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

Hard gelatin capsules No. 1 are white, yellow or bicolour with a white body and a yellow lid. The contents of the capsules are powder and granules white or white with a yellowish tint of color.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.F.01 Zidovudine

Pharmacodynamics:

Zidovudine is an analog of thymidine and belongs to the group of nucleoside reverse transcriptase inhibitors. Has a high inhibitory activity against retroviruses, including human immunodeficiency virus (HIV). Getting into the cell (both in infected and intact), with the involvement of cellular thymidine kinase, thymidylate kinase and non-specific kinase, is phosphorylated to form a mono-, di- and triphosphate compound, respectively. Zidovudine triphosphate is both an inhibitor and a substrate of viral reverse transcriptase. Inclusion of zidovudine triphosphate, which has a structural similarity with thymidine triphosphate, into the DNA chain and subsequent chain termination blocks the further formation of retroviral DNA.Increases the number of CD4 + cells, increases the body's resistance to infection. The ability to inhibit HIV reverse transcriptase is 100 times higher than the ability to suppress human alpha-polymerase.

Zidovudine is active against the hepatitis B virus and the Epstein-Barr virus in vitro; However, when used as a monotherapy in patients with hepatitis B and AIDS, it slightly suppresses the replication of the hepatitis B virus.

Pharmacokinetics:

The pharmacokinetic parameters of zidovudine in children older than 3 months and in adults are similar in many respects. Zidovudine well absorbed from the gastrointestinal tract (GIT). Bioavailability is 60-70%. Admission with fatty foods reduces the rate and degree of absorption. The maximum concentration in the blood after ingestion is reached after 30-90 minutes. The connection with plasma proteins is relatively low (34-38%). The volume of distribution is 1.6 l / kg. Penetrates into most tissues and body fluids, through the placenta and the blood-brain barrier (GEB). Concentration in the cerebrospinal fluid (CSF) is 15-64% of the concentration in the plasma. In children, the concentration in the CSF is 24% of the plasma content. It is determined in amniotic fluid and in fetal blood; the concentration of zidovudine in the plasma in children at birth is the same as that of mothers during childbirth.It is found in breast milk. It accumulates in seminal fluid, where its concentrations exceed those in blood serum 1,3-20,4 times, but does not affect the release of HIV with seminal fluid and therefore can not prevent sexual transmission of HIV.

Metabolized in the liver, where conjugation with glucuronic acid occurs. The basic inactive metabolite is 3'-azido-3'-deoxy-5'-O-beta-B-glucopyranurono-zilthymidine, the half-life (T_½) of which, with normal kidney function - 1h, with renal insufficiency -8 h, with anuria - 29-94 h, with cirrhosis varies depending on the severity of liver failure, an average of 2.4 h; is excreted by the kidneys and does not possess antiviral activity.

In unchanged form, 14-18% of zidovudine is excreted by the kidneys, in children - 30%; in the form of glucuronides - 60-74%, in children - 45%. Do not cumulate. T_½ from cells - 3,3 h, from blood serum in adults - about 1 h (0,8-1,2 h), with renal failure (creatinine clearance less than 30 ml / min) - 1,4-2, 9 hours, with cirrhosis varies depending on the severity of liver failure, an average of 2.4 hours; in newborns (mothers of whom received zidovudine) -13 hours.

Renal clearance is 27.1 ml / min / kg, in children - 30.9 ml / min / kg, exceeds the CC, which indicates the removal of a significant part of the drug with tubular secretion. In chronic renal failure, the accumulation of metabolites (conjugates with glucuronic acid) is possible, which increases the risk of toxic effects. In patients with cirrhosis of the liver and liver failure, cumulation is possible due to a decrease in the intensity of binding to glucuronic acid.

Indications:

Treatment of HIV infection in combination antiretroviral therapy in children and adults;
prevention of transplacental HIV infection of the fetus;
prevention of occupational infection of persons who received injections and cuts when working with HIV-contaminated material.

Contraindications:

hypersensitivity to zidovudine or any component of the drug;
neutropenia / leukopenia (the number of neutrophils is below 0.75 · 10⁹/ l or 750 / μl);
anemia (hemoglobin level below 7.5 g / dl or 4.65 mmol / l);
children up to 3 years;
deficiency of lactase, lactose intolerance, glucose-galactose malabsorption (the preparation contains lactose).

Carefully:

Inhibition of bone marrow hematopoiesis, deficiency of cyanocobalamin or folic acid, hepatic insufficiency, advanced age, obesity, hepatomegaly, hepatitis, or any known risk factors for liver disease.

Pregnancy and lactation:

Zidovudine penetrates the placenta. It is not recommended to appoint women until 14 weeks of pregnancy. If it is necessary to prescribe the drug before the 14th week of pregnancy, the expected benefit for the mother and the potential risk for the fetus should be carefully correlated.

In the case of the drug during lactation it is necessary to stop breastfeeding.

Dosing and Administration:

Inside, not liquid, with a sufficient amount of liquid, regardless of food intake.

Adults and children over 12 years of age:

500-600 mg per day in 2-3 doses in combination with other antiretroviral drugs.

Children from 3 to 12 years:

at the rate of 360-480 mg / m², divided into 3-4 doses, in combination with other antiretroviral drugs.

If the hemoglobin content is reduced by 25% from the initial content, the number of neutrophils by 50% of the initial daily dose is reduced by 2 times or temporarily canceled.After restoring the parameters, the dose can be increased again to the original daily values. Treatment is stopped if the hemoglobin content is less than 75 g / l or the number of neutrophils is below 0.75x10⁹/ l.

Prevention of transplacental transmission of HIV: 100 mg 5 times a day, starting from the 14th week of pregnancy, or 300 mg twice a day, beginning at the 36th week of pregnancy before the onset of labor, then 300 mg every 3 hours until the child is separated from the mother (the cord is crossing) .

Prevention of occupational HIV infection: 600 mg per day in 2-3 divided doses, for 4 weeks. Chemoprophylaxis of parenteral HIV transmission is recommended to begin no later than 72 hours after possible infection.

Patients with impaired liver function. In liver failure, there may be a need for correction of the dosing regimen. In this case, it is necessary to correct the dose of the drug and / or to increase the interval between doses.

Patients with impaired renal function. With QC more than 10 ml / min, correction of dosing regimens is not required. In severe violations of kidney function, the recommended dose of zidovudine is 300-400 mg per day.Depending on the changes in the peripheral blood picture and the clinical effect, further correction of the dose of the drug may be required.

Patients of advanced age. There are no specific recommendations for changing the dosing regimen in elderly patients; should take into account the age-related decline in kidney function and changes in peripheral blood.

Side effects:

From the system of blood and blood-forming organs: myelosuppression, anemia, neutropenia, leukopenia, thrombocytopenia, pancytopenia with bone marrow hypoplasia, aplastic anemia.

From the digestive system: nausea, vomiting, dyspepsia, anorexia, taste distortion, abdominal pain, diarrhea, flatulence, pigmentation of the oral mucosa, hepatomegaly with steatosis, increased bilirubin concentration and activity of "liver" enzymes, pancreatitis.

From the central and peripheral nervous system: headache, dizziness, paresthesia, insomnia, drowsiness, weakness, lethargy, decreased mental performance; anxiety, depression, convulsions.

From the respiratory system: shortness of breath, cough.

From the cardiovascular system: cardiomyopathy.

From the urinary system: rapid urination, hypercreatininaemia.

From the endocrine system and metabolism: lactic acidosis in the absence of hypoxemia and anorexia, gynecomastia.

From the musculoskeletal system: myalgia, myopathy.

Allergic reactions: skin rash, itching, hives.

From the skin and subcutaneous tissue: pigmentation of nails and skin, increased sweating.

Other: malaise, fever, pain syndrome of various locations, chills, increased serum amylase activity, development of secondary infection, redistribution of adipose tissue.

Assessing the tolerability of the drug, it should be borne in mind that skin rashes, dizziness, weakness, headache, anorexia, diarrhea, myalgia, anemia, thrombocytopenia can be a manifestation of HIV infection itself and of secondary diseases associated with it, rather than the toxic effect of zidovudine.

Overdose:

Symptoms: increased manifestations of the described side effects.

Treatment: gastric lavage, Activated carbon, symptomatic therapy.Hemodialysis and peritoneal dialysis are ineffective in eliminating zidovudine, but accelerate the elimination of the glucuronic metabolite.

Interaction:

Paracetamol increases the incidence of neutropenia due to inhibition of zidovudine metabolism (both drugs are glucuronized).

Inhibitors of microsomal oxidation, in the liver (incl. acetylsalicylic acid, morphine, codeine, indomethacin, valproic acid, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, inosine pranobex) increase the concentration of zidovudine in plasma.

Drugs that are nephrotoxic and myelosuppressive (dapsone, pentamidine, pyrimethamine, amphotericin B, flucytosine, ganciclovir, vincristine, vinblastine, interferon alfa, doxorubicin, co-trimoxazole), increase the risk of toxic effects of zidovudine.

Probenicides and others tubular secretion inhibitors prolong the half-life of zidovudine.

When combined with phenytoin it is possible to change the concentration of the latter in the blood.

Zidovudine increases concentration fluconazole.

There is a synergistic effect with other drugs used against HIV (special lamivudine), with respect to HIV replication in cell culture. Ribavirin Suppresses the phosphorylation of zidovudine to triphosphate (not recommended at the same time).

Stavudine has an antagonistic effect at a ratio of the molar concentrations of stavudine and zidovudine 20: 1 (simultaneous administration is not recommended).

Rifampicin reduces the concentration of zidovudine in the plasma, which can lead to a decrease in the effectiveness of the latter (not recommended at the same time). Absorption of zidovudine decreases with simultaneous use with tablets clarithromycin; in this regard, it is recommended to take medications at intervals of two hours.

Radiation therapy enhances the myelosuppressive effect of zidovudine.

Special instructions:

Treatment with zidovudine should only take place under the supervision of a physician.

Irregular intake of the drug may lead to the development of resistance to the virus and reduce the effectiveness of treatment. If you miss a dose, do not double the next.

The frequency of side effects, as a rule, is associated with the dose and duration of the drug (more often in the late stages of the disease).Dizziness, weakness, loss of appetite, diarrhea, possible in the first days of admission, subsequently significantly reduced or disappear within a few weeks of zidovudine therapy.

Lactic acidosis and severe hepatomegaly with steatosis can be fatal, so when clinical or laboratory signs of lactic acidosis, or toxic damage to the liver zidovudine should be canceled.

During treatment it is necessary to carry out a systematic control of the picture of peripheral blood: 1 every 2 weeks for the first 3 months of therapy, then - once a month.

Hematologic changes usually appear 4-6 weeks after the beginning of therapy (anemia and neutropenia develop more frequently against a background of high doses of zidovudine (1.2-1.5 g / day) in patients with a decrease in CD4 + cells, with HIV infection reduced bone marrow reserve before the start of therapy), vitamin B12 deficiency.With a decrease in hemoglobin by more than 25% or a decrease in the number of neutrophils by more than 50% compared with baseline blood tests are performed more often.

It is necessary to perform systematic biochemical control of liver function: in the first 3 months of treatment - every 2 weeks, then - at least 1 time per month.In all cases of clinical or laboratory signs of toxic damage to the liver or lactic acidosis zidovudine should be canceled.

With the simultaneous administration of zidovudine and any of the drugs that have a nephro- or myelotoxic effect, renal function and hematological parameters should be closely monitored.

During the treatment should monitor the immune status of patients. Patients receiving the drug may develop opportunistic infections and other complications of HIV infection.

Antiretroviral therapy does not prevent the transmission of HIV through sexual contact and through infected blood (appropriate safety measures must be taken).

It is necessary to inform the patient about the danger of applying simultaneously with zidovudine non-prescription drugs without prior consultation with the attending physician.

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

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Form release / dosage:

Capsules, 100 mg.

Packaging:

For 100 capsules in cans with screwed lids made of polyethylene.

For 1 plastic can, together with instructions for use, is placed in a pack of cardboard.

Storage conditions:

List B.

In dry, protected from light and out of reach of children at a temperature of no higher than 25 ° C.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:P N003924 / 01

Date of registration:09.06.2010

Expiration Date:Unlimited

The owner of the registration certificate:BIOFARMA, CJSC BIOFARMA, CJSC Russia

Manufacturer: & nbsp

BIOFARMA, CJSC Russia

Information update date: & nbsp04.02.2017

Illustrated instructions

Instructions

Azidothymidine (Azidothymidin)