Zidovudine-Ferein - 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 the action of thymidine kinase to azidothymidine triphosphate, which is a substrate inhibitor of retrovirus reverse transcriptase: when azidothymidine triphosphate is introduced into the synthesized DNA strand of the virus, its further formation is blocked, the virus is stopped, and the therapeutic effect for reducing the concentration of HIV in the patient's blood is based. 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%. It penetrates the blood-brain barrier (BBB) and is found 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.

Patients with impaired hepatic function The cumulation of zidovudine is possible due to a decrease in glucuronidation in the liver.

Data on the pharmacokinetics of zidovudine in pregnant women are limited, as well as in elderly patients. Children aged over 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 does not affect the induction of HIV with seminal fluid and therefore can not prevent sexual transmission of HIV. Mean half-life (T_1/2) from the cells - 3.3 h; 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,on average, 2.4 hours; in children aged 2 weeks-13 years - 1-1.8 hours, in newborns (mothers of whom received zidovudine) -13 hours. The kidney clearance is 27.1 ml / min / kg, in children - 30.9 ml / min / kg, exceeds the CK. In the liver, conjugation with glucuronic acid occurs; the basic inactive metabolite is 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranurono-zilthymidine, T_1/2with normal renal function -1 h, with renal insufficiency -8 h, with 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 2 years with HIV infection in the stage of secondary diseases in the stage of acute infection and with primary clinical manifestations with a decrease in CD4-lymphocytes less than 400-500 in mm³, and also in the stage of incubation.

Pregnant women Zidovudine can be prescribed for the progression of secondary diseases in HIV infection or for a C04-lymphocyte count of less than 0.2 x 10⁹/ l.In other cases, treatment Zidovudine may be interrupted before the expiration of the first trimester of pregnancy.

Prevention of perinatal transmission of HIV from an infected mother to a child, since Zidovudine reduces the risk of intrauterine infection of the fetus.

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

Contraindications:

Hypersensitivity to the drug;
leukopenia (the number of neutrophils is less than 500 in μl);
anemia (hemoglobin (Hb) below 50 g / l);
thrombocytopenia (platelets less than 25 thousand in μl);
increased aminotransferases and creatinine more than 3 times the upper limit of the norm;
children under 2 years old.

Carefully:

Inhibition of bone marrow hematopoiesis, deficiency of cyanocobalamin (vitamin B₁₂) or folic acid, hepatic insufficiency, advanced age, obesity, with hepatomegaly, hepatitis, or any known risk factors for liver disease. When treating Zidovudine such patients should be carefully monitored.

Pregnancy and lactation:

If it is necessary to prescribe the drug during pregnancy, the expected benefit for the mother and the potential risk forthe fetus. 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:

Inside adults on 0,6-0,8 g per day in 3-4 reception. With CNS lesions, the daily dose of HIV is doubled. Children older than 2 years, the drug is prescribed at a rate of 0.01-0.02 g / kg per day.

With the expressed side effects, the dose can be reduced to 0.3 g per day in adults and children at a rate of up to 0.005 g / kg.

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

In antenatal women who are pregnant, Zidovudine is recommended to be taken 0.1 g 5 times a day from 14 weeks gestation to childbirth.

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 0.2 g 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 7.5 g / dl or the number of neutrophils is below 750 / μL. With the development of anemia (a decrease in Hb at 2 g / dL) or neutropenia, which are determined in two analyzes at intervals of 24 hours, or a decrease in the number of platelets to 50,000 / μL, the dose is reduced by 30%. Termination of treatment in children is required: with a decrease in Hb below 8 g / dL; reducing the number of neutrophils to 500 / μL in two consecutive analyzes at intervals of 24 hours; a decrease in the number of platelets to 25,000 / mm3 or with progressive CRF. After stabilizing the hematological parameters, the treatment is resumed in smaller doses.

Side effects:

In the early days of taking Zidovudine - dizziness, weakness, loss of appetite, diarrhea. Usually these phenomena subsequently disappear. With prolonged use of the drug, it may cause skin itching, paresthesia, myalgia. Allergic reactions in the form of hives are rare. A serious complication is anemia, which can develop 4-6 weeks after the start of treatment and granulocytopenia (after 6-8 weeks). Reduction of hemoglobin may occur earlier (within 2-4 weeks after treatment). In this regard, a constant laboratory control of the formula of blood and hemoglobin is necessary. The frequency of complications is associated with the dose and duration of the drug, so complications are more common in the late stages of the disease. With adverse reactions it is advisable to try to continue treatment with Zidovudine and prescribe other drugs to correct complications. With a pronounced toxic effect cancel Zidovudine for a period until the restoration of the affected systems. Other side effects: neutropenia, leukopenia, thrombocytopenia; asthenic syndrome, drowsiness, taste perversion, cardialgia, gastralgia, nausea, vomiting, flatulence,pancreatitis; increased activity of "hepatic" transaminases, hypercreatininemia, increased serum amylase activity; fever, the development of secondary infection; insomnia, depression, increased frequency of urination, chills, cough.

In assessing tolerability, it should be considered that skin rash, dizziness, weakness, headache, anorexia, diarrhea, myalgia, anemia, thrombocytopenia may be a manifestation of HIV infection itself and secondary diseases connected with it, and not the toxic effect of zidovudine.

Overdose:

The maximum recorded zidovudine concentration in the patient's blood was 49.4 μg / ml (after intravenous administration of the drug at a dose of 7.5 mg / kg every 4 hours for 2 weeks). After a similar overdose, no specific symptoms were noted. In case of intoxication, hemodialysis and peritoneal dialysis significantly increase the excretion of the glucuronic metabolite of zidovudine.

Interaction:

Do not use Zidovudine in combined treatment schemes together with stavudine Nikavir and, since these drugs are direct competitive mechanism of action, which may lead to a reduction of HIV activity.

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

Some drugs, such as acetylsalicylic acid, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, Inosine Pranobeks, 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, co-trimoxazole, 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 preparations are glucuronidated).

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

Zidovudine increases the concentration of fluconazole.

There is 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), untreated HIV infection (with reduced bone marrow reserve before therapy), neutropenia, anemia, vitamin B deficiency₂).With a decrease in Hb by more than 25% or a decrease in the number of neutrophils by more than 50% compared to the baseline - 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 0.1 g.

Packaging:

10 capsules per contour cell package.

For 20, 100 capsules in a jar of dark glass or polymer.

Each jar, 2, 3, 5, 10 contour packs in place with instruction for use is placed in a pack of cardboard.

Storage conditions:

List B. In a dry, protected from light, inaccessible temperature not above 25 ° C.

Shelf life:

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

Terms of leave from pharmacies:On prescription

Registration number:P N003384 / 01

Date of registration:09.06.2009

Expiration Date:Unlimited

The owner of the registration certificate:BRYNTSALOV-A, CJSC BRYNTSALOV-A, CJSC Russia

Manufacturer: & nbsp

BRYNTSALOV-A, CJSC Russia

Information update date: & nbsp13.10.2017

Illustrated instructions

Instructions

Zidovudine-Ferein (Zidovudine-Ferein)