Virocomb - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline (PH 102) - 258.75 mg, sodium carboxymethyl starch - 30 mg, silicon dioxide colloid - 3.75 mg, magnesium stearate 7.5 mg.

Composition of the tablet shell: Opadrai 03H58900 white - 15 mg.

Components Odpadray 03H58900 white: hypromellose - 63.65%, titanium dioxide - 30.05%, propylene glycol - 6.3%.

Description:

From white to almost white, oblong biconvex tablets covered with a film sheath, engraved with "RX923" on one side.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

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

Pharmacodynamics:

Lamivudine and zidovudine are highly effective selective inhibitors of HIV-1 and HIV-2. Lamivudine is a synergist of zidovudine against the suppression of HIV replication in cell culture. Both drugs 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, resulting in a chain break. Triphosphates of lamivudine and zidovudine have a much lower affinity for DNA polymerases of human cells.

In vitro lamivudine demonstrates low cytotoxicityin relation to lymphocytic and monocyte-macrophage colony and to a number of precursor cells of the red bone marrow. In this way, lamivudine has a wide therapeutic index.

In clinical trials, the combination of lamivudine and zidovudine led to a reduction in HIV-1 load and an increase in 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 progression of morbidity 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 combination therapy with lamivudine and zidovudine delayed the occurrence of zidovudine-resistant strains in patients who had not previously received antiretroviral therapy (APT).

Combination therapy with lamivudine and zidovudine is widely used as an APT component in conjunction with other antiretroviral drugs of the same class (NRTIs) or other classes (HIV protease inhibitors [IP], nucleoside reverse transcriptase inhibitors [NNRTIs]).

Prevention of infection:

International guidelines recommend the use of a combination of lamivudine and zidovudine within 1-2 hours after exposure to HIV-infected blood (for example, after a needle prick). In the case of a high risk of infection, HIV protease inhibitors should also be included in the prevention regimen. The course of antiretroviral prophylaxis should be 4 weeks. Despite the immediate treatment, seroconversion can still occur.

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

Pharmacokinetics:

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 oral administration, the maximum concentrations of lamivudine and zidovudine were observed after 1.02 h and 0.58 h and were 2.0 μg / ml and 2.3 μg / ml, respectively. For lamivudine, the values of AUC_0-t(Area of the pharmacokinetic curve) 7.6 μg x h / ml, AUC_0-∞ 7.8 μg x h / ml. For zidovudine, the values of AUC_0-t2.6 μg x h / ml, AUC_0-∞ 2.6 μg x h / ml.

The volume distribution of lamivudine and zidovudine is 1.3 and 1.6 l / kg, respectively.In lamivudine, the association with plasma proteins is 35%, in zidovudine 34-36%. Thus, the interaction of lamivudine and zidovudine with other drugs through the replacement of protein bonds is unlikely.

Determined that lamivudine and zidovudine penetrate into the central nervous system (central nervous system) and cerebrospinal fluid.

2-4 hours after oral administration, the ratio between the concentration of lamivudine and zidovudine in the cerebrospinal fluid and in serum is on average 0.12 and 0.5, respectively.

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%) with the formation of an inactive metabolite of transulfoxide and a low binding to plasma proteins. Metabolised in cells before the formation of 5-triphosphate.

The main metabolite of zidovudine in plasma and urine is 5'-glucuronide, with approximately 50-80% of the administered dose of zidovudine excreted by renal excretion. Z'-Amino-ZDecoxytimidine is detected in the urine after intravenous administration.

Half-life (T_1/2) lamivudine - 5-7 hours.The systemic clearance of lamivudine is 0.32 l / h / kg. 70% of lamivudine is excreted by the kidneys with the participation of the cationic transport system, 10% - by the liver.

Half-life (T_1/2) zidovudine - 1.1 hours. Systemic clearance of zidovudine - 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.

Pharmacokinetic parameters in special groups of patients.

Patients of advanced age. The pharmacokinetics of lamivudine and zidovudine in patients older than 65 years has not been studied.

Children. In children older than 5-6 months, the pharmacokinetic parameters of zidovudine are similar to those in adults. Zidovudine well absorbed from the intestine after administration in all studied doses in adults and children; its bioavailability is 60-74%, on average 65%. The maximum concentration in the equilibrium state is 4.45 μmol (1.19 μg / ml) after ingestion of 120 mg / m² zidovudine in the form of a solution 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 (AUC₂₄10.7 μg x h / ml), as well as the dose of 200 mg / m² 6 times a day in adults (AUC₂₄ 10.9 μg x h / ml).

In a study of six HIV-infected children aged 2 to 13 years, the pharmacokinetics of zidovudine after administration of 120 mg / m² 3 times a day and after switching to a dose of 180 mg / m² 2 times a day. Systemic exposure (AUC and C_max) in the 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%) has been 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 AUC₀_-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. With renal failure due to reduced renal clearance, excretion of lamivudine is impaired. Reduction of the dose of lamivudine is recommended in patients with creatinine clearance less than 50 ml / min. The concentration of zidovudine in plasma also increases in patients with severe renal failure.

Patients with impaired liver function. Decreased glucuronuclease due to cirrhosis of the liver may result in the cumulation of zidovudine. Dose correction is required in patients with severe hepatic impairment.

Pregnancy. In pregnancy, the pharmacokinetics of lamivudine and zidovudine does not change. 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:

Treatment of HIV infection in adults and children over 12 years with progressive immunodeficiency (CD4 content⁺-cells less than 500 in 1 mm³).

Used in combination antiviral therapy.

Contraindications:

Hypersensitivity to lamivudine, zidovudine or any other component of the 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).

Children under 12 years of age with a body weight of less than 30 kg (due to the impossibility of dosing this dosage form).

Pregnancy and lactation:

It is not recommended to use Virocomb in the first trimester of pregnancy, unless the expected benefit for the mother does not exceed the possible risk to the fetus.

It was shown that zidovudine treatment of pregnant women and the subsequent introduction of this drug to newborns reduces the frequency of HIV transmission from mother to fetus. There is no such data regarding lamivudine. Consequently, the drug Virocombe can be given to pregnant women only when the expected benefit to the mother exceeds the possible risk to the fetus.

Women who take Virocomb are not recommended to breastfeed.

In newborns and infants who were exposed in utero or during the period of birth to nucleoside reverse transcriptase inhibitors, a slight transient increase in lactate in the blood was noted. There are also rare reports of cases of developmental delay, convulsive seizures and other neurotic pathology. The causal relationship between the onset of these pathological conditions and the intake of nucleoside reverse transcriptase inhibitors during pregnancy has not been established. In general, in children whose mothers received nucleoside reverse transcriptase inhibitors during pregnancy, the benefits of reducing the risk of vertical HIV transmission are clearly greater than the risk,associated with the side effects of these drugs.

Dosing and Administration:

The drug Virocombe is taken orally regardless of the meal. To ensure the accuracy of dosing, the tablets must be swallowed whole. Those patients who have difficulty in swallowing are encouraged to grind 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 over 12 years of age with a body weight of at least 30 kg: 1 tablet 2 times a day.

In those cases where it is necessary to reduce the dose of Virocomb or to cancel one of its components (lamivudine or zidovudine), it is possible to use separate preparations of lamivudine and zidovudine.

Application in children: Virocomb is not indicated for children under 12 years of age with a body weight of less than 30 kg. Doctors should be guided by information on the use of lamivudine and zidovudine.

Use in elderly patients: There are no specific data on the use of Virocomb in elderly people. However, in the treatment of elderly patients, special care should be taken, taking into account age-related changes, changes in blood counts and impaired renal function.

Application for renal failure: in patients with renal insufficiency, concentrations of lamivudine and zidovudine in the blood are increased, due to a slowing of their elimination. Patients with impaired renal function (creatinine clearance less than 50 ml / min) in a number of cases it is necessary to individually select the dose of lamivudine and zidovudine, so they are recommended to prescribe lamivudine and zidovudine apart.

Application for violations of liver function: with hepatic insufficiency, cumulation of zidovudine may be noted as a result of a delay in binding it to glucuronic acid. In patients with severe liver function impairment, it is recommended that lamivudine and zidovudine separately to select a dose of zidovudine.

Use in patients with hematologic side effects: with severe anemia (hemoglobin content less than 9 g / dl or 5.59 mmol / L) or neutropenia (neutrophil count less than 1.0х10⁹/ l), a dose adjustment of zidovudine may be required. The likelihood of these side effects is higher in patients with a reduced reserve of bone marrow before the start of therapy, especially in patients with advanced HIV infection.

Since the appointment of Virocombe can not individually select the dose of lamivudine and zidovudine, it is recommended to use separate preparations of lamivudine and zidovudine.

Side effects:

Treatment of HIV infection with lamivudine and zidovudine in the form of monotherapy or as a combination of these drugs can cause side effects. For many side effects, it is not known whether they are caused by lamivudine, zidovudine, a wide range of other drugs used to treat HIV infection, or are a consequence of the disease itself. Virocomb can cause side effects, characteristic of zidovudine and lamivudine. However, at present there is no data on that. that the combination of lamivudine and zidovudine has additive toxicity.

On the frequency side effects were divided into the following categories: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥ 1/1000 and <1/100), rarely (≥1 / 10000 and <1/1000), the frequency is unknown (<1/10000).

Lamivudine

From the system of blood and blood-forming organs

Infrequent: neutropenia, thrombocytopenia, anemia. The frequency is unknown: true erythrocytic aplasia.

From the endocrine system and metabolism

Often: hyperlactatemia. Rarely: lactic acidosis. Redistribution / accumulation of adipose tissue. The frequency of this side effect depends on many factors, including the specific combination of antiretroviral drugs.

From the respiratory system

Often: cough, nasal symptoms.

From the central nervous system

Often: headache, insomnia. Frequency unknown: paresthesia; there are reports of peripheral neuropathy, however, its association with lamivudine is not clear.

From the gastrointestinal tract

Often: nausea, vomiting, epigastric pain, diarrhea. Rarely: pancreatitis, whose association with lamivudine treatment is not established. Increased activity of serum amylase.

From the liver and biliary tract

Infrequently: transient increase in hepatic enzyme activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT). Rarely: hepatitis.

From the skin and subcutaneous fat

Often: rash, alopecia, allergic reactions. Rarely: angioedema.

From the musculoskeletal system and connective tissue

Often: arthralgia, muscular lesions. Rarely: rhabdomyolysis.

General and local reactions

Often: fatigue, general malaise, fever.

Zidovudine

From the system of blood and blood-forming organs

Often: anemia (blood transfusion may be required), neutropenia and leukopenia. These side effects often occur with high doses of zidovudine (1200-1500 mg per day), in patients with advanced HIV infection (especially with a reduced bone marrow reserve before treatment) and with a CD4 cell count of less than 100 in 1 mm³. In such cases, sometimes it is necessary to reduce the dose of zidovudine or to cancel it. Neutropenia occurs more often in those patients whose neutrophil count, hemoglobin content, and vitamin B content₁₂in the serum lowered before starting treatment with zidovudine. Infrequent: thrombocytopenia and pancytopenia (with bone marrow hypoplasia). Rarely: true erythrocytic aplasia. Frequency unknown: aplastic anemia.

From the endocrine system and metabolism

From the central nervous system

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

Mental disorders Rarely: anxiety, depression.

From the side of the cardiovascular system

Rarely: cardiomyopathy.

On the part of the respiratory system, the organs of the thorax and the mediastinum

Infrequent: shortness of breath. Rarely: cough.

From the gastrointestinal tract

Very often: nausea. Often: vomiting, abdominal pain and diarrhea. Infrequent: flatulence. Rarely: pigmentation of the oral mucosa, changes in taste sensations (dystevia), dyspepsia, pancreatitis, anorexia.

From the liver and biliary tract

Often: increased activity of hepatic transaminases and bilirubin concentrations. Rarely: such liver damage as severe hepatomegaly with steatosis.

From the skin and subcutaneous fat

Infrequent: rash and itching. Rarely: pigmentation of nails and skin, hives and sweating.

From the musculoskeletal system and connective tissue

Often: myalgia. Infrequent: myopathy.

From the urinary system

Rarely: frequent urination.

From the side of the reproductive system and mammary glands

Rarely: gynecomastia.

General and local reactions

Often: general malaise. Infrequently: fever, generalized pain syndrome, asthenia, bronchial asthma. Rarely: chills, chest pain and flu-like syndrome.

Zidovudine + Lamivudine

From the side of the musculoskeletal system

The frequency is unknown: myalgia. myopathy.

Allergic reactions

The frequency is unknown: angioedema, anaphylactic reactions.

Metabolic disorders

The frequency is unknown: hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia.

Laboratory indicators

The frequency is unknown: increased activity of creatine phosphokinase, lactate dehydrogenase.

If any of these effects are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

None of the cases of an overdose of zidovudine or lamivudine did not end in a lethal outcome, and the condition of all patients was normalized. No specific signs or symptoms were recorded.

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. Lamivudine is derived by dialysis, so when overdosing can be used continuous hemodialysis. Hemodialysis and peritoneal dialysis are ineffective when removing zidovudine from the body, but accelerate the elimination of its metabolite (glucuronide).

Interaction:

Because the Virocomb contains lamivudine and zidovudine, it can enter into any interactions that are characteristic of each of its components. The likelihood of metabolic interactions with lamivudine is low, since it is almost completely excreted by the kidneys and only in small amounts is exposed to hepatic metabolism and binds to plasma proteins. The relationship of zidovudine to plasma proteins is also low, but it is subject to preferential metabolism in the liver with the formation of an inactive glucuronide.

Drugs with a predominant hepatic metabolism, especially through glucuronization, can potentially inhibit zidovudine metabolism.

The drugs listed below should be used with caution in the face of Virocomb therapy.

Interaction with lamivudine

Lamivudine is mainly excreted by the cationic transport system, therefore, it is necessary to remember the possibility of interaction of the drug Virocomb with drugs that have the same pathway.

Interaction with trimethoprim. Simultaneous reception of lamivudine and trimethoprim (one of the components of the drug co-trimoxazole) leads to an increase in the concentration of lamivudine in plasma by 40%. Patients with normal renal function are not required to individually select a dose of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. Caution should be exercised while using co-trimoxazole and Virocomb in patients with renal insufficiency.

Interaction with zalcitabine. Lamivudine can inhibit intracellular phosphorylation of zalcitabine with simultaneous administration. Thus, it is not recommended to use the drug Virocomb in combination with zalcitabine.

Interaction with didanosine, fluconazole, phenobarbital, valproic acid, ranitidine. The clinical significance of the interaction is unknown in connection with the limited data. Correction of doses of the drugs used is not required.

Interaction with cladribine. Lamivudine in vitro inhibits intracellular phosphorylation of cladribine, which can lead to a decrease in the efficiency of cladribine. Clinical evidence supports the possibility of such interaction. The simultaneous use of the drug Virocombe and cladribine is not recommended.

Interactions involving zidovudine

Simultaneous reception of zidovudine and lamivudine leads to an increase of 13% in the duration of zidovudine and an increase of 28% in its maximum plasma concentration. It is believed that such an increase is not a danger to patients.

Zidovudine does not affect the pharmacokinetics of lamivudine.

Nucleoside analogs that violate 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 mutual weakening of activity of each of the drugs in vitro.

Interaction with atovahona. 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 area under the zidovudine pharmacokinetic curve (AUC) increases by 33%, the maximum plasma glucuronide concentration decreases 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.

Interaction with clarithromycin. With simultaneous reception of clarithromycin tablets, the absorption of zidovudine is reduced. Observe the interval between clarithromycin and zidovudine at least 2 hours.

Interaction with 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. It is necessary to monitor the concentration of phenytoin in the blood in patients in the case of combined use of Virocomb and phenytoin.

Interaction with paracetamol. The combination of paracetamol and zidovudine was accompanied by an increase in the frequency of neutropenia, especially with prolonged therapy. But, paracetamol in therapeutic doses does not cause an increase in the plasma concentration of zidovudine and its glucuronide.

Interaction with probenecid. According to some data, probenecid increases the mean half-life of zidovudine and the area under the pharmacokinetic curve (AUC) as a result of suppression of the formation of glucuronide. In the presence of probenecid, renal excretion of glucuronide and, possibly, zidovudine itself decreases.

Interaction with rifampicin. Limited data show that when zidovudine and rifampicin are combined, the area under the zidovudine pharmacokinetic curve (AUC) decreases from 48% to 34%. However, the clinical significance of this observation is unknown.

Interaction with stavudine. Zidovudine can inhibit the intracellular phosphorylation of stavudine during their simultaneous administration. Thus, concomitant use of a combination of stavudine and the drug Virocomb is not recommended.

Acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, inosine pranobex and some other medications can alter the metabolism of zidovudine as a result of competitive inhibition of the synthesis of its metabolite (glucuronide) or direct suppression of zidovudine metabolism by microsomal enzymes of the liver. Before prescribing these drugs in combination with Virocomb, especially when planning long-term treatment, it is necessary to evaluate possible drug interactions.

With the simultaneous use of zidovudine and potentially nephrotoxic or myelosuppressive drugs (eg, systemic administration of pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin B, flucytosine, ganciclovir, interferon alfa, vincristine, vinblastine and doxorubicin), the likelihood of side effects the effects increase, so you should carefully monitor the kidney function and blood counts and, if necessary, reduce the dose of drugs.

When receiving Virocomb, some patients can develop infections caused by opportunistic microorganisms. To prevent these infections use cotrimoxazole, pentamidine in the form of an aerosol, pyrimethamine and acyclovir.

A few 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.

Interaction with didanosine, ranitidine. The clinical significance of the interaction is unknown in connection with the limited data. Correction of the dose is not required.

Interaction with fluconazole. With simultaneous application of fluconazole 400 mg once daily and zidovudine 200 mg 3 times daily, the area under the zidovudine pharmacokinetic curve increases by 74% due to inhibition of uridine diphosphate-glucuronosyltransferase. When zidovudine and fluconazole are used concomitantly, observation is recommended to detect symptoms of zidovudine toxicity.

Interaction with phenobarbital. Phenobarbital with simultaneous use slightly reduces the concentration of zidovudine in plasma due to the induction of uridine diphosphate-glucuronosyltransferase. Data indicating the need for dose adjustment is not enough.

Interaction with valproic acid. With the simultaneous use of valproic acid 250-500 mg 3 times a day and zidovudine 100 mg 3 times a day, the area under the zidovudine concentration-time pharmacokinetic curve increases by 80% by inhibiting uridine diphosphate glucuronosyltransferase. When zidovudine and valproic acid are used concomitantly, observation is recommended to detect symptoms of zidovudine toxicity.

Special instructions:

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

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

Despite the use of Virocomb 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 Virocomb, 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.

Patients in the late stages of HIV infection receiving zidovudine, there is a high probability of anemia, neutropenia and leukopenia (the latter is usually secondary to neutropenia). Therefore, during the treatment with Virocomb, careful monitoring of blood counts is necessary.

Changes in blood counts usually appear no earlier than 4-6 weeks after the start of therapy. In patients with advanced 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 with early stage of HIV infection, hematological side effects are rare, so blood tests can be prescribed less frequently, focusing on the general condition of patients, for example, once every 1-3 months.With a decrease in hemoglobin by more than 25% or a decrease in the number of neutrophils by more than 50% compared to baseline, blood tests should be performed more often.

A special dose of zidovudine may be required if severe anemia or myelosuppression develops during treatment with Virocomb, as well as in patients with previous bone marrow suppression, for example, with a hemoglobin content of less than 9 g / dl (5.59 mmol / L) or neutrophil count less than 1,0х10⁹/ l. Since it is not possible to individually select a dose of Virocomb, it is recommended to apply lamivudine and zidovudine separately.

In patients who took lamivudine and zidovudine, rare cases of development of pancreatitis are described. However, it is not established whether the ego is caused by a complication of drugs or HIV infection itself. Treatment with Virocomb should be stopped immediately if clinical or laboratory signs of pancreatitis appear.

Lactate acidosis. In patients who took zidovudine, rare, but severe cases of lactic acidosis without hypoxia with a possible fatal outcome and pronounced hepatomegaly with fatty liver dystrophy are described.Lactate acidosis may be associated with pancreatitis, hepatic or renal insufficiency. It is not known whether these complications are associated with treatment with zidovudine. as they were observed in HIV-infected patients without clinical manifestations of HIV infection. Early symptoms of lactic acidosis include nausea, vomiting, abdominal pain, malaise, loss of appetite, weight loss, rapid and / or deep breathing, and neurologic symptoms (muscle weakness). With rapid growth of aminotransferase activity, progression of hepatomegaly, metabolic acidosis or lactate acidosis of unknown etiology, treatment with Virocomb should be discontinued. Care must be taken when treating patients with hepatomegaly, hepatitis, or with risk factors predisposing to liver damage, especially when prescribed for women with obesity. It is necessary to closely monitor the condition of these patients during treatment with Virocomb.

Redistribution / accumulation of adipose tissue. In some patients receiving combined antiretroviral therapy, there is a redistribution / accumulation of adipose tissue with fat deposition in the region of spinous processes of 6-7 cervical vertebrae, thinning of limbs and face, enlargement of the mammary glands,increased concentration of serum lipids and blood glucose.

All drugs related to HIV protease inhibitors and nucleoside reverse transcriptase inhibitors can cause the above symptoms of lipodystrophy.

It should also be noted that lipodystrophy syndrome has a multifactorial etiology. The stage of HIV infection, the elderly age and the duration of antiretroviral therapy play an important role in its development, possibly as synergists. The long-term effects of lipodystrophy are unknown. When clinically examining patients, it is necessary to pay attention to the presence of symptoms of redistribution of adipose tissue. Serum lipid and blood glucose concentrations should be measured.

Syndrome of restoration of immunity. At the beginning of antiretroviral treatment of HIV-infected patients with severe immunodeficiency, inflammatory reactions and residual opportunistic infections can develop, which sometimes leads to serious clinical consequences or increased symptoms.

Typically, such reactions are observed during the first weeks or months after initiation of antiretroviral therapy.

In conditions of immune reconstitution syndrome, autoimmune diseases (eg, Graves' disease) can develop at different times, sometimes several months after the start of treatment.

Diseases of the liver. The safety and efficacy of zidovudine have not been established in patients with significant impairment of liver function.

Concomitant Hepatitis B. After the withdrawal of lamivudine in patients with hepatitis B, monitoring of liver function and hepatitis B replication markers is recommended, since the withdrawal of lamivudine can lead to a sharp deterioration in the course of hepatitis.

In patients with impaired hepatic function, including chronic active hepatitis, caution should be exercised when using a combination of antiretroviral drugs and monitor liver function according to standard practice. In the case of impaired liver function, consideration should be given to interrupting or abolishing antiretroviral therapy.

Concomitant hepatitis C. In vitro studies have shown that ribavirin can reduce the phosphorylation of analogues of pyrimidine nucleosides of lamivudine and zidovudine.Although data on the pharmacokinetic and pharmacodynamic interaction of ribavirin with lamivudine and zidovudine are not available, there have been cases of decompensated liver function (sometimes fatal) in patients infected with HIV-1 with concomitant hepatitis C receiving antiretroviral therapy for HIV-1 and interferon alfa with ribavirin or without ribavirin. Patients receiving virocomb and alpha interferon with ribavirin or without ribavirin should be carefully monitored for toxicity of drug interactions, especially hepatic decompensation, neutropenia, and anemia. If clinical manifestations of toxicity, especially hepatic decompensation, are exacerbated, doses should be reduced or abolished interferon alfa, ribavirin or both.

Osteonecrosis. Although the etiology of osteonecrosis is multifactorial (taking corticosteroids, alcohol abuse, severe immunosuppression, increasing body mass index), there are cases of osteonecrosis with progressive HIV infection and / or prolonged intake of antiretroviral drugs.When there is pain in the joints, joint stiffness or difficulty in moving in the joints, a doctor's examination is necessary.

Mitochondrial dysfunction. Nucleotide and nucleotide analogues are capable of damaging mitochondria to varying degrees, which can be manifested by hematological (anemia, neutropenia), metabolic (hyperlactatemia, hyperlipasia) and neurologic (muscle hypertonicity, convulsions, behavioral disorders) disorders. Such disorders are described in children with antenatal and / or postnatal receptions of nucleotide analogues. Hematologic and metabolic disorders are often transient.

Every child, regardless of the presence or absence of HIV infection, after the aerial application of nucleoside analogs, needs clinical and laboratory monitoring to identify possible mitochondrial disorders.

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

Not studied.

Form release / dosage:

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

Packaging:

60 tablets in a bottle of high-density polyethylene with a protective film of foil under a screw cap; 1 bottle with instructions for use in a cardboard box.

10 tablets in a blister of aluminum and PVC / PVDC; 6 blisters together with instructions for use in a cardboard box.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

Shelf life 2 years.

Do not use the drug after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001148

Date of registration:11.11.2011 / 13.10.2014

Expiration Date:11.11.2016

The owner of the registration certificate:Ranbaxy Laboratories LimitedRanbaxy Laboratories Limited India

Manufacturer: & nbsp

RANBAXY LABORATORIES, Ltd. India

Representation: & nbspRABBAYS LABORATORY LIMITEDRABBAYS LABORATORY LIMITED

Information update date: & nbsp19.02.2017

Illustrated instructions

Instructions

Virocomb (Virocomb)