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

Excipients: lactose monohydrate 36.00 mg, starch corn 45.00 mg, microcrystalline cellulose 57.00 mg, silicon dioxide colloid 6.00 mg, magnesium stearate 6.00 mg, sodium carboxymethyl starch 10.00 mg,

film sheath: hypromellose 17.50 mg, macrogol 6000 2.03 mg, titanium dioxide 1.43 mg, talc 3.12 mg, methyl parahydroxybenzoate 0.20 mg, propyl parahydroxybenzoate 0.10 mg.

Description:

Tablets, film-coated, white with embossing "LZD" on one side and risk on the other side. On the cross section, the core of the tablet is from white to almost white.

Pharmacotherapeutic group:Antiviral drugs for the treatment of HIV infections in combination

ATX: & nbsp

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

Pharmacodynamics:

Emlazide is a combined antiviral drug, in which includes zidovudine and lamivudine, which are highly effective selective inhibitors of HIV reverse transcriptase. Lamivudine is a synergist of zidovudine against the suppression of HIV replication in cell culture. Zidovudine and lamivudine 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. The antiviral activity of the drug is mainly due to the inclusion of the monophosphate form in the viral DIC chain, resulting in a chain rupture.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 was no detection of 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 the data research in vitro. In studies in vitro determined that zidovudine-resistant isolates of the virus may become susceptible to its action if these isolates develop resistance to lamivudine simultaneously. However, the clinical significance of such changes has been finally established to date. Resistance to thymidine analogues (such as zidovudine) is well described and correlates with sequential accumulation of up to 6 specific mutations of HIV reverse transcriptase in codons 41, 67, 70, 210, 215 and 219. The viruses acquire phenotypic resistance to thymidine analogs by combining mutations in codons 41 and 215 or by accumulation, at four or six mutations. These mutations, against the background of the use of thymidine analogs, do not themselves cause high cross-resistance to other nucleosides, which 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 of HIV in codons 62, 75, 77, 116 and 151, the second type - T69S mutations with insertion into the position of the 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-I 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 had not previously received Apt, combined therapy lamivudine and zidovudine slows the emergence of resistant to zidovudine strains of HIV.

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 HIV 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%, zidovudine - 60 - 70%.

The maximum concentrations of lamivudine and zidovudine were 0.75 h (0.5 h -2.0 h) and 0.5 h (0.25 h -2.0 h) and were 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 ingestion with food were similar to those after fasting, although the rate of absorption was somewhat slowed.

Distribution: average apparent 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 a limited extent with albumin of blood plasma (less than 36% serum albumin in vitro). Zidovudine binds to plasma proteins of blood by 34 - 38%. Thus, the interaction lamivudine and zidovudine with other drugs by replacing 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 an 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 to 80% of the accepted dose of zidovudine excreted by renal excretion. 3'-amido-3'dezoksitimidin, a metabolite of zidovudine, is determined in urine after intravenous administration.

Excretion: The half-life period (T1 / 2) of lamivudine is 5-7 hours with the primary renal clearance (more than 70%) involving the cationic transport system. The excretion of lamivudine depends on the function of the kidneys. Dose reduction is necessary for patients with creatinine clearance ≤ 50 ml / min.

With intravenous administration of zidovudine, the mean T1 / 2 was 1.1 hours. The renal clearance of zidovudine is 0.34 l / h / kg by glomerular filtration and active tubular secretion in the kidneys. The concentration of zidovudine increases in patients with renal insufficiency.

Special patient groups

Elderly patients

The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.

Children

Zidovudine is well absorbed from the intestine after taking in all studied dosages in adults and children; its bioavailability is 60-74%, an average of 65%.

In studies of six HIV-infected children aged 2 to 13 years, the pharmacokinetics of zidovudine after taking 120 mg / m² 3 times a day and after switching to a dose of 180 mg / m² 2 times a day. System exposure (AUC and C_m_Oh) in blood plasma was similar in the double and triple dosing regimen (the daily dose is the same).

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 but growing, reaching indicators as in adults, by 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 AUC₀_-12reaches 3800-5300 ng^xh / ml. 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 plasma also increases 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 weighing at least 14 kg in combination antiretroviral therapy.

Contraindications:

- Hypersensitivity to zidovudine, lamivudine, or some other component of the drug

- Severe neutropenia (the number of neutrophils is less than 0.75 x 10⁹/ l) or anemia (hemoglobin level less than 7.5 g / dl or 4.65 mmol / l)

-children under 12 years of age with a body weight of less than 30 kg (due to the impossibility of dosing this dosage form)

- lactose intolerance, lactase deficiency, glucose-galactose malabsorption

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

- severe degree of liver dysfunction (for this dosage form)

- the period of breastfeeding.

Pregnancy and lactation:

Fertility

There are no data on the effects of lamivudine and zidovudine on fertility in women.

Zidovudine does not affect the number, morphology and motility of spermatozoa in men.

Pregnantlycmь

The safety of lamivudine in women during pregnancy has not been studied to date. It is not recommended to use the drug Emlazid in the first 3 months of pregnancy, unless the expected benefit for the mother does not exceed the possible 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 Emlazid can be given to pregnant women only in those cases when the expected benefit for the mother exceeds the possible risk to the fetus. There is evidence of a slight transient increase in lactate concentration in the blood plasma, possibly due to mitochondrial disorders in newborns and infants whose mothers 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 Apt 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:

Emlazid is taken internally regardless of food intake.

The drug should be treated by physicians with experience in HIV therapy.

To ensure the accuracy of dosing, the tablets must be swallowed whole. For those patients who have difficulty in swallowing, it is recommended to crush the tablets and add them to a small amount of semi-solid food and liquid.All the amount of the mixture should be taken immediately.

Adults and adolescents with a body weight of at least 30 kg

The recommended dose of Emlazide is 1 tablet 2 times a day.

Children with body weight from 21 to 30 kg

The recommended dose of Emlazide is 1/2 tablet in the morning plus 1 tablet in the evening.

Children with body weight from 14 to 21 kg

The recommended dose of Emlazide is 1/2 tablet 2 times a day.

Children with a body weight of less than 14 kg

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

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

Special groups of patients.

Elderly patients

Specific data but the use of the drug Emlazid in elderly patients. However, in the treatment of elderly Nazis, 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) 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.

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 1.0 x 10⁹/ l), a dose adjustment of zidovudine may be required. When using the drug Emlazid it is impossible to individually select the dose of lamivudine and zidovudine, 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 Emlazid includes lamivudine and zidovudine, and therefore, the side reactions described below, by the type and severity of each of these components, may be expected. 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 Apt can cause redistribution / accumulation of fatty tissue (lipodystrophy), in particular, central obesity, the accumulation of fat fiber in the dorsocervical (hump "buffalo") and chest areas, thinning fat in the limbs or face. Application of combined Apt was associated with metabolic disorders such as hypertriglycerinemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

In HIV-infected patients with severe immunodeficiency during the onset of combined Apt possibly exacerbation of the inflammatory process against the background of an 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, but 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 stage of HIV infection, or long-term use of combined Apt. The frequency of occurrence of this phenomenon is unknown.

Frequency of occurrence is defined as follows: Often (≥ 1/10); often (≥ 1/100 and <1/10); infrequently (≥ 1/1000 and <1/100); rarely (≥ 1/10 000 and <1/1000); rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

Lamivudine

On the part of the blood and lymphatic system

Infrequently: neutropenia, anemia, thrombocytopenia.

Rarely: true erythrocyte aplasia.

From the nervous system

Often: headache, insomnia.

Rarely: peripheral neuropathy (paresthesia);

On the part of the respiratory system, the organs of the thorax and the mediastinum

Often: cough, nasal symptoms.

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.

From the liver and biliary tract

Infrequently: transient increase in activity of hepatic enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)).

Rarely: hepatitis

From the skin and subcutaneous tissues

Often: rash, alopecia.

Rarely: angioedema

From the 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

On the part of the blood and lymphatic system

Often: anemia (blood transfusion may be required), neutropenia and leukopenia. These adverse reactions often occur with high doses of zidovudine (1200-1500 mg per day), in patients with advanced HIV infection (especially with a reduced bone marrow reserve before treatment) and with a number Cd4 less than 100 in 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 concentrations and vitamin B12 in the blood serum are reduced at the time of initiation of zidovudine treatment.

Infrequently: thrombocytopenia and pancytopenia (with bone marrow hypoplasia).

Rarely: true erythrocyte aplasia.

Rarely: aplastic anemia.

From the side of metabolism and nutrition

Often: hyperlactatemia.

Rarely: lactic acidosis, anorexia.

Disorders of the psyche

Rarely: anxiety, depression.

From the nervous system

Often: headache.

Often: dizziness.

Rarely: insomnia, paresthesia, drowsiness, decreased mental activity, convulsions.

From the heart

Rarely: cardiomyopathy.

On the part of the respiratory system, chest organs and fromgladnesses

Infrequently: dyspnea.

Rarely: cough.

From the gastrointestinal tract

Often: nausea.

Often: vomiting, abdominal pain and diarrhea,

Infrequently: flatulence.

Rarely: pigmentation of the oral mucosa, changes in taste sensations (dysgeusia), dyspepsia, pancreatitis.

From the liver and biliary tract

Often: increase in the blood activity of hepatic enzymes and concentration of bilirubin.

Rarely: liver damage, such as severe hepatomegaly with steatosis.

From the skin and subcutaneous tissues

Infrequently: rash and itching.

Rarely: pigmentation of nails and skin, hives and sweating.

From the side of musculoskeletal and connective tissue

Often: myalgia.

Infrequently: myopathy.

From the side of the kidneys and urine you are driving the way

Rarely: frequent urination.

From the genitals and breast

Rarely: gynecomastia.

General disorders and disorders at the site of administration

Often: general malaise.

Infrequently: fever, generalized pain syndrome, asthenia.

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

Overdose:

Symptoms: There are limited data on the effects of acute an overdose of lamivudine and zidovudine. Pi one of these cases did not end in a lethal outcome, and the condition of all patients normalized. No specific signs or symptoms were described. There may be an increase in side effects.

Treatment - symptomatic. There is no specific antidote. 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 with the help of dialysis, with overdose it is possible to use continuous hemodialysis. Hemodialysis and peritoneal dialysis are ineffective when removing zidovudine from the body, by accelerating the elimination of its metabolite (glucuronide).

Interaction:

Interactions involving lamivudine

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

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

Lamivudine may inhibit intracellular phosphorylation zalcitabine with simultaneous admission. Thus, it is not recommended to use the drug Emlazide in combination with zalcitabine.

With simultaneous application lamivudine can slow down intracellular phosphorylation 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 cladribine thus leading to a potential risk of decreased cladribine efficacy when combined with lamivudine in clinical practice. The results of some clinical studies confirm the possibility of interaction between lamivudine and cladribine. Thus, it is not recommended to use Emlazide in combination with cladribine.

Interaction didanosine not studied. Correction of the dose is not required.

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

Interaction phenobarbital not studied. Insufficient data for recommendation of dose adjustment.

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

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

Interactions involving zidovudine

Simultaneous reception of zidovudine and lamivudine leads to an increase of 13% of the time of zidovudine exposure and an increase of 28% in its maximum plasma concentrations. This increase does not pose a risk to patients, so there is no need to reduce the dose of Emlazide. Zidovudine does not affect the pharmacokinetics of lamivudine.

Zidovudine does not affect pharmacokinetics 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%, C_m_Oh 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 simultaneous admission 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% of its C_m_Oh at plasma. However, the total exposure zidovudine (AUC) is not significantly changes. 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 reports, probenecid increases the mean T1 / 2 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.

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

Zidovudine can inhibit the process of intracellular phosphorylation stavudine at their simultaneous reception. Thus, concomitant use of a combination of stavudine and Emsazide is not recommended.

Interaction didanosine not studied. No dose adjustment is required.

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

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

With simultaneous application 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 there is an increase AUC zidovudine 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 ranitidine not studied. No dose adjustment is required.

There have been reports of increased anemia in 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 ns is recommended because of the increased risk of anemia.

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 several drugs.

Since in some patients, despite the administration of Emlazide, may develop opportunistic infection, an appointment additional therapy 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 ns is 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.

Despite the use of the drug Emlazid or any other antiretroviral drug, patients can 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 Emlazide, does not prevent the risk of HIV transmission to other people during sexual intercourse or transfusion of infected blood, so patients should comply appropriate precautions. It is necessary to warn patients about the possible interaction of the drug Emlazide with other drugs with their concomitant reception.

Opportunistic infections

Despite the use of the drug Emlazid or any another 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 treating patients with HIV-associated diseases.

Hematologic disorders

Possible development of anemia, neutropenia and 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, in patients receiving the drug Emlazid, it is necessary to carry out a thorough control of hematological parameters. These hematologic changes usually appear ns 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 for severe anemia or myelosuppression during treatment with Emlazide, as well as in patients with prior bone marrow suppression, for example, hemoglobin concentration less than 9 g / dl (5.59 mmol / L) or neutrophil count less than 1.0 x 10⁹/ l. Since it is impossible to select the dose of Emlazide individually, it is recommended to use separate preparations of lamivudine and zidovudine.

Pancreatitis

In patients who took lamivudine and zidovudine, rare cases are described development of pancreatitis. However, it is not established whether the ego is caused by a complication of drugs or a major disease - HIV infection.When a patient has abdominal pain, nausea, vomiting, or an increase in the level of biochemical markers, the possibility of developing pancreatitis should be considered. It is necessary to stop taking the drug Emlazide before excluding the diagnosis of pancreatitis.

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

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.

Immunodeficiency Syndrome

In the presence of HIV-infected patients with severe immunodeficiency of 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. Usually, these reactions occur within the first weeks or months after the onset antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized or focal infection, caused by mycobacteria, and pneumonia caused by Pneumocystis jirovecii (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 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 relapse after stopping lamivudine may appear, which may have more severe consequences in patients with uncompensated liver damage. Therefore, in patients with concomitant viral hepatitis B, when Emlazide is withdrawn, the parameters of functional hepatic samples should be monitored and the level of hepatitis B virus replication regularly determined.

Co-infection of HIV and viral hepatitis C

The aggravation of anemia was observed with the combined use 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.

Diseases of the liver

The efficacy and safety of zidovudine have not been established in patients with severe concomitant liver disease.

In patients with chronic hepatitis B or with, using combination 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 or C, also refer to the relevant 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.

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 to exclude mitochondrial dysfunction if appropriate signs or symptoms.These data do not affect the current national recommendations on the use of antiretroviral therapy in pregnant women women to prevent vertical transmission of HIV infection.

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 encountered in patients at the 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-density polyethylene, sealed with a screw cap, with a bag of desiccant (silica gel) and non-absorbent cotton under the lid. 1 container with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children!

Shelf life:

2 years.

Do not use the drug after the expiry date indicated on the packaging.

Terms of leave from pharmacies:On prescription

Registration number:LP-004427

Date of registration:23.08.2017

Expiration Date:23.08.2022

The owner of the registration certificate:Emkur Pharmaceuticals Inc. Emkur Pharmaceuticals Inc. USA

Manufacturer: & nbsp

EMCURE PHARMACEUTICALS Ltd India

Representation: & nbspEMKYUR PHARMACEUTICALS LIMITEDEMKYUR PHARMACEUTICALS LIMITEDRussia

Information update date: & nbsp12.09.2017

Illustrated instructions

Instructions

Emlazide (Emlazid)