Dizajeroks - instructions for use, doses, side effects, contraindications

Core: sodium carboxymethyl starch (primogel) 22.5 mg, pregelatinized starch 22.5 mg, silicon colloidal dioxide (aerosil grade A-300) 2.5 mg, magnesium stearate 4.5 mg, microcrystalline cellulose 78.0 mg .

Film Sheath: ready water-soluble film shell - 15.0 mg. (Shell composition: hydroxypropylmethylcellulose (hypromellose) - 25.0% copovidone (kopolividon) - 22.5%, polyethylene glycol 6000 (Macrogol 6000) - 9.5% glyceryl kaprilokaprat - 3.0%, polydextrose - 15.0% , titanium dioxide - 25.0%).

Description:

Tablets, covered with a film shell, spherical oval shape, white. On a cross-section a tablet of white or white with a yellowish shade of color.

Pharmacotherapeutic group:An antiviral [HIV] agent.

ATX: & nbsp

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

Pharmacodynamics:

Antiviral combination. Lamivudine and zidovudine are highly effective selective inhibitors of HIV-1 and HIV-2. Lamivudine is a synergist of zidovudine with respect to the drug component is sequentially metabolized by intracellular kinases to triphosphate derivatives. Lamivudine triphosphate and zidovudine triphosphate are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme. However, the antiviral activity of lamivudine and zidovudine is mainly due to the inclusion of their monophosphate form in the viral DNA chain, as a result of which a chain break occurs.Triphosphates of lamivudine and zidovudine have a much lower affinity for DNA polymerases of human cells.

Combination therapy with lamivudine and zidovudine slows the development of resistance to zidovudine in patients who have not previously received antiretroviral therapy.

Lamivudine in combination with zidovudine reduces viral load and increases the number of CD4 cells⁺. Combination therapy with lamivudine and zidovudine reduces the risk of disease progression and death.

Pharmacokinetics:

It is well absorbed from the gastrointestinal tract (in adults, bioavailability of lamivudine is 80-85%, zidovudine is 60-70%). Both components of the drug bind weakly to plasma proteins. Penetrate the central nervous system and cerebrospinal fluid. Lamivudine is excreted from the body mainly by the kidneys in an unchanged form. The half-life (T1 / 2) is 5-7 hours. Zidovudine is metabolized in the liver, where conjugation with glucuronic acid takes place. It is excreted by the kidneys mainly in the form of glucuronide. T1 / 2 zidovudine is about 1 hour.

Special patient groups

Older patients: pharmacokinetics were not investigated 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 64-70%, on average 65%. The maximum concentration in the equilibrium state is 4.45 μM (1.19 μg / ml) after taking 120 mg / m zidovudine in the form of a solution and 7.7 μM (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 (area under the concentration-time curve from 0 to 24 hours after taking the drug (AUC₂₄) is 10.7 × μg / ml), as is the administration of 200 mg 6 times daily in adults (AUC₂₄ 10.9 μg / ml).

In general, the pharmacokinetics of lamivudine in children is similar to the pharmacokinetics in adult patients. However, absolute bioavailability (approximately 55-56%) 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^xh / 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 the decrease in renal clearance, excretion of lamivudine is impaired in renal failure. Reduction of the dose of lamivudine is recommended in patients with creatine clearance of 50 ml / min. The concentration of zidovudine in plasma also increases in patients with severe renal failure.

Impaired liver 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 renal failure.

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

Indications:

HIV infection in children older than 12 years and adults with progressive immunodeficiency (number CD4 + cells less than 500 / μL).

Contraindications:

Hypersensitivity to zidovudine and lamivudine and to other components of the drug, the number of neutrophils (less than 750 / μl), anemia (hemoglobin less than 7.5 g / dl or 4.65 mmol / l), children under 12 years of age and body weight less than 30 kg, lactation period.

Carefully:

Hepatomegaly, hepatitis, liver cirrhosis, obesity, risk factors predisposing to liver damage.

Pregnancy and lactation:

Dystavorox can be prescribed to pregnant women only in those cases when the expected benefit for the mother exceeds the possible risk to the fetus. Women who take the drug are not recommended to breastfeed.

Dosing and Administration:

Inside, regardless of food intake for adults and children over 12 years of age and with a body weight of at least 30 kg, 1 tablet 2 times a day.

In chronic renal failure (with creatinine clearance less than 50 ml / min), liver failure, hemoglobin concentration less than 9 g / dL or 5.59 mmol / L, neutropenia below 1 thousand / μL, it is necessary to apply lamivudine and zidovudine in the form of individual drugs to individually choose a dose of lamivudine and zidovudine.

Children weighing less than 30 kg

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

Older patients: specific data on the use of the drug

Dystavorox in the elderly is not. However, in the treatment of elderly patients, special care should be taken, taking into account age-related changes, for example, changes in hematologic parameters and renal dysfunction.

Side effects:

The undesirable reactions described below were noted in the treatment of HIV infection with lamivudine and zidovudine in the form of monotherapy or as a combination of these drugs. For many unwanted reactions, it is unclear whether they are caused by lamivudine, zidovudine, a wide range of other drugs used to treat HIV infection, or are complications of the actual HIV infection.

The composition of the drug Dizajerok includes lamivudine and zidovudine, and therefore it can cause side effects, characteristic of each of these components. At present, there is no evidence that the combination of lamivudine and zidovudine has additive toxicity.

The following classification of undesirable reactions is used depending on the frequency of occurrence: very often (> 1/10), often (> 1/100 or <1/10), infrequently (> 1/1000 and <1/100), rarely (> 1 / 10,000 and <1/1000), very rarely (<1/10000 including individual cases).

Lamivudine

From the hematopoietic and lymphatic system:

Infrequently: neutropenia, anemia, thrombocytopenia. Rarely: true erythrocyte aplasia.

From the side of metabolism and nutrition:

Often: hyperlactatemia. Rarely: lactic acidosis.

From the nervous system:

Often: headache. Rarely: paresthesia, peripheral neuropathy.

From the gastrointestinal tract:

Often: nausea, vomiting, epigastric pain, diarrhea. Rarely: pancreatitis, increased serum amylase activity.

From the liver and bile ducts:

Infrequently: transitional increase in the activity of hepatic enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)). Rarely: hepatitis.

From the skin and subcutaneous fat: rash, alopecia.

From the osteomuscular system and connective tissue:

Often: arthralgia, muscle disorders. Rarely: rhabdomyolysis.

Other:

fatigue, fever, general malaise, redistribution / accumulation of subcutaneous fat.

Zidovudine

From the hematopoietic and lymphatic system:

Often: anemia (blood transfusion may be required), neutropenia and leukopenia. Infrequently: thrombocytopenia and pancytopenia (with bone marrow hypoplasia). Rarely: true erythrocyte aplasia. Rarely: aplastic anemia.

From the side of metabolism and nutrition:

Often: hyperlactatemia. Rarely: lactic acidosis, anorexia.

From the side of the psyche:

Rarely: anxiety, depression.

From the nervous system:

Often: headache. Often: dizziness. Rarely: insomnia, paresthesia, drowsiness, decreased mental activity, convulsions, confusion.

From the cardiovascular system:

Rarely: cardiomyopathy.

From the respiratory system, chest and mediastinum:

Infrequently: dyspnea. Rarely: rhinitis, sinusitis, cough.

From the gastrointestinal tract:

Often: nausea, vomiting, stomach pain, diarrhea. Infrequently: flatulence. Rarely: pigmentation of the oral mucosa, taste distortion, dyspepsia, pancreatitis.

From the liver and bile ducts:

Often: increased activity of hepatic enzymes and bilirubin concentrations. Rarely: liver damage, such as severe hepatomegaly with stenosis.

From the skin and subcutaneous fat:

Infrequently: rash and itching. Rarely: pigmentation of nails and skin, urticaria and excessive sweating.

From the osteomuscular system and connective tissue:

Often: myalgia. Infrequently: myopathy.

From the side of the kidneys and urinary tract:

Rarely: frequent urination.

On the part of the reproductive system and mammary glands:

Rarely: gynecomastia.

Other:

general malaise, fever, generalized pain syndrome and asthenia, chills, chest pain and flu-like syndrome, redistribution / accumulation of subcutaneous fat.

Overdose:

Symptoms: no specific dose-dependent symptoms were detected in acute overdose of lamivudine or zidovudine except those listed in the "Side effect" section.

Treatment: it is recommended to monitor the patient's condition and standard maintenance therapy, continuous hemodialysis.

Interaction:

Since the drug Dystavorox contains lamivudine and zidovudine, it can enter into any interactions characteristic of each of the components. The likelihood of metabolic interactions with lamivudine is low, since only a small part of the injected drug undergoes metabolism and binds to plasma proteins, and the drug is almost completely excreted by the kidneys in an unchanged form.

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

Listed below are some medicines that represent classes of drugs that must be used with caution in the face of Diaverox therapy.

Interactions involving lamivudine

Lamivudine is mainly excreted by means of a cationic transport system, therefore, it should be remembered about the possibility of interaction of the drug Dizajeroks with drugs having the same route of excretion.

Trimethoprim / sulfamethoxazole: simultaneous administration of lamivudine and a combination of trimethoprim and sulfamethoxazole (160 mg +800 mg, co-trimoxazole) leads to an increase in plasma lamivudine concentration by 40% when administered in therapeutic doses. However, patients with normal renal function are not required to adjust the dose of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Caution should be exercised while using co-trimoxazole and the drug Dystarox in patients with renal insufficiency. The effect of co-administration of lamivudine and high doses of cotrimoxazole for the treatment of pneumocystis pneumonia and toxoplasmosis has not been studied.

Zalcitabine: lamivudine can inhibit intracellular phosphorylation of zalcitabine with simultaneous administration. Thus, it is not recommended to use the drug Dystavorox in combination with zalcitabine.

Interactions involving zidovudine.

Atovahon: zidovudine does not affect the pharmacokinetics of atovahona. However, pharmacokinetic data suggest that atovahon reduces the degree of zidovudine metabolism to its glucuronide (in the equilibrium state, the zidovudine AUC is increased by 33%, the maximum concentration in the plasma of glucuronide is reduced by 19%). When zidovudine is prescribed in doses of 500-600 mg / day and the concomitant 3-week course of treatment of acute pneumocystis pneumonia with atovahon, an increase in the incidence of adverse reactions associated with elevated zidovudine concentrations in plasma is unlikely.If a longer combination of the use of these drugs is required, careful monitoring of the clinical condition of the patient is recommended.

Clarithromycin: absorption of zidovudine decreases with simultaneous administration of clarithromycin tablets. The interval between zidovudine and clarithromycin should be at least 2 hours.

Lamivudine: simultaneous administration 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 plasma concentrations. However, 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 Dystoiors and phenytoin.

Probenecid: according to some data, probenecid increases the average half-life of zidovudine and AUC as a result of inhibition of the formation of glucuronide.In the presence of probenecid, renal excretion of glucuronide and, possibly, zidovudine itself decreases.

Rifampicin: limited data show that when zidovudine and rifampicin are combined, the zidovudine AUC decreases by 48 ± 34 %. However, the clinical significance of this observation is unknown.

Stavudine: zidovudine can inhibit the intracellular phosphorylation of stavudine during their simultaneous administration. Thus, the combined use of stavudine and the drug Dyadorox is not recommended.

Other drugs: acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, isoprinazine can alter the metabolism of zidovudine as a result of competitive inhibition of the formation of its glucuronide. Before the appointment of these drugs in combination with the drug Dystavorox, especially for long-term treatment, it is necessary to evaluate possible drug interactions.

Combination with nephrotoxic and myelosuppressive drugs (pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucitazine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the likelihood of side effects of zidovudine. With the simultaneous administration of the drug Dystarox and any of these drugs, the kidney function and hematologic parameters should be closely monitored and, if necessary, the dose of one or more drugs should be reduced.

Ribavirin blocks the antiviral activity of zidovudine.

To prevent opportunistic infections, co-trimoxazole, pentamidine in the form of an aerosol, pyrimethamine and acyclovir. Limited data from clinical trials indicate that there is no significant increase in the incidence of side effects of zidovudine when used concomitantly with these drugs.

Special instructions:

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

Despite the use of the drug Dystarox or any other antiretroviral drug, opportunistic infections and other complications of HIV infection can develop in patients.Therefore, patients should be under constant supervision of physicians with experience in the treatment of HIV infection.

Patients should be informed that treatment with antiretroviral drugs, such as Dizajeroks, does not prevent the risk of HIV transmission to other people during sexual intercourse or transfusion of infected blood, so patients should take appropriate precautions.

It is necessary to warn patients about the possible interaction of the drug Dizajorok with other drugs at their concomitant reception.

Hematologic disorders

Possible development of anemia, neutropenia and leukopenia (the latter is usually secondary 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 with late stages of HIV infection with a reduced bone marrow reserve before the start of treatment. Therefore, in patients receiving Dizajeroks, careful monitoring of hematologic parameters is necessary. These hematologic changes usually appear no earlier than 4-6 weeks after the start of therapy.In patients with late stage clinically expressed HIV infection, blood tests are recommended to be monitored at least once every 2 weeks during the first three months of therapy, and then at least once a month.

In patients with early stage of HIV infection, side effects from the blood system are rare. Blood tests can be done less often, focusing on the general condition of patients, for example, once every 1-3 months. A special selection of zidovudine may be required if severe anemia or myelosuppression develops during treatment with Diaverox, as well as in patients with previous bone marrow suppression, for example hemoglobin concentrations less than 9 g / dl (5.59 mmol / L) or neutrophil counts less than 1, 0 x 10⁹/ l. Since it is impossible to select a dose of Diaveroks individually, it is recommended to use separate preparations of lamivudine and zidovudine.

Pancreatitis

In patients who took lamivudine and zidovudine, cases of development of pancreatitis are described. However, it is not established whether this complication is caused by drugs or the main disease - HIV infection. Treatment with the drug Dystavorox should be stopped immediately if there are clinical symptoms or laboratory data,evidence of the development of pancreatitis (abdominal pain, nausea, vomiting, or increased biochemical markers).

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (for example, taking glucocorticosteroids, drinking alcohol, acute immunosuppression, increased body mass index play an important role in the development of this complication), these cases are reported in particular in patients with progressive HIV infection / or long-term antiretroviral therapy. Patients should seek medical advice from a physician if symptoms such as lethargy, stiffness, joint pain or difficulty with movement occur.

Lactic acidosis / severe hepatomegaly with steatosis

In patients taking antiretroviral drugs - analogues of nucleosides, in the form of monotherapy or in combination, including, lamivudine and zidovudine, rare cases of lactic acidosis and severe hepatomegaly with fatty liver dystrophy are described, but with a possible fatal outcome. The majority of cases were recorded in women.

Clinical symptoms of lactic acidosis include general weakness, loss of appetite and sudden unexplained weight loss, gastrointestinal and respiratory disorders (shortness of breath and increased breathing).

Dystavorox should be used with caution in patients who have risk factors for liver damage. The drug should be stopped in patients with clinical and laboratory symptoms of lactic acidosis or hepatotoxicity (including hepatomegaly and steatosis, even in the absence of increased transaminase activity).

Redistribution of subcutaneous fat

In some patients receiving nominated antiretroviral therapy, there is a redistribution / accumulation of adipose tissue, including central obesity, dorsovissorial fat deposition ("buffalo buffalo"), weight loss of limbs and face, breast enlargement, increased serum lipid and serum levels. The listed symptoms in patients can be observed together or separately.

Although one or more of the above listed side effects associated with a common syndrome, often referred to as lipodystrophy, can cause all drugs of the classes of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), the data suggest that there are differences between individual representatives of these classes drugs in the ability to cause side effects.

It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, old age, the duration of antiretroviral therapy plays an important, possibly synergistic role.

The long-term effects of these side effects are not known at this time. Clinical examination of patients should include an assessment of the physical signs of redistribution of adipose tissue. It is necessary to determine the concentration of lipids and glucose in the blood serum. Disorders of lipid metabolism should be treated, guided by their clinical manifestations.

Mitochondrial dysfunction

In vitro and in vivo conditions, the ability of nucleotide and nucleoside analogues to cause damage to mitochondria of different degrees was revealed. There are reports of mitochondrial dysfunction in HIV-negative children who have been exposed to nucleoside analogues in utero or immediately after birth. The main manifestations of mitochondrial dysfunction, often transient, were anemia, neutropenia, hyperlactatemia and increased lipase activity in blood plasma. There were also later manifestations of this disorder: hypertonus of the muscles, convulsions, anomalies of behavior.

Immunodeficiency Syndrome

At the beginning of antiretroviral treatment of HIV-infected patients with severe immunodeficiency, inflammation may aggravate against an asymptomatic or residual opportunistic infection, which can cause serious deterioration or worsening of symptoms. Typically, such reactions are observed during the first weeks or months after initiation of antiretroviral therapy. The most significant examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumocystis pneumonia. Any symptoms of inflammation should be immediately identified and if necessary begin 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.

Patients with liver disease

In patients with previously identified liver disease (including chronic hepatitis),when combined antiretroviral therapy is used, the frequency of liver function disorders increases. The drug Dystaroks should be used with caution in this category of patients. Careful observation of patients is necessary; If signs of impaired liver function appear, consideration should be given to the possibility of reversing therapy.

Patients with chronic hepatitis B or C

The risk of hepatotoxic effect of antiretroviral drugs in patients with co-infected HIV infection and the hepatitis B or C virus is higher than in the presence of only HIV infection. Therefore, patients with chronic hepatitis B or C who simultaneously take antiretroviral drugs are at increased risk of adverse effects on the liver with possible fatal outcome. These patients should be carefully monitored, both clinically and laboratory.

Concomitant viral hepatitis B

The drug Dystaroks should be used with caution in patients infected with HIV and hepatitis B at the same time, because after the termination of lamivudine therapy, there may be clinical or laboratory signs of exacerbation of hepatitis, which can have serious consequences in decompensating liver function.After the end of therapy with the drug Dystarox in patients infected with HIV and hepatitis B virus, it is necessary to monitor biochemical parameters of liver function and markers of replication of the hepatitis B virus.

Concomitant 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 changing the regimen of antiretroviral therapy with the aim of reversing zidovudine.

Effect on the ability to drive transp. cf. and fur:

There was no special study of the effects of lamivudine and zidovudine on the ability to drive and work with machinery. Pharmacological properties of these drugs indicate a low probability of such an effect. The patient's clinical condition, as well as the side effects of lamivudine and zidovudine, should be taken into account.

Form release / dosage:

The tablets covered with a film cover, on 300мг + 150мг

Packaging:

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

For 60 or 100 tablets in a can of polymer with a cover pulled with the control of the first opening. Free space is filled with cotton wool. On cans are labeled with paper label or from polymer materials, self-adhesive.

Secondary packaging of medicinal product.

By 2, 3, 6 or 10 contour mesh packages together with the instruction for use are placed in a pack of cardboard for consumer containers.

For 1 can, along with instructions for use, are placed in a pack of cardboard for consumer containers.

Storage conditions:

In the original packaging of the manufacturer at a temperature of no higher than 25 ° C. Out of reach of children.

Shelf life:

2 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002414

Date of registration:02.04.2014

The owner of the registration certificate:FARMSINTEZ, PAO FARMSINTEZ, PAO Russia

Manufacturer: & nbsp

FARMSINTEZ, JSC Russia

Information update date: & nbsp02.04.2014

Illustrated instructions

Instructions

Dizajurks (Dizaverox)