therapy.

Osteonecrosis cases have been reported, especially in patients with typical risk factors, late HIV infection, or long-term use of combined antiretroviral therapy. The frequency of occurrence of this phenomenon is unknown.

The following undesirable reactions are given in accordance with the following gradations of their occurrence frequency: very often (≥10%); often (≥1%, <10%); infrequently (≥0.1%, <1%); rarely (≥0.01%, <0.1%); very rarely (<0.01%); frequency is unknown (according to available data, it is not possible to establish the frequency of occurrence).

Lamivudine

Violations of the blood and lymphatic system: infrequently - neutropenia, anemia, thrombocytopenia; very rarely - true erythrocytic aplasia.

Disturbances from the nervous system: often - headache, insomnia; very rarely - peripheral neuropathy (paresthesia).

Disturbances from the respiratory system, chest and mediastinal organs: often - cough, nasal symptoms.

Disorders from the gastrointestinal tract: often - nausea, vomiting, abdominal pain or colic, diarrhea; rarely - pancreatitis, whose association with lamivudine is not established, an increase in the activity of amylase in the blood serum.

Disturbances from the liver and bile ducts: infrequently, a transient increase in hepatic enzyme activity (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)); rarely - hepatitis.

Disturbances from the skin and subcutaneous tissues: often - a rash, alopecia; rarely - angioedema.

Disturbances from musculoskeletal and connective tissue: often - arthralgia, muscle disorders; rarely rhabdomyolysis.

General disorders and disorders at the site of administration: often - fatigue, general malaise, fever.

Zidovudine

Violations of the blood and lymphatic system: often - anemia (blood transfusion may be required), neutropenia, leukopenia.

These adverse reactions often occur with high doses of zidovudine (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 a number of cells Cd4⁺ less than 100 in 1 mm³. In some patients it is necessary to reduce the dose of zidovudine up to cancellation.

Neutropenia occurs more often in those patients in whom the number of neutrophils, hemoglobin and vitamin concentrations AT₁₂ in the serum reduced at the time of initiation of zidovudine therapy.

Infrequent - thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rarely - true erythrocyte aplasia; very rarely - aplastic anemia.

Disorders from the metabolism and nutrition: often - hyperlactatemia; rarely - lactic acidosis, anorexia.

Disorders of the psyche: rarely - anxiety, depression.

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

Heart Disease: rarely - cardiomyopathy.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath; rarely - a cough.

Disorders from the gastrointestinal tract: very often - nausea; often - vomiting, abdominal pain, diarrhea; infrequently - flatulence; rarely - pigmentation of the oral mucosa, changes in taste, dyspepsia, pancreatitis.

Disturbances from the liver and bile ducts: increase in blood activity of hepatic enzymes and bilirubin concentration; rarely - liver damage, such as severe hepatomegaly with steatosis.

Disturbances from the skin and subcutaneous tissues: infrequent - rash, itching; rarely - pigmentation of nails and skin, hives, sweating.

Disturbances from musculoskeletal and connective tissue: often - myalgia; infrequently - myopathy.

Disorders from the kidneys and urinary tract: rarely - frequent urination.

Violations of the genitals and mammary gland: rarely - gynecomastia.

General disorders and disorders at the site of administration: often - a general malaise; infrequently - fever, generalized pain syndrome, asthenia; rarely - chills, chest pain, flu-like syndrome.

Overdose:

Symptoms: there are no reports of overdose with Lazevun®.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, the condition of all patients was normalized. No specific signs or symptoms were described.

Treatment: In case of an overdose, it is recommended to monitor the patient's condition for the timely detection of signs 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 for excretion of zidovudine from the body, but these methods accelerate the elimination of its metabolite (glucuronide).

Interaction:

Since the preparation Lazevun® contains lamivudine and zidovudine, it can enter into any interactions that are characteristic of each of its components.

The probability of metabolic interactions with lamivudine is low, since only a small part of the injected drug undergoes metabolism and binds to blood plasma proteins, and the drug is almost completely excreted by the kidneys in unchanged form.

Zidovudine also binds to a small extent with plasma proteins, but is eliminated mainly through hepatic metabolism to inactive glucuronide.

Drugs with a predominant hepatic metabolism, especially through glucuronization, can potentially inhibit zidovudine metabolism.

Listed below are some medicines that represent classes of drugs that should be used with caution in the context of Lazevun® therapy.

Interactions due to the presence of lamivudine

Lamivudine is mainly excreted by active tubular secretion (organic cation transport system), therefore, it should be remembered that Lazevun® can interact with drugs that have the same pathway.

Trimethoprim

Simultaneous reception of trimethoprim / sulfamethoxazole 160 mg / 800 mg (co-trimoxazole) causes an increase in the exposure of lamivudine in plasma by 40%, which is due to the presence of trimethoprim. However, patients with normal renal function are not required to adjust the dose of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. Joint use of lamivudine with higher doses of co-trimoxazole used to treat pneumonia (caused by Pneumocystis carinii) and toxoplasmosis, has not been studied, and should be avoided.

Zalcitabine

Lamivudine can suppress intracellular phosphorylation of zalcitabine while simultaneously taking these drugs. In this regard, it is not recommended to take the drug Lazevun® in combination 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 a mutation in the same codon of the reverse transcriptase gene (M184V), so the therapeutic effectiveness of these drugs in combination therapy can be organized. The use of lamivudine in combination with emtricitabine or fixed dose combinations containing emtricitabine, Not recommended.

Didanosine

The interaction has not been studied. No dose adjustment is required.

Fluconazole

The interaction has not been studied.Since limited data are available, the clinical significance is unknown.

Phenobarbital

The interaction has not been studied. There is not enough data to recommend a dose adjustment.

Valproic acid

The interaction has not been studied. Since limited data are available, the clinical significance is unknown.

Ranitidine

The interaction 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.

Cladribine

The interaction has not been studied. In vitro lamivudine inhibits intracellular phosphorylation of cladribine, leading to a possible risk of loss of cladribine efficacy in the case of a combination in clinical practice. Some clinical data also confirm the possible interaction between lamivudine and cladribine. Therefore, the combined use of lamivudine and cladribine is not recommended.

Interactions due to the presence of zidovudine

Atovahon

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 AUC zidovudine increases by 33%, the maximum concentration in the blood plasma of glucuronide is reduced by 19%).

When zidovudine is prescribed in doses of 500-600 mg / day and the concomitant 3-week course of treatment of acute pneumocystis pneumonia with atovahon, an increase in the incidence of unwanted reactions associated with elevated plasma zidovudine concentrations is unlikely. If a longer combined use of these drugs is necessary, careful monitoring of the clinical condition of the patient is recommended.

Clarithromycin

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

Lamivudine

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 maximum concentrations in the blood plasma. However, in this case, the total exposure of zidovudine (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin

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

Probenecid

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

Rifampicin

Limited data show that when combined with zidovudine and rifampicin AUC zidovudine decreased by 48 ± 34%. However, the clinical significance of this observation is unknown.

Stavudine

Zidovudine can inhibit the intracellular phosphorylation of stavudine during their simultaneous administration. Thus, the combined use of stavudine and Lazevun® is not recommended.

Didanosine

The interaction has not been studied. No dose adjustment is required.

Fluconazole

Joint application with fluconazole at a dosage of 400 mg 1 time per day and zidovudine at a dosage of 200 mg 3 times a day lead to an increase AUC zidovudine by 74% (inhibition of UDP-glucuronyl transferase (UDP-HT)); Because limited data are available, the clinical significance is unknown. Monitoring of symptoms of zidovudine toxicity is required.

Phenobarbital

The interaction has not been studied. Potentially reduces the concentration of zidovudine in blood plasma by induction of UDF-HT. There is not enough data to recommend a dose adjustment.

Valproic acid

The combined 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 lead to an increase AUC by 80% (inhibition of UDP-HT). Monitoring of symptoms of zidovudine toxicity is required.

Ranitidine

The interaction has not been studied. No dose adjustment is required.

Ribavirin

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

Other drugs: 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 the microsomal metabolism of zidovudine.

Before the appointment of these drugs in combination with the drug Lazevun®, especially for long-term treatment, it is necessary to evaluate possible drug interactions. 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 the simultaneous administration of Lazevun® and any of these drugs, kidney function and haematological parameters should be monitored regularly and, if necessary, the dose of one or more drugs should be reduced.

Since some patients, despite the use of Lazevun®, may develop opportunistic infections, additional antimicrobial therapy may be required to prevent them. 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 adverse reactions of zidovudine when applied simultaneously 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 the mutual weakening of the activity of each of the medicines in vitro.

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.

Patients should be warned about the possible consequences associated with the joint use of other drugs without prescribing a doctor.

Patients should be informed that treatment with antiretroviral drugs, such as the Lazevun® drug, does not prevent the risk of HIV transmission to other people during sexual intercourse or blood contamination, so patients should take appropriate precautions.

Opportunistic infections

Despite the use of Lazevun® or any other antiretroviral drug, opportunistic infections and other complications of HIV infection can develop in patients. Therefore, patients should be under constant supervision of physicians with experience in treating patients with HIV-associated diseases.

Hematologic disorders

Perhaps the development of anemia, neutropenia, leukopenia (usually secondary due to neutropenia) in patients receiving zidovudine. These phenomena are more often observed with the appointment of high doses of zidovudine (1200-1500 mg / day) in patients in the late stages of HIV infection with a reduced bone marrow reserve before the start of treatment. Therefore, patients receiving the drug Lazevun®, it is necessary to conduct regular monitoring of hematological indicators. These hematologic changes usually appear no earlier than 4-6 weeks after the start of therapy. In patients with a developed clinical picture of HIV infection, blood tests should be monitored at least once every 2 weeks during the first three months of therapy, and then at least once a month.In patients at an early stage of HIV infection, unwanted reactions from the blood system are rare. In this situation, a general blood test can be done less often, focusing on the general condition of the patient, for example, once every 1-3 months.

A special dose of zidovudine may be required if severe anemia or myelosuppression develops during Lazevun® treatment, as well as in patients with previous bone marrow suppression, for example, hemoglobin concentrations of less than 9 g / dl (5.59 mmol / L) neutrophils less than 1.0x10⁹/ l. Since it is impossible to select the dose of Lazevun® individually, 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. If the patient has abdominal pain, nausea, vomiting, or increased biochemical markers, the possibility of developing pancreatitis should be considered. You should stop taking Lazevun® before the diagnosis of pancreatitis.

Lactic acidosis and severe hepatomegaly with steatosis

There are reports of the development of lactic acidosis, severe hepatomegaly with steatosis, including fatal outcomes due to antiretroviral therapy with nucleoside analogues in the form of individual drugs, including lamivudine or a combination thereof. Similar phenomena were observed, mainly, in women.

The clinical signs of developing lactic acidosis are general weakness, anorexia, rapid unexplained weight loss, symptoms of gastrointestinal tract damage (nausea, vomiting and abdominal pain) and respiratory system (rapid and / or deep breathing), neurological symptoms (including motor weakness) .

Treatment with analogues of nucleosides should be discontinued in case of symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis, progressive hepatomegaly, or a rapid increase in aminotransferase activity.

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 damage and liver steatosis (including the use of certain drugs and alcohol use).

Patients with co-infection with hepatitis C and patients who receive treatment with alpha interferon and ribavirin may constitute a special risk group.

Lipodystrophy

In some patients receiving combined antiretroviral therapy, there may be a redistribution and / or accumulation of subcutaneous fat, including central obesity, dorsocervical fat deposition ("buffalo buffalo"), a reduction in the subcutaneous fat layer on the face and extremities, enlargement of the mammary glands , increased serum lipid concentrations and glucose concentrations, both individually and collectively.

Although all preparations from classes of HIV protease inhibitors and NRTIs can cause one or more of the abovementioned unwanted reactions associated with a common syndrome, often called lipodystrophy, the accumulated evidence suggests that there are differences between individual representatives of these classes of drugs in the ability to induce these undesirable reactions.

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

The long-term consequences of these undesirable reactions are as yet unknown.

During the clinical 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.

Syndrome of restored immunity

If HIV-infected patients with severe immunodeficiency have asymptomatic opportunistic infections or their residual effects at the time of initiation of antiretroviral therapy, such therapy may lead to an increase in the symptoms of opportunistic infections or other severe consequences. Typically, these reactions occur within the first weeks or months after initiation of antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (P.carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

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

Co-infection of HIV and viral hepatitis B

Clinical studies and post-registration data on the use of lamivudine suggest that in some patients with concomitant viral hepatitis B (HBV), clinical or laboratory signs of hepatitis recurrence may appear after stopping lamivudine, which may have more severe consequences in patients with decompensated liver damage. Therefore, in patients with concomitant viral hepatitis B, when Lazevun® is withdrawn, indicators of functional hepatic samples should be monitored and the hepatitis B virus replication markers should be regularly monitored for 4 months.

In patients with an initially present impaired liver function, including an active form of chronic hepatitis, there is an increase in the incidence of liver function abnormalities in combination antiretroviraltherapy. Such patients need to be monitored in accordance with standard clinical practice. It is necessary to consider the possibility of suspending or stopping treatment in cases of manifestations of worsening liver disease in such patients.

Co-infection of HIV and viral hepatitis C

The aggravation of anemia was observed with the combined use of ribavirin and zudovudine, 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.

Diseases of the liver

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

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 (hypertension, seizures, 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 guidelines for the use of antiretroviral therapy in pregnant women to prevent the vertical transmission of HIV infection.

Osteonecrosis

Although the etiology of this disease is multifactorial (including the intake of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis were most often encountered in patients at a late stage of HIV infection and / or who took long-term combined antiretroviral therapy.

Patients should consult a doctor if they experience pain and joint stiffness or difficulty in moving.

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 patient's clinical condition, as well as the side effects of lamivudine and zidovudine, should be taken into account.

Form release / dosage:

Tablets, film-coated, 300 mg + 150 mg.

Packaging:

For 60 tablets in a container of high-pressure polyethylene, sealed with a screw cap made of polypropylene with a desiccant of silica gel, placed in a container of polypropylene, with the control of the first opening.

Each container, together with the instruction for use, is placed in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003444

Date of registration:04.02.2016

Expiration Date:04.02.2021

The owner of the registration certificate:AKRIKHIN HFK, JSC AKRIKHIN HFK, JSC Russia

Manufacturer: & nbsp

Celon Pharma S.A. Poland

Representation: & nbspAKRIKHIN OJSC AKRIKHIN OJSC Russia

Information update date: & nbsp09.02.2018

Illustrated instructions

Instructions

Lazevun® (Lazevun)