Description
Pharmacological action
Pharmacotherapeutic group:
Antiviral [HIV] agent.
ATX code:
J05AF01
Pharmacological properties:
Pharmacodynamics.
Mechanism of action:
Zidovudine is an antiviral drug that is highly active in vitro against retroviruses, including human immunodeficiency virus (HIV).
As in infected, so in uninfected cells, zidovudine undergoes phosphorylation with the formation of a monophosphate derivative. This reaction is catalyzed by cell thymidine kinase. After that, zidovudine monophosphate is phosphorylated to diphosphate, then to triphosphate (reactions are catalyzed by cell thymidine kinase and non-specific kinases, respectively). Zidovudine triphosphate acts as an inhibitor and substrate for the reverse transcriptase of the virus. The synthesis of viral DNA is blocked by the inclusion of zidovudine monophosphate in its chain, the chain is broken. The affinity of zidovudine triphosphate for HIV reverse transcriptase is 100 times higher than for cellular DNA polymerase alpha.
Clinical Virology.
In vitro HIV susceptibility assessment is not a standardized method, and results may vary due to the nature of the method. There are reports of a decrease in HIV sensitivity to zidovudine in vitro in patients receiving zidovudine for a long time. In addition, in the early stages of HIV infection, the frequency and degree of decrease in the sensitivity of the virus in vitro is significantly lower than in the late stages of the disease.
Reducing the sensitivity of viruses and the emergence of zidovudine-resistant strains limits the use of zidovudine monotherapy. Zidovudine, especially in combination with lamivudine, as well as didanosine or zalcitabine, significantly reduces the risk of disease progression and mortality. The use of protease inhibitors together with zidovudine and lamivudine provides additional benefits by slowing the progression of the disease and improving survival rates, compared with the combination of the two drugs.
shown that the combination of zidovudine and lamivudine, as well as in vitro studies have demonstrated that isolates of zidovudine-resistant viruses can become zidovudine-sensitive when they become resistant to lamivudine. Moreover, there is evidence that the combination of zidovudine and lamivudine slows down the development of zidovudine resistance in patients who have not previously received antiretroviral therapy.
Zidovudine may act additively or synergistically with other drugs used to treat HIV (lamivudine, didanosine and interferon alfa), inhibiting virus replication in cell culture. However, combinations of three nucleoside analogues or two nucleoside analogues and a protease inhibitor more effectively suppress the cytopathic effects of HIV-1, compared with monotherapy or a combination of two drugs.
Resistance to thymidine analogs (to which zidovudine belongs) is characterized in detail and is associated with stepwise accumulation of specific mutations (in 6 codons) in the HIV reverse transcriptase gene (codons 41, 67, 70, 210, 215 and 219). Viruses acquire phenotypic resistance to thymidine analogs with a combination of mutations in codons 41 and 215 or with the accumulation of 4 to 6 mutations. These mutations do not cause cross-resistance to other nucleoside analogues, which allows the use of other drugs of reverse transcriptase inhibitors for further treatment of HIV infection.
Two types of mutations lead to the development of multidrug resistance. In the first case, these are mutations in codons 62, 75, 77, 116, and 151 of HIV reverse transcriptase, in the second, the T69S mutation in combination with the insertion of nitrogenous bases into the position of the 6th pair, corresponding to this position. These changes lead to the development of phenotypic resistance to zidovudine, as well as to other nucleoside reverse transcriptase inhibitors. Both types of mutations leading to multidrug resistance significantly limit the therapeutic options for HIV infection.
Pharmacokinetics.
Adults
Absorption.
Zidovudine is well absorbed in the intestines. For all studied dosages, the bioavailability of the drug is 60-70%. When taking zidovudine at a dose of 300 mg twice a day, the average concentrations in equilibrium are: maximum (Cssmax) 8.57 (54%) Ñmol / L (2.29 Ñg / ml), minimum (Cssmin) 0.08 ( 96%) Ñmol / L (0.02 Ñg / ml) and the area under the concentration-time curve (AUCSS) is 8.39 (40%) hour * Ñg / ml (2.24 hour * Ñg / ml).
distribution.
The apparent volume of distribution of zidovudine is 1.6 l / kg. Binding to plasma proteins from 34% to 38%.
Metabolism.
Zidovudine is eliminated primarily in the liver by converting it into an inactive metabolite (conjugation to glucuronide). Zidovudine 5′-glucuronide is the main metabolite of the drug, which is determined in blood plasma and urine. In the form of 5′-glucuronide, 50-80% of the dose of the drug is excreted in the urine.
Excretion.
Renal clearance of zidovudine significantly exceeds creatinine clearance, indicating a significant role for tubular secretion.
Special patient groups
Children
Absorption.
In children older than 5-6 months, the pharmacokinetic profile of zidovudine does not differ from the pharmacokinetic profile of adults. Zidovudin is well absorbed in the intestines. For all studied dosages, the bioavailability of the drug was 60-74% (average value – 65%).
distribution.
In children, the average ratio of the concentration of zidovudine in plasma and cerebrospinal fluid after 0.5-4 hours after oral administration of the drug is 0.52-0.85.
Metabolism.
The main metabolite of zidovudine – 5 -glucuronide in plasma and urine is approximately 50-80% of the administered dose. Eliminated by renal excretion.
Excretion.
Renal clearance of zidovudine significantly exceeds creatinine clearance, indicating a significant role for tubular secretion.
Data on the pharmacokinetics of the drug in newborns and infants indicate that in newborns, a decrease in zidovudine glucuronidation, accompanied by an increase in bioavailability, a decrease in clearance and a longer half-life of the drug, expressed to a lesser extent than in children aged 14 days. At an older age, the pharmacokinetics of zidovudine in children does not differ from the pharmacokinetics in adults.
Pregnancy
In pregnant women, drug accumulation is not observed, and the pharmacokinetics of zidovudine are not different from the pharmacokinetics of non-pregnant women. In accordance with the passive mechanism of the drug passing through the placenta, the plasma concentrations of zidovudine in newborns were equal to the concentration of the drug in the blood of mothers during childbirth.
Elderly patients
There are no specific data on the pharmacokinetics of zidovudine in elderly patients.
Renal failure
In severe renal failure, clearance of zidovudine after oral administration is 50% of the clearance of the drug in individuals with normal renal function. The effectiveness of hemodialysis and peritoneal dialysis to eliminate zidovudine is limited, but they can accelerate the excretion of glucuronide (a metabolite of zidovudine).
Hepatic insufficiency
In patients with hepatic insufficiency, zidovudine accumulation may be associated with suppression of glucuronidation, which may require dose adjustment.
Indications
Treatment of HIV-1 infection as part of combination antiretroviral therapy.
Treatment of HIV-1 infection in pregnant women to reduce the incidence of transplacental transmission of HIV from mother to fetus.
Contraindications
Hypersensitivity to zidovudine itself or to any other components of the drug expressed neutropenia / leukopenia (the number of neutrophils is below 0, 75 x 109 / l) or anemia (hemoglobin below 75 g / l or below 4.65 mmol / l) children under 3 years of age (for this dosage form).
Caution:
Inhibition of bone marrow hematopoiesis, deficiency of cyanocobalamin or folic acid, advanced age (over 65), liver failure, obesity, hepatomegaly, hepatitis or any risk factors for liver disease, neutropenia / leukopenia (neutrophil count 0.75-1, 0 x 109 / l), anemia (hemoglobin 75-90 g / l).
Composition
Composition per capsule:
Active ingredient: Zidovudine – 100.00 mg.
excipients: corn starch – 82.80 mg
microcrystalline cellulose – 34.50 mg
carboxymethyl starch sodium – 11.50 mg
magnesium stearate – 1.2 mg.
Capsule shell: No. 1 hard gelatin capsule [case: titanium dioxide – 1%
iron dye – 80.00 mg
yellow oxide – 0.192%
gelatin – up to 100%
cap: dye iron oxide black – 0.53%
dye iron oxide red – 0.93%
dye iron oxide yellow – 0.2%
titanium dioxide – 0.3333%.
Dosage and Administration
Inside.
Adults and children over 12 years of age with a body weight of 30 kg or more:
The recommended dose of zidovudine as part of combination therapy is 600 mg per day in several doses.
Children aged 3 to 12 years:
Children weighing more than 21 kg but less than 30 kg:
The recommended dose of zidovudine as part of combination therapy is 200 mg (two 100 mg capsules) in the morning and 200 mg (two capsules 100 mg) in the evening.
Children weighing at least 14 kg and up to 21 kg
The recommended dose of zidovudine as part of combination therapy is 100 mg (one capsule per 100 mg) in the morning and 200 mg (two capsules per 100 mg) in the evening.
Children weighing at least 8 kg and up to 14 kg:
The recommended dose of zidovudine is 100 mg (one 100 mg capsule) in the morning and 100 mg (one 100 mg capsule) in the evening.
Children with body weight less than 8 kg, as well as children unable to swallow capsules (regardless of body weight), it is recommended to use other dosage forms of zidovudine for oral use.
Prevention of mother-to-child transmission of HIV:
Zidovudine is prescribed to pregnant women after 14 weeks of pregnancy at a dose of 500 mg / day (100 mg five times a day). The drug is taken before birth. During childbirth, with caesarean section, as well as newborns, for the prevention of vertical transmission of HIV, it is necessary to use other dosage forms of zidovudine in accordance with the recommended administration schemes. Dose adjustment for adverse reactions from the blood and lymphatic system.
With a marked decrease in hemoglobin (up to 75-90 g / l (4.65-5.59 mmol / l)) or the number of neutrophils (up to 0.75-1.0 109 / l), a dosage regimen correction may be required – a decrease doses or drug withdrawal.
Elderly patients
In patients older than 65, the pharmacokinetics of zidovudine has not been studied, relevant data are not available. However, taking into account age-related features – a decrease in renal function, a change in blood counts – elderly patients need special control. Before starting zidovudine and during therapy, the condition of such patients should be carefully monitored.
Renal failure:
Recommended dose of zidovudine in severe renal failure (creatinine clearance <10 ml / min) and end-stage renal failure (patients on hemodialysis or peritoneal dialysis) - 100 mg every 6-8 hours (300-400 mg / day). Changes in blood counts and some clinical reactions may require dose adjustment. Hepatic insufficiency: Data from patients with cirrhosis suggest that hepatic failure may result in accumulation of zidovudine associated with suppression of glucuronidation. Dose adjustment may be required. however, the exposure of zidovudine in liver failure of varying degrees (from mild to severe) varies significantly, and therefore it is difficult to provide specific recommendations on dose changes. If it is not possible to control the concentration of zidovudine in the plasma, it is necessary to be guided by the clinical signs of the drug intolerance (for example, severe adverse reactions from the blood system: anemia, leukopenia, neutropenia). If necessary, reduce the dose of zidovudine and / or increase the interval between doses of the drug. Side effects Adverse reactions that occur during treatment with zidovudine in children and adults coincide. The following gradations were used to assess the incidence of adverse reactions: very often (more than 10%), often (1-10%), infrequently (0.1-1%), rarely (0.01-0.1%) and very rarely (less than 0.01%). Disorders from the blood and lymphatic system: often anemia (which may require blood transfusion), neutropenia and leukopenia (the incidence of neutropenia increases in patients who have decreased neutrophils, hemoglobin and vitamin B12 levels in the serum at the beginning of treatment) – pancytopenia with bone marrow hypoplasia, thrombocytopenia is rare – true erythrocytic aplasia is very rare – aplastic anemia. Disorders from the side of metabolism and nutrition: often – hyperlactatemia rarely – lactic acidosis in the absence of hypoxemia, anorexia. Mental disorders: rarely – anxiety and depression. Disorders of the nervous system: often – headache often – dizziness rarely – convulsions, decreased cognitive function, insomnia, paresthesia, drowsiness. Disorders of the heart: rarely – cardiomyopathy. Disorders of the respiratory system, chest and mediastinal organs: infrequently – dyspnea rarely – cough. Disorders of the gastrointestinal tract: very often – nausea often – vomiting, diarrhea, abdominal pain infrequently – flatulence rarely – pancreatitis, pigmentation of the oral mucosa, taste disturbances, dyspeptic symptoms. Disorders of the liver and biliary tract: often – an increase in the activity of liver enzymes and a concentration of bilirubin rarely – liver diseases such as severe hepatomegaly in combination with steatosis. Disorders of the skin and subcutaneous tissues: infrequently – rash and itching rarely – hives, pigmentation of the skin and nails, sweating. Disorders of the musculoskeletal and connective tissue: often – myalgia infrequently – myopathy. Disorders of the kidneys and urinary tract: rarely – frequent urination. Disorders of the genitals and mammary gland: rarely – gynecomastia. Other: often – malaise infrequently – asthenia, fever, generalized pain syndrome rarely – chest pain, flu-like syndrome, chills. Common adverse reactions are consistently reduced during the first few weeks of zidovudine therapy. Adverse reactions resulting from the use of zidovudine to prevent mother-to-child transmission of HIV infection. Pregnant women tolerate zidovudine in recommended doses. In children, there is a decrease in the hemoglobin content, which, however, does not require blood transfusions. Anemia disappears 6 weeks after completion of zidovudine therapy. When using nucleoside analogs, cases of lactic acidosis, sometimes fatal, were often reported, often accompanied by severe hepatomegaly and liver steatosis. Highly active antiretroviral therapy (HAART) in HIV-infected patients is often accompanied by redistribution of adipose tissue (lipodystrophy). The manifestations of lipodystrophy include a decrease in the number of peripheral subcutaneous fatty tissue and fatty tissue in the face, visceral obesity, mammary gland hypertrophy and accumulation of adipose tissue in the back (in the cervical and thoracic spine, ² Ñbovine hump ² Ñ). HAART is associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia. In HIV-infected patients with severe immunodeficiency, the onset of HAART may be accompanied by an inflammatory response to asymptomatic or residual opportunistic pathogens. There are reports of cases of osteonecrosis, especially for known risk factors (advanced HIV infection and / or prolonged use of HAART). The frequency of this reaction is unknown. Overdose of Symptoms: There are no specific symptoms or signs of an acute overdose of zidovudine. Known reactions are observed, listed as side effects: fatigue, headache, vomiting, in some cases, disorders of the blood system develop. There is one report of an overdose of an unknown amount of zidovudine according to serum concentrations, the dose was more than 17 g. However, no clinical, biochemical or hematological short-term effects were observed. Treatment: Patients should be carefully monitored for toxic symptoms. If necessary, appropriate maintenance therapy is prescribed. The effectiveness of hemodialysis and peritoneal dialysis to eliminate zidovudine is limited, but they can accelerate the excretion of glucuronide (a metabolite of zidovudine). Storage conditions In a dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children. Expiration 2 years. Deystvuyuschee substances Zidovudine Terms and conditions prescription dosage form capsules