LAMY-ZIDOKS - instructions for use, dosage, adverse effects, contraindications

Component	Amount, mg
*Inside the pellet core granules*
Active substances
Zidovudine	300,00
Lamivudine	150,00
Excipients
Microcrystalline cellulose (Avicel PH 101)	114,50
Sodium carboxymethyl starch	10,00
Purified water	to the required volume
*Sheath of granules of a core of a tablet*
Sodium carboxymethyl starch	5,00
Microcrystalline cellulose (Avicel PH 101)	130,00
Silica colloidal (Aerosil 200)	8,00
Magnesium stearate	7,50
*Tablet core weight*	725,00
Casing of the tablet
Fold the white 13В58802:	21,43
- hypromellose	59,75%
- titanium dioxide	31,25%
- macrogol	8,00%
- polysorbate 80	1,00%
Purified water	to the required volume
*Weight of a tablet*	740,00

Description:

Biconvex tablets are oval-shaped, film-coated, from white to almost white, embossed with "C" and "60" on one side and smooth on the other side.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

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

Pharmacodynamics:

Mechanism of action

Zidovudine and lamivudine are potent selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. Both substances are sequentially metabolized by intracellular kinases to 5'-triphosphate (TF). Zidovudine-TF and lamivudine-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 the chain is broken.Trisphosphates of zidovudine and lamivudine have significantly less affinity for the 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.

Pharmacodynamic effects

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 (Apt), which includes 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 zidovudine and lamivudine resulted in a decrease in HIV-1 viral load and an increase in the content Cd4 cells. Clinical evidence suggests that the use of a combination of zidovudine and lamivudine or a combination of zidovudine-containing regimens and lamivudine significantly reduces the risk of disease progression and mortality.

Separately, monotherapy with zidovudine or lamivudine 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, combination therapy with zidovudine and lamivudine slows the emergence of resistant to zidovudine strains of HIV. Tests on the sensitivity of HIV to drugs in vitro They were not standardized, therefore various methodological factors can influence their results. At present, the relationship between sensitivity to zidovudine and / or lamivudine in vitro and the clinical effect of therapy has not been studied.

Zidovudine and lamivudine widely used as components of a combined Apt together 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 modes Apt, 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

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

Grinding tablets and taking them with a small amount of semi-solid food or liquid does not affect the pharmacological properties of the drug and, therefore, the clinical effect. These conclusions are based on the physico-chemical and pharmacokinetic characteristics of the active substances,that the patient immediately takes 100% of the ground tablets.

Distribution

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

Lamivudine has a 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 blood plasma proteins by 34-38%. Thus, the interaction of zidovudine and lamivudine with other drugs through their substitution in binding sites on proteins is unlikely.

Determined that zidovudine and lamivudine penetrate into the central nervous system (CNS) and cerebrospinal fluid. After 2-4 hours after oral administration, the ratio between the concentration of zidovudine and lamivudine 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 due to a slight metabolism in the liver (from 5 to 10%) and weak association with plasma proteins.

Zidovudine 5'-glucuronide is the main metabolite in 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 through active tubular secretion (organic cation transport systems) of more than 70%.

With intravenous administration of zidovudine, the average half-life is 1.1 hours, and the average system 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 zidovudine and lamivudine have not been studied in patients older than 65 years.

Children

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%, on average 65%.

The maximum concentration in the equilibrium state is 4.45 μmol (1.19 μg / ml) after taking zidovudine in the form of a solution at a dose of 120 mg / m² body surface area and 7.7 μmol (2.06 μg / ml) after taking a dose of 180 mg / m².

The dose of 180 mg / m² 4 times a day leads to the same systemic exposure in children (AUC₂₄ 10.7 h x mcg / ml), as well as taking 200 mg 6 times a day in adults (AUC₂₄ 10.9 h x mcg / ml).

In general, the pharmacokinetics of lamivudine in children is similar to the pharmacokinetics in adult patients. However, absolute bioavailability (approximately 55-65%) is lower 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 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_0-12reaches 3800-5300 ng x h / ml. 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 zidovudine and lamivudine. Zidovudine and lamivudine 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:

LAMI-ZIDOX® is indicated for the treatment of HIV infection in adults and children weighing at least 30 kg.

Contraindications:

The drug LAMI-ZIDOX® is contraindicated in patients with increased sensitivity to zidovudine, lamivudine or any other component of the drug.

Zidovudine and LAMI-ZIDOX® are contraindicated in patients with severe neutropenia (neutrophil count less than 0.75 x 10⁹/ l) or anemia (hemoglobin less than 7.5 g / dl or 4.65 mmol / l); Children weighing less than 30 kg (for this dosage form).

Pregnancy and lactation:

Fertility

Data on the effect of zidovudine and lamivudine on fertility in women are not available.

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 LAMI-ZIDOX® 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, LAMI-ZIDOX® can be administered to pregnant women only when the expected benefit to the mother exceeds the possible risk to the fetus.

There is evidence of a slightly transient increase in plasma lactate concentration, possibly due to mitochondrial disorders, in newborns and infants whose mothers received NRTI 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 zidovudine, lamivudine and HIV penetrate into breast milk, breastfeeding is contraindicated.

Dosing and Administration:

The drug LAMI-ZIDOX® is taken internally, regardless of food intake.

Treatment with LAMI-ZIDOX® should be performed by doctors 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 or 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 LAMI-ZIDOX® is 1 tablet 2 times a day.

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

Elderly patients

There are no specific data on the use of LAMI-ZIDOX® in elderly people. However, in the treatment of elderly persons, special care must 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 zidovudine and lamivudine, it is recommended to assign them individual preparations of zidovudine and lamivudine.

Patients with impaired hepatic function

With hepatic insufficiency, zidovudine can be cumulated as a result of a slower binding of it to glucuronic acid.In patients with a severe degree of impaired liver function, it is recommended to use separate preparations of zidovudine and lamivudine to be able to individually select the dose of 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 LAMI-ZIDOX^® it is impossible to individually select the dose of zidovudine and lamivudine, it is recommended to use separate preparations of zidovudine and lamivudine.

Side effects:

Adverse reactions have been described in the treatment of patients with HIV zidovudine and lamivudine in the form of monotherapy or as a combination of these drugs can cause side effects.

For many adverse reactions, it is not known whether they are caused by zidovudine, lamivudine, 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 LAMI-ZIDOX^® includes zidovudine and lamivudine, 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 zidovudine and lamivudine 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 fatty tissue in the dorsocervical (buffalo hump) and chest areas, thinning of fat in the limb or face area.

Application of combined Apt was 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 Apt possibly exacerbation of the inflammatory process against a background of 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 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 <10), infrequently (≥1 / 1,000 and <1/100), rarely (≥1 / 10,000 and <1/1 000), rarely (≥1 / 10000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

Zidovudine

Violations of the blood and lymphatic system

Often: anemia (blood transfusion may be required), neutropenia and leukopenia.

These side effects are more likely to 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 CD4 cell counts⁺ 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 whose neutrophil count, hemoglobin concentration and serum vitamin B12 levels are lower at the time of zidovudine treatment.

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

Rarely: true erythrocyte aplasia.

Rarely: aplastic anemia.

Disorders from the metabolism and nutrition

Often: hyperlactatemia.

Rarely: lactic acidosis, anorexia.

Disorders of the psyche

Rarely: anxiety and depression.

Disturbances from the nervous system

Often: headache.

Often: dizziness.

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

Heart Disease

Rarely: cardiomyopathy.

Disturbances from the respiratory system, organs of the chest and the mediastinum

Infrequently: dyspnea.

Rarely: cough.

Disorders from the gastrointestinal tract

Often: nausea.

Often: vomiting, abdominal pain and diarrhea.

Infrequently: flatulence.

Rarely: pigmentation of the oral mucosa, taste distortion, dyspepsia, pancreatitis.

Disturbances from the liver and bile ducts

Often: 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 fat

Infrequently: rash and itching.

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

Disturbances from musculoskeletal system and connective tissue

Often: myalgia.

Infrequently: myopathy.

Disorders from the kidneys and urinary tract

Rarely: frequent urination.

Violations of the genitals and mammary glands

Rarely: gynecomastia.

General disorders and disorders at the site of administration

Often: general malaise.

Infrequently: fever, generalized pain syndrome and asthenia.

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

Lamivudine

Violations of the blood and lymphatic system

Infrequently: neutropenia, anemia, thrombocytopenia.

Rarely: true erythrocyte aplasia.

Disturbances from the nervous system

Often: headache, insomnia.

Rarely: peripheral neuropathy (paresthesia).

Disturbances from the respiratory system of the 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 treatment has not been established. Increase of activity of amylase in blood serum.

Disturbances from the liver and bile ducts

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

Rarely: hepatitis.

Violation of the skin and subcutaneous fat

Often: rash, alopecia.

Rarely: angioedema.

Disturbances from musculoskeletal system and connective tissue

Often: arthralgia, muscle disorders.

Rarely: rhabdomyolysis.

General disorders and disorders at the site of administration

Often: fatigue, general malaise, fever.

Overdose:

Symptoms

Information on cases of overdose of LAMI-ZIDOX^® are limited. No specific symptoms were detected in acute overdose of zidovudine or lamivudine other than those listed in the "Side effect" section. None of these cases ended in a fatal outcome, and the condition of all patients returned to normal.

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 removing zidovudine from the body, but these methods accelerate the elimination of its metabolite (glucuronide). More detailed information is contained in the instructions for the use of zidovudine and lamivudine.

Interaction:

Since the drug LAMI-ZIDOX^® contains zidovudine and lamivudine, 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.

Below are listed some drugs that represent classes of drugs that should be used with caution in the face of LAMI-ZIDOX® therapy.

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, 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 the drug LAMI-ZIDOX^® 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 LAMI-ZIDOX 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-glucuronyltransferase (UDF-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 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.

Other drugs: acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone and 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 LAMI-ZIDOX^®, 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 (for example, systemic administration of pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin B, flucytosine, ganciclovir, interferon,vincristine, vinblastine and doxorubicin) may also increase the risk of side effects of zidovudine. With the simultaneous administration of LAMI-ZIDOX^® and any of these drugs should closely monitor kidney function and hematological parameters and, if necessary, reduce the dose of one or more drugs.

Since in some patients, despite the use of the drug LAMI-ZIDOX^®, opportunistic infections may develop, 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.

Interactions due to the presence of lamivudine

Lamivudine is mainly excreted by active tubular secretion (the system of transport of organic cations), therefore, it should be remembered that LAMI-ZIDOX® can interact with drugs having the same pathway.

Trimethoprim

Acceptance of trimethoprim / sulfamethoxazole 160 mg / 800 mg (co-trimoxazole) causes an increase in lamivudine exposure by 40%, which is due to the presence of trimethoprim. However, except for patients with renal insufficiency, correction of the dose of lamivudine is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. 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 LAMI-ZIDOX^® 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), 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.

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 cladribine and lamivudine. Therefore, the combined use of cladribine and lamivudine is not recommended.

Special instructions:

- If individual dose selection is necessary, it is recommended to use separate preparations of zidovudine and lamivudine. Doctors should be guided by the information when using 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 LAMI-ZIDOX^®, 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 drug LAMI-ZIDOKS^® 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 treating patients with HIV-associated diseases.

Undesirable reactions from the hematopoiesis system

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 LAMI-ZIDOX^®, 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 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 LAMI-ZIDOX®, as well as in patients with prior bone marrow suppression, for example hemoglobin concentrations of less than 9 g / dL (5.59 mmol / L) or the number of neutrophils is less than 1.0 x 10⁹/ l. Since the individual dose of LAMI-ZIDOX^® It is impossible, it is recommended to use separate preparations of zidovudine and lamivudine.

Pancreatitis

In patients who took zidovudine and lamivudine, 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. Consider the possibility of developing pancreatitis.

LAMI-ZIDOX should be stopped.^® until 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 Apt analogues of nucleosides in the form of individual preparations, 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 nucleoside analogues should be discontinued if symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis develop, progressive hepatomegaly, or a rapid increase in aminotransferase levels.

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 Apt, redistribution and / or accumulation of subcutaneous fat can be observed, including obesity in the central type, 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 concentration glucose in the blood, either individually or together.

Although all drugs from HIV and NRTI classes can cause one or more of the above unwanted reactions associated with a common syndrome, often called lipodystrophy, the accumulated data suggest 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 duration Apt 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

If HIV-infected patients with severe immunodeficiency have asymptomatic opportunistic infections or their residual effects at the time of initiation of APT, 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 the onset of APT. Typical examples are cytomegalovirus retinitis, generalized or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (R. 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, but 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. As a result, in patients with concomitant viral hepatitis B, when LAMI-ZIDOX is withdrawn^® should monitor the performance of functional liver samples and regularly determine the markers of hepatitis B virus replication within 4 months.

In patients with an initially present impaired hepatic function, including an active form of chronic hepatitis, there is an increase in the incidence of liver dysfunction in combination Apt. 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 the event 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 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 regime change Apt with the goal 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 C, using combined APT, 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.

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 recommendations for use Apt in pregnant women for the prevention of vertical transmission of HIV infection.

Osteonecrosis

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

Patients should consult a doctor if they experience pain and 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 zidovudine and lamivudine on the ability to drive and work with machinery. Pharmacological properties of drugs indicate a low probability of such influence. The clinical state of the patient, as well as the side effects of zidovudine and lamivudine, should be taken into account.

Form release / dosage:Tablets, film-coated, 300 mg + 150 mg.

Packaging:

In a polymer bank equipped with a self-adhesive label.

On 1 bank together with the instruction on application place in a pack a cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 30 ° C.

Shelf life:

3 years.

Terms of leave from pharmacies:On prescription

Registration number:LP-003933

Date of registration:02.11.2016

Expiration Date:02.11.2021

The owner of the registration certificate:NANOLEC, LTD. NANOLEC, LTD. Russia

Manufacturer: & nbsp

AUROBINDO PHARMA, Ltd. India

Representation: & nbspNANOLEC, LTD.NANOLEC, LTD.

Information update date: & nbsp11.02.2018

Illustrated instructions

Instructions

LAMI-ZIDOX® (Lami-Zidox®)