Composition, form of production and packaging
Tablets covered with a film membrane white to almost white, biconvex, capsular form; On a cross-section of white or almost white color.
1 tab.
zidovudine 300 mg
lamivudine 150 mg
Excipients: microcrystalline cellulose - 269.6 mg, hypromellose 2910 - 16.3 mg, sodium carboxymethyl starch - 22.5 mg, silicon dioxide colloid - 2.3 mg, magnesium stearate - 5.6 mg.
Composition of the film shell: film coating - 15.3 mg, including hypromellose-2910 - 61%, titanium dioxide - 28%, macrogol - 10%, polysorbate-80 - 1%.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
Tablets covered with a film membrane white to almost white, biconvex, capsular form; On a cross-section of white or almost white color.
1 tab.
zidovudine 300 mg
lamivudine 150 mg
Excipients: microcrystalline cellulose - 269.6 mg, hypromellose 2910 - 16.3 mg, sodium carboxymethyl starch - 22.5 mg, silicon dioxide colloid - 2.3 mg, magnesium stearate - 5.6 mg.
Composition of the film shell: film coating - 15.3 mg, including hypromellose-2910 - 61%, titanium dioxide - 28%, macrogol - 10%, polysorbate-80 - 1%.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Combined antiviral drug, which includes lamivudine and zidovudine, are highly effective selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. 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 , low cytotoxicity of lamivudine has been shown for lymphocytic and monocyte-macrophage colonies and a number of red bone marrow progenitor cells. Thus, lamivudine has a wide therapeutic index.
Resistance. The resistance of HIV-1 to lamivudine is due to a mutation in the codon M184V near the active center of HIV reverse transcriptase. This strain is isolated both in vitro and in HIV-1-infected patients receiving antiretroviral regimens including lamivudine. Strains of viruses with M184V mutation show a significant decrease in sensitivity to lamivudine and show less replicative activity in vitro . Studies conducted in vitro have shown that zidovudine-resistant virus isolates may develop sensitivity to zidovudine if they acquire resistance to lamivudine. The clinical significance of this phenomenon is unclear.
Cross-resistance. Cross-sensitivity due to M184V mutation in HIV reverse transcriptase limits the use of all drugs of the class of nucleoside reverse transcriptase inhibitors (NRTIs). Zidovudine and stavudine retain their antiretroviral activity against lamivudine-resistant strains of HIV-1. Abacavir shows antiretroviral properties for lamivudine-resistant HIV-1, the resistance of which is due only to the M184V mutation. M184V mutant strains exhibit a 4-fold lower sensitivity to didanosine and zolcitabine; the clinical significance of this phenomenon is still unclear.
Resistance to thymidine analogues (such as zidovudine) is well described and correlated 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 analogues through a combination of mutations in codons 41 and 215, or by accumulation of at least four of the six mutations. These mutations against the background of the use of anatomoles thymidine alone do not cause high cross-resistance to other nucleosides, which subsequently allows the use of other approved NRTIs. There are two types of development of mutations leading to multidrug resistance, the first type - mutations of viral reverse transcriptase in codons 62, 75, 77, 116 and 151, the second type - T69S mutations with insertion into the position of 6 pairs of nitrogenous bases in this position, the emergence of phenotypic resistance to zidovudine and other NRTIs. Any of these types of mutations leading to the development of multidrug resistance severely limits the possibilities of treatment.
In clinical trials, the combination of lamivudine and zidovudine led to a decrease in HIV-1 load and an increase in 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 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 delays the emergence of zidovudine-resistant strains in patients who have not previously received antiretroviral therapy (APT). The clinical significance of the in vitro viral susceptibility to zidovudine and lamivudine is investigated. Combination therapy with lamivudine and zidovudine is widely used as an APT component in conjunction with other antiretroviral drugs from other classes (HIV progease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs)). 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 of HIV with an M184V mutation.
PHARMACOKINETICS
Absorption: lamivudine and zidovudine are well absorbed from the intestine. In adults after oral administration, the bioavailability of lamivudine is 80-85%, and of zidovudine 60-70%.
A bioequivalence study was conducted to compare a fixed combination of lamivudine / zidovudine with lamivudine (150 mg) and zidovudine (300 mg) taken alone at the same time, while the extent of absorption and the effect of food were examined. The combination of lamivudine / zidovudine is equivalent to taking lamivudine and zidovudine on an empty stomach separately.
After taking a combination of lamivudine / zidovudine, Cmax of lamivudine and zidovudine were recorded through 0.75 (0.5-2) h and 0.5 (0.25-2) h and comprised 1.5 (1.3-1.8 ) mg / ml and 1.8 (1.5-2.2) mg / ml, respectively.
The degree of absorption of lamivudine and zidovudine (based on the area under the concentration-time curve AUC) and T 1/2 after administration with food were similar to those after fasting, although the rate of absorption was somewhat slowed.
Receiving crushed tablets together with a small amount of semi-solid food or liquid does not affect the pharmacological properties of the drug and, therefore, the clinical effect. This conclusion is based on the physico-chemical and pharmacokinetic characteristics of the active substances, provided that the patient immediately takes 100% of the ground tablets.
Distribution: The average apparent volume of distribution (V d ) for lamivudine and zidovudine is 1.3 and 1.6 l / kg, respectively. Lamivudine has a linear pharmacokinetics when used in therapeutic doses and is bound to bound to albumin of blood plasma (less than 36% of serum albumin in vitro ). Zidovudine binds to plasma proteins by 34-36%. Thus, the interaction of lamivudine and zidovudine with other drugs through the replacement of protein bonds is unlikely.
It was established that lamivudine and zidovudine penetrate into the central nervous system and spinal 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.
Metabolism: lamivudine is excreted from the body mainly by the kidneys in an unchanged form. Metabolic interactions of lamivudine are unlikely because of a slight metabolism in the liver (from 5 to 10%) and low binding to plasma proteins.
Zidovudine 5'-glucuronide is the main metabolite in plasma and urine, 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.
Excretion: T 1/2 of lamivudine is 5-7 hours. The systemic clearance of lamivudine is approximately 0.32 l / h / kg, with a kidney clearance of more than 70% involving organic cations of the transport system. With intravenous administration of zidovudine, the mean T 1/2 was 1.1 hours, and the average system clearance was 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 groups
Elderly age
The pharmacokinetics of lamivudine and zidovudine has not been studied in patients older than 65 years.
Childhood
In children older than 5-6 months, the pharmacokinetic parameters of zidovudine are similar to those in adults. Zidovudine is 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 ss max) is 4.45 Ојmol (1.19 Ојg / ml) after taking zidovudine at a dose of 120 mg / m 2 body surface area in the form of a solution and 7.7 Ојmol (2.06 Ојg / ml) after taking a dose of 180 mg / m 2 body surface area. The dose of 180 mg / m 2 of body surface area 4 times / day results in the same systemic exposure in children (AUC 24 is 10.7 h * Ојg / ml), as is the dose of 200 mg / m 2 of body surface area 6 times / day in adults (AUC 24 is 10.9 h * Ојg / ml).
In a study of 6 HIV-infected children aged 2 to 13 years, the pharmacokinetics of zidovudine was evaluated after taking 120 mg / m 2 of the body surface area 3 times / day and after switching to a dose of 180 mg / m 2 body surface area 2 times / day systemic the exposure of AUC and C max in plasma was similar for a two-and three-fold dosing regimen (the daily dose was the same).
In general, the pharmacokinetics of lamivudine in children is similar to the pharmacokinetics in adult patients. However, absolute bioavailability (approximately 55-65%) was reduced in children younger than 12 years. Systemic clearance in children is higher than in adults, and is prone to decline as it grows up, reaching indicators as in adults by the age of 12. 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 * h / ml. Recent data indicate that exposure in children aged 2 to 6 years can be reduced by 30% compared with other age groups.
Impaired renal function
With renal failure, excretion of lamivudine is impaired due to reduced renal clearance. 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 insufficiency.
Impaired liver function
Decreased glucuronuclease due to cirrhosis of the liver may result in the 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 serum of the baby 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 with a body weight of at least 30 kg.
DOSING MODE
The way of application is inside.
Treatment with Zilacombe should be carried out by doctors with experience in HIV therapy.
Zilakomb can be taken regardless of food intake.
To ensure the accuracy of dosing, the tablets must be swallowed whole. For those patients who have difficulty in swallowing, it is recommended to crush the tablets with the addition of a small amount of semi-solid food or liquid. All the amount of the mixture should be taken immediately.
Adults and adolescents with a body weight of at least 30 kg of the recommended dose of Zilakomb - 1 tablet 2 times a day.
In children with a body weight of less than 30 kg , separate preparations of lamivudine and zidovudine should be used.
In cases where you need to reduce the dose of Zilacombe, reduce the dose or cancel one of its components (lamivudine or zidovudine), you can use separate preparations of lamivudine and zidovudine in dosage forms of the tablet / capsule and solution for ingestion.
Use in special patient groups
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, lamivudine and zidovudine in the form of individual drugs are recommended to be able to individually select the dose of zidovudine.
Application for violations of kidney function
In patients with renal insufficiency, concentrations of lamivudine and zidovudine in the blood are increased due to a slowing of their elimination. Since patients with impaired renal function (creatinine clearance less than 50 ml / min) in a number of cases, it is necessary to individually select the dose of lamivudine and zidovudine, it is recommended that they be given separate preparations of lamivudine and zidovudine.
Use in elderly patients
Specific data on the use of Zilacombe in elderly patients do not. 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.
Use in patients with hematologic side effects
If severe anemia (hemoglobin content less than 90 g / L or 5.59 mmol / L) or neutropenia (neutrophil count less than 1.0 * 10 9 / L), a dose adjustment of zidovudine may be required. When using the drug Zilacom, it is impossible to individually select the dose of lamivudine and zidovudine, it is recommended to use separate preparations of lamivudine and zidovudine.
SIDE EFFECT
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 underlying disease. When carrying out combined antiretroviral therapy, metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia are possible.
The composition of the drug Zilacombe includes lamivudine and zidovudine, and therefore it can cause side effects, characteristic for each of these ingredients. At present, there is no evidence that the combination of lamivudine and zidovudine has additive toxicity.
Determination of the frequency of side effects: very often (? 1/10); often (? 1/100 and <1/10); infrequently (? 1/1000 and <1/100); rarely (? 1/10000 and <1/1000); very rarely (<1/10000).
Lamivudine
Disturbances from the blood and lymphatic system: infrequently - neutropenia, anemia, thrombocytopenia; very rarely - true erythrocytic aplasia.
Disorders from the immune system: rarely - angioedema.
Disorders from the metabolism and nutrition: 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).
Disorders from the nervous system: often - headache, insomnia; very rarely paresthesia, there are reports of peripheral neuropathy, but its association with lamivudine therapy is not clear.
Disturbances from the respiratory system, chest and mediastinum: often - cough, nasal symptoms.
Disorders from the digestive tract: often - nausea, vomiting, epigastric pain, diarrhea; rarely - pancreatitis (association with treatment with lamivudine not established), increased serum amylase activity.
Disorders from the liver and bile ducts: infrequently - transient increase in the activity of liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (ACT), rarely - hepatitis.
Disturbances from the skin and subcutaneous tissues: often - rashes, alopecia.
Disorders from the musculoskeletal system and connective tissue: often - arthralgia, muscle disorders; rarely - rabdomopolis.
General disorders and disorders at the injection site: often - fatigue, general malaise, fever.
Zidovudine
Violations from the blood and lymphatic system: often - anemia (blood transfusion may be required), neutropenia and leukopenia. These side effects often occur during use of zidovudine in high doses (1200-1500 mg / day), patients with advanced HIV infection (especially with decreased bone marrow reserve prior to treatment) and in particular patients with less number of CD4 + cells 100 l, some patients need to reduce the dose of zidovudine until canceled. Neutropenia occurs more frequently in those patients whose neutrophil counts, hemoglobin concentration, and the concentration of vitamin B 12 in serum are reduced at the time of initiation of treatment with zidovudine. Infrequently - thrombocytopenia and pantsitopeiiya (bone marrow hypoplasia); rarely - pure red cell aplasia; very rarely - aplastic anemia.
Violations by the Metabolism and nutrition:often - hyperlactatemia; rarely - lactic acidosis, anorexia; redistribution / accumulation of adipose tissue (the frequency of this side effect is dependent on many factors, including the particular combination of antiretroviral drugs).
Mental disorders: rare - anxiety and depression.
Disorders of the nervous system: very often - headache; often - dizziness; rarely - insomnia, paresthesia, drowsiness, decreased mental alertness, seizures.
Violations by the organ of vision: the frequency is unknown - macular edema, amblyopia, photophobia.
Violations by the organ of hearing and labyrinth disorders: vertigo, hearing loss;
Cardio-vascular system: seldom - cardiomyopathy.
Violations of the respiratory system, organs, thoracic and mediastinal disorders: rarely - shortness of breath; rarely - cough.
Violations of the gastrointestinal tract: often - nausea; often - vomiting, abdominal pain and diarrhea, rarely - flatulence; rarely - pigmentation oral mucosa, taste perversion (dysgeusia) and dyspepsia, pancreatitis.
Disorders of the liver and biliary tract: often - increased activity "liver" enzymes and bilirubin; rarely - liver disease, such as severe hepatomegaly with steatosis.
Violations of the skin and subcutaneous tissue disorders: rare - rash, itching; rarely - pigmentation of nails and skin, rash and sweating.
Violations by the musculoskeletal system and connective tissue:often - myalgia; rare - myopathy.
Violations by the kidneys and urinary tract: rarely - frequent urination.
Reproductive system and breast: rare - a gynecomastia.
General disorders and the site of injection: often - a common ailment; rarely - fever, generalized pain and asthenia; rarely - fever, chest pain, and flu-like symptoms.
CONTRAINDICATIONS
- Zidovudine and Zilakomb contraindicated in patients with severe neutropenia (neutrophil count of less than 0.75 10? 9 / l) or anemia (hemoglobin less than 75 g / l or 4.65 mmol / l);
- hypersensitivity to lamivudine, zidovudine or to any other component of the drug.
PREGNANCY AND LACTATION
Not recommended for use Zilakomb in the first 3 months of pregnancy, except in cases where the expected benefit of therapy to the mother outweighs the possible risk to the fetus.
It is shown that treatment with zidovudine for pregnant women and subsequent administration of the drug decreases newborn HIV transmission frequency from mother to fetus. Lamivudine with respect to such data no. Consequently, Zilakomb can be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
HIV-infected patients is recommended refusal of breastfeeding to prevent HIV transmission.
In newborns and infants who are in pregnancy or during childbirth exposed NRTIs, there was a slight temporary increase in blood lactate concentration. There are also rare reports of developmental delay and seizures. In general, children whose mothers took NRTIs during pregnancy, the benefits of reducing the risk of HIV infection obviously exceeds the danger associated with the side effects of these drugs.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with renal insufficiency, the concentration of lamivudine and zidovudine in the blood increased as a result of the deceleration of their elimination. Because patients with renal impairment (creatinine clearance less than 50 mL / min) in some cases necessary to individually adjust the dose of lamivudine and zidovudine, it is recommended to assign the individual drugs lamivudine and zidovudine.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
When liver failure can be marked accumulation of AZT as a result of its slow binding with glucuronic acid. In patients with severe hepatic dysfunction is recommended lamivudine and zidovudine as separate medicines, to be able to individually select the dose of zidovudine.
APPLICATION FOR CHILDREN
The drug is contraindicated in children weighing less than 30 kg.
APPLICATION IN ELDERLY PATIENTS
Specific data on the drug Zilakomb elderly patients there. However, in the treatment of elderly patients is recommended to be very careful, taking into account age-related changes, such as changes in hematological parameters and impaired renal function.
SPECIAL INSTRUCTIONS
If necessary, the individual dose adjustment is recommended to use separate preparations of lamivudine and zidovudine. Physicians should follow the information on the use of these drugs.
In spite of the Zilakomb the drug or any other antiretroviral drugs, patients may develop opportunistic infections and other complications of HIV infection. Therefore, patients should be kept under the supervision of physicians experienced in the treatment of HIV infection.
Patients should be informed that treatment with antiretroviral drugs, such as Zilakomb, does not prevent the transmission of HIV to others through sexual contact or contaminated blood transfusion, so patients need to comply with the relevant safety precautions.
It is necessary to warn patients about possible drug interactions with other drugs Zilakomb with their concomitant.
Hematologic disorders
Against the background of therapy with Zilakomb possible development of hematological disorders: anemia, neutropenia and leucopenia (the latter is usually secondary to neutropenia). These effects are more frequently observed in the appointment of zidovudine in high doses (1200-1500 mg / day) in patients with advanced HIV infection with reduced bone marrow reserve prior to treatment. Therefore, during treatment with Zilakomb necessary to carry out careful monitoring of haematological parameters. These haematological changes usually occur no sooner than 4-6 weeks after initiation of therapy. In patients with advanced symptomatic HIV blood test is recommended at least 1 every 2 weeks during the first 3 months of therapy, and then - at least 1 time per month.
In patients with early-stage HIV infection side effects of the blood system are rare. Blood tests can be done less often, focusing on the general condition of patients, for example, 1 time in 1-3 months. May require special selection of zidovudine dose in the case of severe anemia or myelosuppression during Zilakomb drug treatment, and in patients with prior bone marrow suppression, such as hemoglobin concentration 90 g / l (5.59 mmol / L) or less than an amount neutrophils 1,0h10 9/ l. As the dose is individually choose Zilakomb the drug can not be recommended to use separate preparations of lamivudine and zidovudine.
Pancreatitis
In patients treated with lamivudine and zidovudine, are described rare cases of pancreatitis. However it is not established whether this complication drugs or main disease caused - HIV infection. Treatment with Zilakomb must be stopped immediately with the appearance of clinical symptoms or laboratory evidence of pancreatitis development (abdominal pain, nausea, vomiting, or increased activity of the biochemical markers).
Lactic acidosis / severe hepatomegaly with steatosis
Patients treated with nucleoside analogues alone or in combination, including, lamivudine and zidovudine are described rare but with possible fatal cases of lactic acidosis and severe hepatomegaly with steatosis. Similar phenomena were reported, mainly among women. Clinical symptoms of lactic acidosis include general weakness, loss of appetite, sudden, unexplained weight loss, gastrointestinal lesions symptoms (nausea, vomiting, abdominal pain), respiratory disorders (dyspnea and shortness of breath), neurological symptoms (muscle weakness).
Nucleoside analogues should be used with caution in all patients (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Increased risk are patients coinfected with hepatitis C who receive therapy with interferon alpha and ribavirin. Receiving nucleoside analogues should be discontinued at the appearance of clinical or laboratory signs of lactic acidosis or hepatotoxicity (which include hepatomegaly and steatosis even in the absence of a significant increase of aminotransferases).
Redistribution / accumulation of subcutaneous fat
In some patients receiving combination antiretroviral therapy, there is a redistribution / accumulation of adipose tissue, including central obesity, dorsovistseralnoe fat deposition ( "buffalo hump"), a weight loss of limbs and face, breast enlargement, increasing the concentration of serum lipids and blood glucose. These symptoms may occur in patients with or separately.
Although one or more of the above side effects associated with a common syndrome, which is often referred to as lipodystrophy can cause all drugs belonging to protease inhibitors and nucleoside analogs, the data suggest that there are differences between individual representatives of these classes of drugs for the ability to cause these side effects.
It should also be noted that the lipodystrophy syndrome is a multifactorial etiology; such as stage of HIV infection, older age and duration of antiretroviral therapy are important, perhaps sipergichnuyu role. The long-term consequences of these adverse events are currently unknown. Clinical examination should include an assessment of physical signs of redistribution of adipose tissue. It is necessary to determine the concentrations of serum lipids and blood glucose. Lipid disorders should be treated, guided by their clinical manifestations.
Opportunistic infections.
When receiving Zilakomb drugs and other antiretroviral therapy the possibility of developing opportunistic infections persists. Therefore patients should be monitored by a specialist in the treatment of HIV infection.
Immune reconstitution syndrome
In early antiretroviral agents of HIV-infected patients with severe immune deficiency may develop an inflammatory response, as well as residual opportunistic infections, which sometimes leads to serious clinical consequences or strengthening symptoms. Typically, such reactions are observed within the first weeks or months after initiation of antiretroviral therapy. Typical examples are cytomegalovirus retinint, focal or generalized infection caused by Pneumocystis jiroveci (P. Carinii). The appearance of any symptoms of inflammation requires immediate inspection and, if necessary, treatment.
On the background of immune restoration syndrome also possible formation of autoimmune diseases (Grave's disease, polymyositis, Guillain-Barre syndrome). Primary manifestations of time varied, and the disease may occur many months after initiation of therapy and have an atypical course. In the case of muscle weakness, tremor, tremors, hyperactivity patients are advised to promptly notify the physician.
Patients infected with both HIV and hepatitis B virus
Zilakomb should be used with caution in patients with decompensated liver cirrhosis caused by chronic hepatitis B, because in rare cases it is possible exacerbation of hepatitis cases lamivudine. It is necessary to monitor liver and markers of HBV replication function B within 4 months after drug withdrawal.
Patients with mild or moderate hepatic insufficiency or cirrhosis of the liver may be necessary to decrease the daily dose of zidovudine. Zilakomb, as a combination drug, fixed-dose, not recommended for use in patients with hepatic insufficiency.
Patients infected with both HIV and hepatitis C virus
Worsening anemia was observed with concomitant ribavirin and zidovudine, although the mechanism of this phenomenon remains unclear. Thus, without the simultaneous application of ribavirin and Zilakomb drug, especially in patients with AZT-induced anemia in history. In this case, it is recommended to consider the possibility of regime change antiretroviruspoy therapy to cancel zidovudine.
Osteonecrosis
Development of osteonecrosis caused by the action of a variety of factors (including the intake of corticosteroids, alcohol consumption, severe immunosuppression, higher body mass index), in particular, cases of osteonecrosis have been reported in patients with advanced HIV and / or long-term combined antiretroviral therapy. These patients should be advised to consult a specialist in case of joint pain, stiffness and stiffness in the joints.
Mitochondrial dysfunction
analogs of nucleotides and nucleosides exhibit the ability to cause mitochondrial damage in vitro and in vivo. There are data about the development of mitochondrial dysfunction in HIV-negative infants exposed to nucleoside analogues in utero and / or postnatally. The following adverse events were reported: haematological disorders - anemia, neutropenia; metabolic disorders - increase of lactate concentration and lipase. These phenomena have been largely transient. There have been long-term neurological manifestations (hypertonicity, convulsive disorder, a behavioral disorder). At present it is not known whether neurological disorders persistent or transient. Children exposed to analogs of nucleotides and nucleosides in utero,in cases of the corresponding symptoms require clinical observation and examination for the diagnosis of mitochondrial dysfunction.
Liver disease
The risk of serious, up to lethal complications of the liver is increased in patients with hepatitis B or C. Patients with preceding liver disease, including chronic active hepatitis, have an increased risk of liver dysfunction on the background of combination antiretroviral therapy and in need of supervision in accordance with accepted standards. Given the obvious worsening of liver disease in these patients is necessary to decide on the suspension or termination of therapy.
Effects on ability to trans
