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

Zidovudine is an analogue of thymidine and belongs to the group of nucleoside antiviral drugs. Has a high inhibitory activity against retroviruses, including human immunodeficiency virus (HIV).

In human infected cells zidovudine phosphorylated by thymidine kinase to azidothymidine triphosphate, which is a substrate inhibitor of retrovirus reverse transcriptase: when azidothymidine triphosphate is introduced into the synthesized chain of the deoxyribonucleic acid (DNA) of the virus, its further formation is blocked, the virus is stopped, and the therapeutic effect for reducing the HIV concentration in the patient's blood is based on this . The competitive inhibitory activity of azidothymidine triphosphate with respect to HIV reverse transcriptase is about 100 times greater than that of DNA polymerase of human alpha cells, i.e. zidovudine does not affect the normal metabolism of the human body.

It has been found that low concentrations of zidovudine also inhibit many Enterobacteriaceae strains in vitro, including strains of different species of Shigella, Salmonella, Klebsiella, Enterobacter and Citrobacter, and Escherichia coli (with zidovudine resistance rapidly developing in bacteria). The activity against Pseudomonas aeruginosa in vitro has not been established. At very high concentrations (1.9 μg / ml (7 μmol / l)) inhibits Giardia lamblia, although there is no activity for other protozoa.

Pharmacokinetics:

Zidovudine is well absorbed from the gastrointestinal tract, the maximum concentration (C_max) in the blood is reached after 30-90 minutes, bioavailability is 63%: Penetrates through the blood-brain barrier (BBB) and is detected in the cerebrospinal fluid (CSF) at a concentration of 15-64% of the initial dose.

Well penetrates the placenta, so that its concentration in the blood of the umbilical cord is comparable to that in the blood of the mother. It is found in breast milk. Metabolism occurs in the liver with the formation of glucuronide, which is excreted from the body by the kidneys with urine.

In patients with impaired hepatic function, zidovudine can be cumulated by reducing glucuronidation in the liver.

Data on the pharmacokinetics of zidovudine in pregnant women are limited, as in older patients.In children older than 5-6 months. the pharmacokinetic data of zidovudine are similar to those of adults.

The binding of zidovudine to plasma proteins is relatively low (34-38%). Bioavailability in newborns under the age of 14 days - 89%, over 14 days - 61%. Admission with fatty foods reduces the rate and degree of absorption.

When administered inside 200 mg 6 times a day C_max- 1.5 μg / ml of plasma, the minimum concentration (C_min) - 0.1 μg / ml of plasma. Penetrates through the BBB, concentration in the CSF - 24% of the concentration in the blood plasma in children. Passes through the placenta (concentration in the tissues of the central nervous system (CNS) in a 13-week fetus - 0.01 μmol / l, which is lower than effective antiviral concentrations). The volume of distribution in adults and children is 1.4-1.7 l / kg (42-52 l / m 2). It accumulates in seminal fluid, where its concentrations exceed those in blood serum 1,3-20,4 times, but it does not affect the excretion of HIV with seminal fluid and therefore can not prevent sexual transmission of HIV. The mean half-life (T1 / 2) of cells is 3.3 hours; from serum in adults - about 1 hour (0.8-1.2 hours), with renal failure (creatinine clearance less than 30 ml / min) - 1.4-2.9 hours, with cirrhosis - varies in depending on the severity of liver failure, an average of 2.4 hours; in children aged 2 weeks - 13 years - 1-1.8 hours, in newborns (mothers who received zidovudine) - 13 hours.Renal clearance - 27.1 ml / min / kg, in children - 30.9 ml / min / kg, exceeds KK. The liver is conjugated with glucuronic acid; the main inactive metabolite is 3'-azido-3'-de-5-O-beta-P-glucopyranurono-zilthymidine, T1 / 2 with normal renal function 1 hour, renal insufficiency 8 hours, anuria 29- 94 h, with cirrhosis - varies depending on the degree of liver failure, on average, about 2.4 h; is excreted by the kidneys and does not possess antiviral activity.

In unchanged form, kidneys are excreted by 14-18%, in children - 30%; in the form of glucuronides - 60-74%, in children - 45%. Do not cumulate; in chronic liver failure, the accumulation of metabolites (conjugates with glucuronic acid) is possible, which increases the risk of toxic effects.

Indications:

In adults and children older than 3 years for the treatment of HIV infection, as part of combination therapy.

Treatment of HIV infection in pregnant women to reduce the frequency of transplacental transmission of HIV from the mother to the fetus.

Prevention of infection of people who received injections and cuts when working with contaminated HIV material.

Contraindications:

Hypersensitivity to zidovudine or any other component of the drug;
neutropenia (neutrophil count less than 0.75x10⁹/ l);
reduction of hemoglobin (Hb) (less than 75 g / l or 4.65 mmol / l);
Children younger than 3 years (for this dosage form).

Carefully:

Precautions should be taken with oppression of bone marrow hematopoiesis, deficiency of cyanocobalamin (vitamin B12) or folic acid, liver failure, old age, obesity, with hepatomegaly, hepatitis, or any known risk factors for liver disease. In the treatment of zidovudine, these patients need careful monitoring.

Pregnancy and lactation:

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

Women who use zidovudine, it is not recommended to breast-feed.

Dosing and Administration:

Adults and children over 12 years of age:

The recommended dose is 500 or 600 mg per day, divided into 2 to 3 doses.

Children from 3 years to 12 years:

Recommended dose range from 360 to 480 mg / m² per day, divided into 3-4 reception.

The course of treatment is a long, almost unlimited period. Possible breaks in the course of treatment up to 1 month.

In the antenatal period, women who are pregnant, are recommended to take zidovudine 100 mg 5 times a day from 14 weeks of pregnancy until delivery.

Special dosage adjustment data in the elderly no.

Patients with severe renal insufficiency should be appointed zidovudine in lower doses. Further changes in dosage should be correlated with hematological parameters and clinical response to the drug.

When hepatic insufficiency a dose adjustment may also be required: the physician should pay attention to signs of drug intolerance and, if necessary, increase the intervals between doses.

To prevent occupational HIV infection (work with infected biological material), as well as in other cases of parenteral risk of HIV infection, it is recommended to take as soon as possible zidovudine 200 mg 3 times a day (no later than 72 hours after possible infection) for 4 weeks.

With a decrease in Hb on 25% of the initial, the number of neutrophils by 50% of the initial - the 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 discontinued if Hb is less than 75 g / L or the number of neutrophils is less than 0.75x10⁹/ l. With the development of anemia (a decrease in Hb on 20 g / l) or neutropenia, which are determined in two analyzes at intervals of 24 hours, or a decrease in the number of platelets to 50x10⁹/ l dose is reduced by 30%. Termination of treatment in children is required: with a decrease in Hb below 80 g / l; decrease in the number of neutrophils to 0.5 × 10⁹/ l in two consecutive analyzes with an interval of 24 hours; decrease in the number of platelets to 25x10⁹/ l or with progressive chronic renal failure (CRF). After stabilizing the hematological parameters, the treatment is resumed in smaller doses.

Side effects:

The following gradations were used to estimate the incidence of undesired reactions: very often (> 1/10), often (> 1/100, <1/10), sometimes (> 1/1000, <1/100), rarely (> 1 / 10000, <1/1000), very rarely (<1/10000).

On the part of the hematopoiesis system: often anemia (which may require blood transfusions), neutropenia and leukopenia. The frequency of neutropenia develops in patients who experienced a decrease in the number of neutrophils, hemoglobin and vitamin B₁₂in the serum at the beginning of treatment.Sometimes - thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rarely erythrocyte aplasia; very rarely - aplastic anemia.

From the side of metabolism: often - hyperlactatemia; rarely - lactic acidosis, anorexia; redistribution / accumulation of subcutaneous fat (the development of this phenomenon depends on many factors, including the combination of antiretroviral drugs).

From the central and peripheral nervous system: very often - headache; often - dizziness; rarely - insomnia, paresthesia, drowsiness, decreased speed of thinking, convulsions.

From the side of the psyche: rarely - anxiety, depression.

From the cardiovascular system: rarely - cardiomyopathy.

From the respiratory system: sometimes - shortness of breath; rarely - a cough.

From the gastrointestinal tract: very often - nausea; often - vomiting, pain in the upper abdomen, diarrhea; sometimes flatulence; rarely - pigmentation of the oral mucosa, a taste disorder, dyspepsia.

From the liver and pancreas: often - an increase in the level of bilirubin and the activity of liver enzymes; rarely severe hepatomegaly with steatosis; pancreatitis.

From the skin and its appendages: sometimes - a skin rash (other than urticaria), itchy skin; rarely - pigmentation of nails and skin, urticaria, increased sweating.

From the musculoskeletal system: often - myalgia; sometimes - myopathy.

From the urinary system: rarely - frequent urination.

From the endocrine system: rarely: gynecomastia.

Other: often - malaise; sometimes - fever, generalized pain syndrome, asthenia; rarely - chills, pain in the chest; influenza-like syndrome.

Undesirable reactions that occur when zidovudine is used to prevent the transmission of HIV from mother to fetus.

Pregnant women are well tolerated zidovudine in recommended doses. Children have a decrease in hemoglobin, which, however, does not require blood transfusions. Anemia disappears 6 weeks after the end of zidovudine therapy.

Overdose:

Symptoms

There may be a feeling of fatigue, headache, vomiting; very rarely - changes from the blood indicators. There is one report of an overdose of an unknown amount of zidovudine, when the concentration of zidovudine in the blood exceeded the usual therapeutic concentration 16 times, nevertheless, the clinical,biochemical or hematologic symptoms were absent.

Treatment

Symptomatic therapy. Hemodialysis and peritoneal dialysis are not highly effective in removing zidovudine from the body, but increase the excretion of its metabolite, glucuronide.

Interaction:

Do not use zidovudine in combined treatment regimens together with Nikavir and stavudine, since these drugs are direct competitors in the mechanism of action, which can lead to a decrease in activity against HIV.

In some patients who used zidovudine together with phenytoin, a decrease in the concentration of the latter in the blood was observed.

With simultaneous use with lamivudine, an increase in the maximum concentration (28%) of zidovudine is observed, however, the area under the "concentration / time" (AUC) curve does not change. Zidovudine does not affect the pharmacokinetics of lamivudine.

Atovahon: zidovudine does not affect the pharmacokinetic parameters of the atovahona. Atovahon slows down the transformation of zidovudine to the glucuronide derivative (zidovudine AUC in the equilibrium state is increased by 33% and the maximum concentrations of glucuronide are reduced by 19%).It is unlikely that the safety profile of zidovudine changes at doses of zidovudine 500 or 600 mg / day when combined with atavahone for three weeks. If it is necessary to have a longer-term combination, the use of these drugs is recommended to closely monitor the clinical condition of the patient.

Clarithromycin decreases the absorption of zidovudine. The interval between dosing should be at least 2 hours.

Valproic acid, fluconazole, methadone reduce the clearance of zidovudine, which increases its systemic exposure.

Some drugs, such as acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, inosine, pranobex, can affect the metabolism of zidovudine by competitive inhibition of glucuronidation and direct inhibition of microsomal enzymes in the liver. When prescribing such drugs together with zidovudine, the possibility of interaction should be taken into account.

Adriamycin, a-interferon, amphotericin-B, pentamidine, pyrimethamine, co-trimoxazole, doxorubicin, flucytosine, vinblastine, vincristine, ganciclovir, dapsone, sulfadiazine and other sulfonamides, used in conjunction with zidovudine, mutually enhance myelotoxicity.

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

Radiation therapy - increases the risk of toxic effects of zidovudine.

Zidovudine increases the concentration of fluconazole.

There is a synergistic effect with other drugs (drugs) used against HIV (especially lamivudine), with respect to HIV replication in cell culture.

The nucleoside analog ribavirin is an antagonist of the antiviral activity of zidovudine in vitro, therefore simultaneous use of these two drugs should be avoided. Under the influence of probenecid, the excretion of glucuronide by the kidneys (and, possibly, of zidovudine itself) decreases.

Special instructions:

To avoid complications zidovudine apply under the supervision of a doctor.

Patients should be warned that they should not simultaneously use other drugs themselves. Irregular intake of the drug may lead to the development of resistance to the virus and reduce the effectiveness of treatment.

Patients should be informed that zidovudine therapy does not reduce the risk of HIV transmission to other people during sexual intercourse or blood transfusion. During the treatment, peripheral blood is monitored: once every 2 weeks. during the first 3 months. therapy, then - once a month.

Hematologic changes appear after 4-6 weeks. from the onset of therapy (anemia and neutropenia develop more often when used at high doses of 1500 mg / day in patients with reduced T helper (T4), with untreated HIV infection (with reduced reserve bone marrow prior to initiation of therapy), neutropenia, anemia, vitamin B12 deficiency). With a decrease in Hb more than 25% or a decrease in the number of neutrophils by more than 50% compared with the original - blood tests are performed more often. Patients receiving the drug may develop opportunistic infections and other complications of HIV infection, so they should remain under the supervision of doctors.

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

With care appoint to patients engaged in potentially hazardous activities, requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:

Capsules of 100 mg.

Packaging:

10 capsules per contour cell package.

For 50 or 100 capsules in cans of orange glass.

Each jar or 10 contour packs, together with the instruction for use, is placed in a pack of cardboard.

Storage conditions:

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

Shelf life:

2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-001082

Date of registration:18.05.2011 / 05.10.2015

Expiration Date:Unlimited

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Information update date: & nbsp13.10.2017

Illustrated instructions

Instructions

Zidovirin (Zidovirine)