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

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 drugs is due to mainly by incorporating their monophosphate form into the viral DNA chain, resulting in chain termination. 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 the 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 positions of HIV reverse transcriptase. and in the second case we are talking about 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 the emergence of resistant to zidovudine HIV strains.

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 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

Lamivudine and zidovudine well absorbed from the intestine. In adult patients after oral administration, the bioavailability of lamivudine is 80 to 85%, and of zidovudine 60 to 70%. After taking the drug inside the maximum concentrations in the plasma of lamivudine and zidovudine (C_m_Oh) were noted through 0.75 (0.50-2.00) and 0.50 (0.25-2.00) h and were 1.5 (1.3-1.8) μg / ml and 1.8 (1.5-2.2) μg / ml, respectively. The extent of absorption of lamivudine and zidovudine (based on the value of AUC, the area under the pharmacokinetic curve "concentration-time") and the half-life (T1 / 2) after intake with food were similar to those after fasting, although the rate of absorption was somewhat slowed down.

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, provided that the patient immediately takes 100% of the ground tablets.

Distribution

When administered intravenously, the average volume of distribution (Vd) for lamivudine and zidovudine is 1.3 and 1.6 l / kg, respectively. Lamivudine has linear pharmacokinetics when used in therapeutic doses and is bound to bound to blood plasma albumin (less than 36% of serum albumin in vitro). Zidovudine binds to blood plasma proteins by 34 - 38%. Thus, the interaction of lamivudine and zidovudine with other drugs through their replacement at binding sites on proteins is unlikely.

Determined that lamivudine and zidovudine penetrate into the central nervous system (CNS) and cerebrospinal fluid. After 2 to 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. 5'-zidovudine glucuronide is the main metabolite in plasma and urine, with approximately 50 to 80 % from the accepted dose of zidovudine is excreted by renal excretion.

Excretion

The half-life of lamivudine (T1 / 2) is 5-7 hours. The systemic clearance of lamivudine is approximately 0.32 l / h / kg, with kidney clearance carried out by active tubular secretion (organic cation transport system) of more than 70%.

With intravenous administration of zidovudine, the average half-life (T1 / 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 (C_m_a_x) 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 х mcg / ml), as well as taking 200 mg 6 times a day in adults (AUC₂₄ 10.9 h x mcg / ml).

In a study of six HIV-infected children aged 2 to 13 years, the pharmacokinetics of zidovudine was evaluated after taking 120 mg / m 3 daily 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 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. Recent data indicate that exposure in children aged 2 to 6 years can be reduced by 30% compared with other age groups.

Patients with impaired renal function

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

Patients with impaired hepatic function

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

Pregnancy

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

Indications:

Treatment of HIV infection in adults and children weighing at least 14 kg in combination antiretroviral therapy.

Contraindications:

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

- Severe neutropenia (neutrophil count less than 0.75 x 10⁹/ l);

- Severe anemia (hemoglobin level less than 7.5 g / dl, or 4.65 mmol / l);

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

- Severe degree of impaired liver function (for this dosage form);

- The period of breastfeeding;

- Children weighing less than 14 kg.

Pregnancy and lactation:

Fertility

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

Pregnancy

The safety of lamivudine in women during pregnancy has not been studied to date. Do not use drugs containing zidovudine and lamivudine, in the first 3 months of pregnancy, unless the expected benefit for the mother does not exceed the probable risk to the fetus.

It was shown that zidovudine treatment of pregnant women and the subsequent introduction of this drug reduces the incidence 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 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:

A drug Zidovudine + Lamivudine taken inside, regardless of food intake. Treatment with drug Zidovudine + Lamivudine should be carried out by doctors with experience of 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 children with a body weight of at least 30 kg

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

Children with body weight from 21 to 30 kg

recommended dose of the drug Zidovudine + Lamivudine - ½ tablets in the morning plus 1 tablet in the evening.

Children with body weight from 14 to 21 kg

recommended dose of the drug Zidovudine + Lamivudine - by ½ pills 2 times a day.

Children weighing less than 14 kg

drug administration Zidovudine + Lamivudine In this category of patients it is contraindicated, separate preparations of lamivudine and zidovudine should be used.

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 of lamivudine and zidovudine.

Elderly patients

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

Since patients with impaired renal function (creatinine clearance less than 50 ml / min) should individually select a dose of lamivudine and zidovudine, it is recommended that they be given separate medications for lamivudine and zidovudine.

Patients with impaired hepatic function

In patients with a severe degree of impaired liver function, separate preparations of lamivudine and zidovudine should be used.

Application in hematological disorders

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 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 infection 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 mediated 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 includes lamivudine and zidovudine, and therefore, the side reactions described below, by the type and severity of each of the components, can 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, accumulation fatty tissue in dorsocervical (hump "buffalo") and chest areas, thinning fat in the limbs or face.

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 (eg, Travis' disease) developing 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.

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.

The frequency of occurrence is determined according to WHO classification:

Very often: ≥ 1/10;

Frequently: ≥ 1/100 and <1/10;

Infrequently: ≥ 1/1000 and <1/100;

Rarely: ≥ 1/10000 and <1/1000;

Very rarely: <1/10000;

Lamivudine

Violations from the blood and lymphatic system:

Infrequently: neutropenia, anemia, thrombocytopenia;

Rarely: true erythrocyte aplasia.

Impaired nervous system:

Often: headache, insomnia;

Rarely: peripheral neuropathy (paresthesia).

Disturbances from the respiratory system, organs of the thorax 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; an increase in the activity of amylase in the blood serum.

Disorders from the liver and bile ducts:

Infrequently: transient increase in 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 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

Violations from 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 reduced bone marrow reserve before treatment) and. in particular, in patients with a number of cells 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.

Disorders from the metabolism and nutrition:

Often: hyperlactatemia:

Rarely: lactic acidosis, anorexia.

Disorders of the psyche:

Rarely: anxiety and depression.

Impaired nervous system:

Often: headache;

Often: dizziness;

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

Heart Disease:

Rarely: cardiomyopathy.

Disturbances from the respiratory system, chest and mediastinal organs:

Infrequently: 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.

Disorders 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 tissues:

Infrequently: rash and itching;

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

Disturbances from the musculoskeletal and connective tissue:

Often: myalgia;

Infrequently: myopathy.

Disorders from the kidneys and urinary tract:

Rarely: frequent urination.

Violations of the genitals and breast:

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.

Overdose:

Symptoms:

Information about cases of drug overdose Zidovudine + Lamivudine are limited. No specific symptoms were found in acute overdose of lamivudine or zidovudine except those listed in the "Side action. "None of these cases ended in a fatal outcome and the condition of all patients was normalized.

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 lamivudine and zidovudine.

Interaction:

Because the drug 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 excreted by the kidneys unchanged.

Zidovudine also binds to a small extent with plasma proteins, but is eliminated mainly through hepatic metabolism to inactive glucuronide.Preparations with a predominant hepatic metabolism, especially through glucuronization. potentially can 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

Receiving 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 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 may be limited. The use of lamivudine in combination with emtricitabine or fixed dose combinations containing emtricitabine, Not recommended.

Didanosine

The interaction is not studied; correction of the dose is not required.

Fluconazole

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

Phenobarbital

The interaction is not studied; data for recommendation of dose adjustment is not enough.

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). Correction of the dose is not 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, so 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 (C_m_Oh) is reduced by 19%).When zidovudine is prescribed in doses of 500 to 600 mg / day and the concomitant 3-week course of treatment of 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 of C_m_Oh 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

By some data, probenecid increases the mean half-life (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.

Rifampicin

Limited data show that when combined with zidovudine and rifampicin AUC zidovudine decreased by 48 ± 34%. However, clinical significance this observation is not known.

Stavudine

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

Didanosine

The interaction is not studied; correction of the dose is not required.

Fluconazole

The combined use of fluconazole at a dosage of 400 mg 1 time per day and zidovudine at a dosage of 200 mg 3 times a day leads to an increase AUC zidovudine by 74% (inhibition of UDP-glucuronyltransferase (UDF-HT)) because limited data are available, clinical significance is not known.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 correct the dose.

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. Correction of the dose is not 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 pranobeks 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 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 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 use of such drugs with zidovudine is not recommended. Simultaneous use of zidovudine and doxorubicin is not recommended due to the mutual weakening of the activity of each of the medicines in vitro.

Special instructions:

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

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

Patients should be informed that treatment with antiretroviral drugs, such as 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 infection 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 previous bone marrow suppression, for example, with a hemoglobin level of less than 9 g / dL (5.59 mmol / L) or neutrophil counts 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.Immediately 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 outcome due to the use of Apt analogues of nucleosides in the form of separate preparations, including lamivudine or a combination thereof. Similar phenomena were mainly observed 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 steatosis of the liver (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 glucose concentration in the blood, both individually and together.

Although all drugs from HIV classes and NRTIs can cause one or more of the above unwanted reactions associated with a common syndrome, often called lipodystrophy, the accumulated data suggest that there is a difference 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 effects of these side effects are currently unknown. During the clinical examination, attention should be paid to the signs of redistribution of subcutaneous fat. Serum lipids and glucose concentration in the blood should be closely monitored. In violation of lipid metabolism is prescribed appropriate treatment.

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, the conduct of 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 (P.carinii).The appearance of any symptoms of inflammation requires immediate examination and, if necessary, appropriate treatment.

Autoimmune diseases (such as Graves' disease, polymyositis, 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 B recurrence may appear after stopping lamivudine, which may have more severe consequences in patients with uncompensated 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 patients with zidovudine-induced anemia in the anamnesis. In these cases, it is recommended to consider the possibility of regime change Apt with the goal of reversing zidovudine.

Liver diseases:

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 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.

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 has been no special study of the effects of zidovudine and lamivudine on the ability to drive vehicles and engage in other potentially hazardous activities. The pharmacological properties of lamivudine and zidovudine indicate a low probability of such an effect. Clinical status of the patient, as well as the presence and nature of adverse reactions of lamivudine and zidovudine should be taken into account.

Form release / dosage:

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

Packaging:

10 tablets in a contour mesh box made of polyvinylchloride film and foil of aluminum printed lacquered or 60 tablets in a can of polymeric, capped lid. 6 contour mesh packages or 1 jar along with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-004313

Date of registration:29.05.2017

Expiration Date:29.05.2022

The owner of the registration certificate:IRVIN 2, LLC IRVIN 2, LLC Russia

Manufacturer: & nbsp

ZIO-HEALTH, JSC Russia

Information update date: & nbsp22.06.2017

Illustrated instructions

Instructions

Zidovudine + Lamivudine (Zidovudine + Lamivudine)