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

Excipients: silicon dioxide colloid - 8 mg, croscarmellose sodium 35.7 mg, magnesium stearate 7.5 mg, povidone K-30 21.3 mg, microcrystalline cellulose 197.5 mg.

Composition of the film shell: Opadrai II white 22 mg, including: polyvinyl alcohol - 10.318 mg, macrogol (polyethylene glycol) - 5.192 mg, talc - 3.828 mg, titanium dioxide - 2.662 mg.

Description:

Oval biconvex tablets with a risk, covered with a film shell of white or almost white color. On a cross-section of white or almost white color.

Pharmacotherapeutic group:Antiviral (HIV) agent

ATX: & nbsp

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

Pharmacodynamics:

Mechanism of action

Combined antiviral drug, which includes zidovudine and lamivudine, which are potent selective inhibitors of human immunodeficiency virus reverse transcriptase (HIV-1 and HIV-2). Both substances are sequentially metabolized by intracellular kinases to 5'-triphosphate (TF).

Lamivudine-TF and zidovudine-TF are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme. However, the antiviral activity of the preparations is mainly due to the inclusion of their monophosphate form in the viral DNA chain, as a result, 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 (investigated 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 vitro shows low cytotoxicity of lamivudine against peripheral blood lymphocytes, as well as 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 Ml84V, located close to the active center of HIV viral reverse transcriptase. This mutation is observed both in conditions in vitro, and in HIV-1-infected patients who underwent combined antiretroviral therapy (Apt), including lamivudine. In case of mutation in the codon M184V significantly reduces the sensitivity to lamivudine and significantly reduces the ability of the virus to replicate according to 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 described and correlates with sequential accumulation of up to 6 specific mutations of HIV reverse transcriptase in codons 41, 67, 70, 210, 215 and 219. The viruses acquire phenotypic resistance to thymidine analogs by combining mutations in codons 41 and 215 or by accumulation, at four or six mutations. These mutations, when used with thymidine analogs, do not in themselves cause high cross-resistance to other nucleosides, which subsequently allows the use of other approved reverse transcriptase inhibitors.

There are two types of development of mutations leading to multiple drug resistance. In one case, viral reverse transcriptase mutations occur in codons 62, 75, 77, 116 and 151, 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 and other nucleoside reverse transcriptase inhibitors (NRTIs). Any of these types of mutations significantly limits the therapeutic possibilities for HIV infection.

In clinical trials, the combination of lamivudine and zidovudine reduced HIV-1 load and increased content CD4 + cells. Clinical evidence suggests that the use of a combination of lamivudine and zidovudine or a combination of lamivudine and zidovudine-containing regimens leads to a significant reduction in the risk of disease progression and mortality.

Separately, monotherapy with lamivudine or zidovudine resulted in the appearance of HIV isolates with reduced sensitivity to these drugs in vitro. Clinical evidence suggests that patients, previously not receiving antiretroviral therapy, combined 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 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 regimens of antiretroviral therapy, including lamivudine are effective in the treatment of patients who have not previously received antiretroviral drugs and patients who have strains HIV with M184V a mutation.

Pharmacokinetics:

Suction

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

After taking the drug inside, the maximum concentrations (C_m_Oh) lamivudine and zidovudine in the blood plasma are noted through 0.75 (0.5-2) h and 0.5 (0.25-2) h and are 1.5 (1.3-1.8) mg / mg and 1.8 (1.5-2.2) mg / ml, respectively.

The degree of absorption of lamivudine and zidovudine (based on the area under the pharmacokinetic curve "concentration-time" (AUC)) and half-life (T_1/2) after intake from food were similar to those after fasting, although the rate of absorption was somewhat slowed.

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 (V_d) 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 lamivudine and zidovudine with other drugs by replacing protein bonds is unlikely.

Determined that lamivudine and zidovudine penetrate into the central nervous system (CNS) and cerebrospinal fluid. After 2-4 hours after oral administration, the ratio between the concentration of lamivudine and zidovudine in CSF and serum is on average 0.12 and 0.5, respectively.

Metabolism

Lamivudine is excreted from the body mainly by the kidneys in unchanged form. Metabolic interactions of lamivudine are unlikely due to a slight metabolism in the liver (from 5 to 10%) and weak association with plasma proteins. The main metabolite in plasma and urine is 5'-glucuronide of zidovudine.

Excretion

Half-life (T_1/2) lamivudine is 5-7 hours. Approximately 50-80% of the accepted dose of zidovudine is excreted by renal excretion. 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 T_1/2 is 1.1 h, 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 in the kidneys.

Pharmacokinetics in special clinical cases

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_Oh) is 4.45 μmol (1.19 μg / ml) after taking zidovudine in the form of a solution in a dose 120 mg / m² body surface area and 7.7 μmol (2.06 μg / ml) after taking in 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 is 10.7 h x mcg / ml), as is the dose of 200 mg 6 times a day in adults (AUC₂₄ is 10.9 h x μg / ml).

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

In general, the pharmacokinetics of lamivudine in children is similar to the pharmacokinetics in adult patients.However, absolute bioavailability (approximately 55-65%) was reduced in children younger than 12 years. Systemic clearance in children is higher than in adults, and is prone to decrease 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_0-12 reaches 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 disturbed in case of renal insufficiency. Reduction of the dose of lamivudine is recommended in patients with creatinine clearance (CC) less than 50 ml / min. The concentration of zidovudine in plasma also increases in patients with severe renal insufficiency.

Patients with impaired hepatic function

Decreased glucuronidation in patients with impaired hepatic function due to cirrhosis may lead to a 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 any other component of this drug;

- severe neutropenia (neutrophil count less than 0,75x10⁹/ l) or anemia (hemoglobin level less than 7.5 g / dl or 4.65 mmol / l);

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

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

- the period of breastfeeding;

- children with a body weight of less than 14 kg (for this dosage form).

Pregnancy and lactation:

Fertility

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

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

Pregnancy

The safety of lamivudine in women during pregnancy has not been studied to date. It is not recommended to use the drug in the first 3 months of pregnancy, except when the expected benefit of therapy for the mother does not exceed the likely 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 can be given to pregnant women only in cases where the expected benefit to the mother exceeds the possible risk to the fetus. There is evidence of a slight transient increase in lactate concentration in the blood plasma, possibly due to mitochondrial disorders in newborns and infants whose mothers took NRTIs during pregnancy and in the perinatal period. The clinical significance of this enhancement is not currently established. In addition, there are some reports of developmental delay, convulsive seizures and other neurological disorders.However, the causal relationship of these disorders to the effect of NRTIs during the intrauterine and perinatal periods has not been established. These data do not abolish existing recommendations for antiretroviral therapy during pregnancy to prevent vertical transmission of HIV.

Breastfeeding period

Specialists do not recommend HIV-infected patients feeding to avoid transmitting HIV to the child.

Because the lamivudine, zidovudine and HIV penetrate into breast milk, Breastfeeding is contraindicated.

Dosing and Administration:

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 divide and crumble the tablets with the addition of a small amount of semi-solid food or liquid. The entire amount of the mixture should be taken immediately.

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

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

Children with a body weight of 21 kg to 30 kg

The recommended dose of the drug is ½ tablets in the morning plus 1 tablet in the evening.

Children with body weight from 14 to 21 kg

The recommended dose of the drug is ½ pills 2 times a day.

Children weighing less than 14 kg

The use of the drug in this category of patients is contraindicated. It is necessary to use separate preparations of lamivudine and zidovudine.

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.

Application the separate patient groups

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), it is necessary to individually select the dose of lamivudine and zidovudine,it is recommended to prescribe separate medications for lamivudine and zidovudine.

Patients with impaired hepatic function

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

Patients with hematologic side effects

When the hemoglobin content is lower than 9 g / dl (5.59 mmol / l) or neutropenia (the number of neutrophils is less than 1,0х10⁹/ l) may be required correction of zidovudine dose. When using the drug Zidovudine + Lamivudine It is impossible to individually select doses of lamivudine and zidovudine, it is recommended that separate 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 mediated by lamivudine, zidovudine, or a wide range of other drugs used to treat HIV infection, or the same result 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 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 antiretroviral therapy can cause redistribution / accumulation of fatty tissue (lipodystrophy), in particular, central obesity, the accumulation of subcutaneous fat in the dorsocervical ("buffalo buffalo") and chest areas, thinning of fat in the face and limbs.

Application Apt was associated with metabolic disorders, such as as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

In HIV-infected patients with severe immunodeficiency during the onset of combined API possibly exacerbation of the inflammatory process against a background of asymptomatic or residual opportunistic infection.There have also been cases of autoimmune diseases (eg, 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 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.

Determination of the frequency of side effects: very often (≥1 / 10); often (≥1 / 100 and <1/10); infrequently (≥1 / 1000 and <1/100); rarely (≥1 / 10,000 and <1/1000); very 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

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

Impaired nervous system: often a headache, insomnia; very rarely - peripheral neuropathy (paresthesia).

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

Disorders from the gastrointestinal tract: often - nausea, vomiting, abdominal pain or colic, diarrhea; rarely - pancreatitis (association with lamivudine is not established), increased activity of serum amylase.

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

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

Disturbances from 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 zidovudine in high doses (1200-1500 mg / day), in patients with advanced HIV infection (especially with a reduced bone marrow reserve before treatment), and in particular in patients with a number of cells Cd4 less than 100 in 1 mm³. In some patients it is necessary to reduce the dose of zidovudine up to cancellation. Neutropenia occurs more often in those patients in whom the number of neutrophils, hemoglobin and vitamin concentrations B12 in the serum reduced at the time of starting treatment zidovudinom.

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

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

Disorders of the psyche: rarely - anxiety and depression.

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

Heart Disease: rarely - cardiomyopathy.

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

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

Disorders from the liver and bile ducts: often - increased blood levels of hepatic enzymes and bilirubin concentrations; rarely - liver damage, such as severe hepatomegalia with steatosis.

Disturbances from the skin and subcutaneous tissues: infrequent - rash, 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 - a 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. However, there are limited data on the consequences of an acute overdose of lamivudine and zidovudine. None of these cases ended in a fatal outcome, the condition of all patients was normalized.No specific signs or symptoms were described.

Treatment: in case of an overdose, it is recommended to monitor the patient's condition for the timely detection of signs of intoxication and to conduct standard maintenance therapy. Because the lamivudine is derived by dialysis, continuous hemodialysis can be used for overdose, however, there is no relevant clinical experience yet. Apparently, hemodialysis and peritoneal dialysis are ineffective for excretion of zidovudine from the body, but these methods accelerate the elimination of its metabolite (glucuronide).

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 is metabolized and binds to blood plasma proteins, and the drug is almost completely excreted by the kidneys in an 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 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. The combined 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 may inhibit intracellular phosphorylation of zalcitabine while taking these drugs simultaneously. Therefore, it is not recommended to use 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, clinical significance is not known.

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, the pharmacokinetic data indicate that,that atovahon reduces the degree of zidovudine metabolism to its glucuronide (in the equilibrium state AUC zidovudine increases by 33%, C_m_Oh in the blood plasma 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 atovahona, 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. Observe the interval between clarithromycin and zidovudine 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 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

But to some data, probenecid increases the average 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 both stavudine and the drug is not recommended Zidovudine + Lamivudine.

Didanosine

The interaction has not been studied. No dose adjustment is 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-glucuronyl transferase (UDF-HT)). Since 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 leads 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, inosine, pranobeks are able to alter the metabolism of zidovudine as a result of competitive inhibition of the glucuronization process or direct suppression of metabolism zidovudine microsomal enzymes of the liver. Before the appointment of these drugs in combination with the drug Zidovudine + Lamivudine, especially for long-term treatment, it is necessary to evaluate the possible drug interaction.

Simultaneous use, especially for the treatment of acute conditions, zidovudine and potentially nephrotoxic or myelosuppressive drugs (eg, systemic administration 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 indicators 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. The simultaneous use of such drugs with zidovudine 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 (the latter is usually secondary to neutropenia) in patients receiving zidovudine. These phenomena are more often observed when zidovudine is administered in high doses (1200-1500 mg / day) in patients with advanced 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 developed clinical it is recommended to monitor blood levels at least once every 2 weeks during the first 3 months of therapy, and then at least once a month. In patients with 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 patients, for example, 1 time in 1-3 months. A special dose of zidovudine may be required if severe anemia or myelosuppression develops during treatment with the drug, as well as in patients with previous bone marrow suppression, for example, hemoglobin concentration less than 9 g / dL (5.59 mmol / L) or neutrophil count less than 1.0^x 10 / l. Because the individual dose of the drug Zidovudine + Lamivudine 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 a patient experiences abdominal pain, nausea, vomiting, or an increase in 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 / 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. Clinical signs of developing lactic acidosis are general weakness, anorexia, rapid unexplained weight loss, symptoms of gastrointestinal tract damage (nausea, vomiting, abdominal pain) and respiratory system (rapid and / or deep breathing), neurological symptoms (including motor weakness).

Treatment with analogues of nucleosides should be discontinued in case of development of symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis, 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 the duration of antiretroviral therapy play an important, possibly synergistic role in the development of this complication.

The long-term consequences of these undesirable reactions are currently unknown. During the clinical examination of patients, attention should be paid to the signs of redistribution of subcutaneous fat. It is necessary to closely monitor the serum lipids concentration and blood glucose concentration. If the lipid metabolism is disturbed, an appropriate treatment is prescribed.

Immunodeficiency Syndrome

In the presence of HIV-infected patients with severe immunodeficiency 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 mycobacterial infection 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 hepatic samples and regularly determine the level of replication of viral hepatitis B for 4 months.

In patients with initially existing impairments of liver function, including an active form of chronic hepatitis, there is an increase in the incidence of liver function abnormalities in combination antiretroviral therapy. 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 a worsening of liver disease in such patients.

Co-infection of HIV and viral hepatitis C

The aggravation of anemia was observed with the combined administration 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 safety and effectiveness of zidovudine have not been established in patients with severe concomitant liver disease. Patients with chronic hepatitis B or C receiving combination antiretroviral therapy are at increased risk of developing serious and potentially leading to the death of unwanted reactions from the liver. 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,impaired behavior). Whether neurological disorders are transient or persistent is currently unknown. Any child, even HIV-negative, who has undergone intrauterine exposure to nucleoside and nucleotide analogues, must undergo a clinical and laboratory examination in order to exclude mitochondrial dysfunction in case of revealing the relevant signs or symptoms. The data described do not affect the current national 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 lamivudine and zidovudine on the ability to drive and work withtechnique. 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 zidovudine and lamivudine, should be taken into account.

Form release / dosage:

Tablets coated with a film membrane 300 mg + 150 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30, 60 tablets in a polymer can for drugs from polyethylene terephthalate with a lid of polypropylene.

By 3, 6 contour cellular packs or 1 bank polymer for medicines together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C in the manufacturer's packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004307

Date of registration:22.05.2017

Expiration Date:22.05.2022

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Information update date: & nbsp22.06.2017

Illustrated instructions

Instructions

Zidovudine + Lamivudine (Zidovudine + Lamivudine)