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

Excipients: lactose monohydrate 89 mg, cellulose microcrystalline 83 mg, sodium carboxymethyl starch 10 mg, povidone-K 30 9 mg, talc 4 mg, magnesium stearate 5 mg;

Shell composition: povidone-K 30 0.5 mg, hypromellose 3.45 mg, talc 1.5 mg, titanium dioxide 1.55 mg.

Description:

Capsule tablets, coated with a film shell from white to almost white. On the cross-section - the core is from white to almost white.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

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

Pharmacodynamics:

Mechanism of action

Lamivudine and zidovudine are potent selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. Both substances are sequentially metabolized by intracellular kinases to 5'-triphosphate (TF). Lamivudine-TF and zidovudine-TF are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme. However, the antiviral activity of the preparations is mainly due to the inclusion of their monophosphate form in the viral DNA chain, as a result of which the chain is broken. 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.

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 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 leads to 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 patients who have not previously received Apt, combination therapy with lamivudine and zidovudine slows down the appearance 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 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 APT 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 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

Lamivudine and zidovudine well absorbed from the intestine. In adults after oral administration, the bioavailability of lamivudine is 80-85%, and of zidovudine 60-70%. The combination of lamivudine / zidovudine is equivalent to taking lamivudine and zidovudine on an empty stomach separately.

After taking the drug Zidovudine + Lamivudine inside the maximum concentrations in the plasma of lamivudine and zidovudine (FROM_max) were noted through 0.75 (0.50-2.00) h and 0.50 (0.25-2.00) h and were 1.5 (1.3-1.8) mcg / ml and 1, 8 (1.5-2.2) μg / ml, respectively. The degree of absorption of lamivudine and zidovudine (based on the AUC value, the area under the pharmacokinetic curve "concentration-time") and the half-life (T_1/2) after ingestion with food were similar to those after fasting, although the rate of absorption was 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 linear pharmacokinetics when used in therapeutic doses and is bound to bound to blood plasma albumin (less than 36% of serum albumin in vitro). Zidovudine binds to plasma proteins by 34-38%. 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 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% from the accepted dose of zidovudine is excreted by renal excretion.

Excretion

The half-life (T_1/2lamivudine is 5-7 hours. The systemic clearance of lamivudine is approximately 0.32 l / h / kg, with renal clearance through active tubular secretion (organic cation transport system) of more than 70%.

With intravenous administration of zidovudine, the mean half-life (T_1/2) 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 lamivudine and zidovudine has 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 was the administration of 200 mg 6 times daily in adults (AUC₂₄ 10.9 h x mcg / ml).

A study of six HIV-infected children aged 2 to 13 years evaluated 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. Systemic exposure (AUC and C_max) 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 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 of AUC_0-12reaches 3800-5300 ng x h / ml. Recent evidence suggests that exposure in children aged 2 to 6 years can be reduced by 30% in comparison 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 with a body weight of at least 30 kg.

Contraindications:

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

- Zidovudine and drug Zidovudine + Lamivudine contraindicated in patients with severe neutropenia (the number of neutrophils is less than 0.75x10⁹/ l) or anemia (hemoglobin less than 7.5 g / dl, or 4.65 mmol / l);

- Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption;

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

- Severe hepatic insufficiency (for this dosage form);

- Children weighing up to 30 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 apply the drug Zidovudine + Lamivudine 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 Zidovudine + Lamivudine 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 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:

A drug Zidovudine + Lamivudine taken inside, regardless of food intake.

For those patients who have difficulty in swallowing, it is recommended that the tablets be crushed and added to a small amount of semi-solid food or liquid. The entire amount of the mixture should be taken immediately.

Treatment with drug Zidovudine + Lamivudine should be carried out by doctors with experience of HIV therapy.

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

The recommended dose of the drug Zidovudine + Lamivudine - 1 tablet 2 times a day.

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

Elderly patients

Specific data on the use of the drug Zidovudine + Lamivudine in elderly patients there. 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

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

Patients with impaired hepatic function

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

Patients with hematologic side effects

When the hemoglobin content is lower than 90 g / L or (5.59 mmol / L) or neutropenia (the number of neutrophils is less than 1,0x10⁹/ l), a dose adjustment of zidovudine may be required. When using the drug Zidovudine + Lamivudine 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 Zidovudine + Lamivudine 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 in the dorsocervical (buffalo hump) and chest areas, thinning of fat in the limbs 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 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 / 1,000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

Lamivudine

Violations of the blood and lymphatic system:

infrequently - neutropenia, anemia, thrombocytopenia;

rarely - true erythrocytic aplasia.

Disturbances from the nervous system:

often - headache, insomnia;

rarely - peripheral neuropathy (paresthesia).

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

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 the activity of hepatic enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (ACT));

rarely - Hepatitis.

Disturbances from the skin and subcutaneous tissues:

often 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 and leukopenia.

These adverse reactions often occur with high doses of zidovudine (1200-1500 mg per day), in patients with advanced HIV infection (especially when reduced bone marrow reserve before the start of treatment) and, in particular, in patients with a CD4 cell count of 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 AT₁₂in the blood serum reduced at the time of starting treatment with zidovudine;

infrequently - thrombocytopenia and pancytopenia (with bone marrow hypoplasia);

rarely - true erythrocytic 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 mediastinum:

infrequently - Shortness of breath;

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 the blood activity of liver enzymes and bilirubin concentrations;

rarely - Liver damage, such as severe hepatomegaly with steatosis.

Disturbances from the skin and subcutaneous tissues:

infrequently rash, itching;

rarely - pigmentation of nails and skin, hives and 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 general malaise;

infrequently - fever, generalized pain syndrome and asthenia;

rarely - chills, chest pain and flu-like syndrome.

Overdose:

Symptoms

Information on cases of drug overdose Zidovudine + Lamivudine no. No specific symptoms were detected in acute overdose of lamivudine or zidovudine except 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 symptoms of intoxication and to conduct standard maintenance therapy. Because the lamivudine is derived by dialysis, continuous hemodialysis can be used for overdose, however, there is no relevant clinical experience yet. Apparently, hemodialysis and peritoneal dialysis are ineffective in removing zidovudine from the body, but these methods accelerate the elimination of its metabolite (glucuronide).

Interaction:

Because the drug Zidovudine + Lamivudine 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.

Below are listed some drugs that represent classes of drugs that should be used with caution in the face of drug therapy Zidovudine + Lamivudine.

Interactions due to the presence of lamivudine

Lamivudine is mainly excreted by active tubular secretion (the system of transport of organic cations), respectively, it should be remembered about the possibility of drug interaction Zidovudine + Lamivudine with drugs that have the same pathway.

Trimethoprim

Acceptance of trimethoprim / sulfamethoxazole 160 mg / 800 mg (co-trimoxazole) leads to an increase in plasma lamivudine concentration 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 Zidovudine + Lamivudine 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 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 administered at doses of 500-600 mg / day and the concomitant 3-week course of treatment for acute pneumocystis pneumonia with atovahon, an increase in the incidence of adverse 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 Zidovudine + Lamivudine 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. In this way,It is not recommended to use stavudine and the drug jointly Zidovudine + Lamivudine

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)), as 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 Zidovudine + Lamivudine, 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 the drug Zidovudine + Lamivudine 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 administration of the drug Zidovudine + Lamivudine, 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 application 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 medication Zidovudine + Lamivudine, 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 taking the drug Zidovudine + Lamivudine 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 Zidovudine + Lamivudine, 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 if severe anemia or myelosuppression develops during treatment with the drug Zidovudine + Lamivudine, as well as in patients with prior bone marrow suppression, for example, with a hemoglobin concentration of less than 9 g / dL (5.59 mmol / L) or a neutrophil count of less than 1.0 x 10⁹/ l. Because the individual dose of the drug Zidovudine + Lamivudine It is impossible, 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 the drug Zidovudine + Lamivudine 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. Disorders of lipid metabolism should be adjusted, guided by their clinical manifestations.

Immunodeficiency Syndrome

In the presence of HIV-infected patients with severe immunodeficiency asymptomatic opportunistic infections or their residual effects at the time of onset Apt, 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 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 consequence, in patients with concomitant viral hepatitis B when the drug is withdrawn Zidovudine + Lamivudine 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 a combination Apt, the risk of developing serious and potentially leading to death unwanted 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.

In patients with previously identified liver diseases (including chronic active hepatitis), when combined antiretroviral therapy is used, the frequency of liver dysfunction increases,so these patients should be screened in accordance with standard practice. If the liver functions worsen, these patients should suspend or stop treatment with the drug.

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, subjected to intrauterine exposure to analogues of nucleosides and nucleotides,should 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

Despite the fact that 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 for a long time taking a 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 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.In case of occurrence of undesirable reactions from the side of the central nervous system, one should refrain from performing actions requiring an increased concentration of attention and speed of psychomotor reactions.

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

Packaging:

For 10 tablets in a blister of aluminum foil and PVC film amber. For 1, 3 or 10 blisters together with instructions for use in a cardboard box.

For 100, 500 or 1000 tablets in a plastic bag. 1 package in a can of HDPE with silica gel, sealed with aluminum foil with a polyethylene coating, with a screw cap. On the bank stick a label from paper label or writing or from polymer materials, self-adhesive. By 1, 6, 12 or 24 cans together with an equal number of instructions for use in group packaging - a box of corrugated cardboard (for hospitals).

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-004164

Date of registration:28.02.2017

Expiration Date:28.02.2022

The owner of the registration certificate:Lock-Beta Pharmaceuticals (I) Pvt.LtdLock-Beta Pharmaceuticals (I) Pvt.Ltd India

Manufacturer: & nbsp

LOK-BETA PHARMACEUTICALS (I), Pvt. Ltd. India

Representation: & nbspLock-Beta Pharmaceuticals (I) Pvt.LtdLock-Beta Pharmaceuticals (I) Pvt.Ltd

Information update date: & nbsp30.03.2017

Illustrated instructions

Instructions

Zidovudine + Lamivudine (Zidovudine + Lamivudine)