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

An antiviral drug with high activity against retroviruses, including human immunodeficiency virus (HIV), is an analog of thymidine and belongs to the group of nucleoside reverse transcriptase inhibitors. Selectively inhibits the replication of viral DNA through competitive inhibition of reverse transcriptase. Zidovudine triphosphate has a structural similarity with thymidine triphosphate, by virtue of its similarity, competes with it for inserting viral RNA-dependent DNA polymerase (reverse transcriptase) into growing chains, thereby suppressing the replication of retroviral DNA. Getting into the cell (both in infected and intact), with the participation of cell thymidine kinase, thymidylate kinase and non-specific kinase, respectively, is phosphorylated to form a mono-, di- and triphosphate compound. Zidovudine triphosphate is an inhibitor as well as a substrate for the action of reverse transcriptase of the virus; mediates the formation of viral DNA on the matrix of viral RNA.

Increases the number of CD4⁺ cells (indicators of immune status), increases the body's ability to resist infection.

The ability to inhibit reverse transcriptase of HIV is 100-300 times higher than the ability to suppress human alpha-polymerase. Zidovudine is active against hepatitis B virus and 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:

Pharmacokinetics for oral administration is dose-independent in the dose range from 2 mg / kg every 8 hours to 10 mg / kg every 4 hours.

Absorption - fast, food intake does not affect the pharmacokinetics of zidovudine. Bioavailability of 60-70%. Time to reach the maximum concentration (TC_max) - 0.5-1.5 h. The volume of distribution (Vd) is 1-2.2 l / kg. The connection with plasma proteins is insignificant - less than 38%.

Metabolised in the liver. The main metabolite is zidovudine glucuronide, the area under the concentration-time curve (AUC) of which is 3 times greater than the zidovudine AUC. After ingestion, about 14% of zidovudine and about 74% of its metabolite are found in the urine. Systemic clearance is about 2 l / h / kg, renal clearance is about 0.4 l / h / kg. The ratio of zidovudine concentration in the cerebrospinal fluid and plasma is about 0.6 / 1.

In patients with chronic renal failure (creatinine clearance 16-18 ml / min), AUC increases by 100%, C_max - 50%, half-life (T_1/2) does not change significantly and is about 1.5 h.

With hepatic failure, zidovudine clearance decreases. T_1/2varies depending on the severity of liver failure - 0.5-3 h.

Indications:

Treatment of HIV infection caused by HIV-1 (as part of combined antiretroviral therapy) in adults and children (over 3 years old with a body weight of more than 14 kg).

Prevention of transplacental HIV infection of the fetus.

Contraindications:

Hypersensitivity to zidovudine; neutropenia / leukopenia (the number of neutrophils is below 750 / μl); anemia (hemoglobin below 7.5 g / dl or 4.65 mmol / l); simultaneous reception with stavudine, doxorubicin, other drugs that reduce antiviral activity of zidovudine; children's age (up to 3 years).

Carefully:

Inhibition of bone marrow hemopoiesis, deficiency of cyanocobalamin or folic acid, hepatic insufficiency, advanced age, obesity, hepatomegaly, hepatitis or any risk factors for liver disease, neutropenia / leukopenia (neutrophil count 750-1000 / μl); Anemia (hemoglobin 75-90 g / l).

Pregnancy and lactation:

Zidovudine penetrates the placenta.It is not recommended to appoint women until 14 weeks of pregnancy. If you need to use the drug before the 14th week of pregnancy, you should carefully correlate the intended benefit to the mother and the potential risk to the fetus. 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 old: from 360-480 mg / m2, divided into 3-4 doses, in combination with other antiretroviral drugs.

Prevention of vertical transmission of HIV-1 from the mother to the fetus (with a gestation period of more than 14 weeks): pregnant women - 100 mg 5 times a day before the onset of labor (during the birth the drug is administered iv).

For severe anemia (hemoglobin less than 75 g / L or a 25% decrease from the baseline) and / or neutropenia (a number of granulocytes less than 750 / μL or a decrease of 50% of the baseline), a dose reduction may be required before hematopoiesis is restored.

At the terminal stage of chronic renal failure, patients on dialysis are given 100 mg every 6-8 hours.

The dosage regimen in patients with mild and moderate hepatic impairment is not established.

Side effects:

On the part of the organs of hematopoiesis: myelosuppression, anemia, neutropenia, leukopenia, lymphadenopathy, thrombocytopenia, pancytopenia with bone marrow hypoplasia, aplastic or hemolytic anemia.

From the digestive systemnausea, vomiting, dyspepsia, dysphagia, anorexia, taste distortion, abdominal pain, diarrhea, flatulence, bloating, pigmentation or ulceration of the oral mucosa, hepatitis, hepatomegaly with steatosis, jaundice, hyperbilirubinemia, increased activity of "liver" enzymes, pancreatitis.

From the nervous system: headache, dizziness, paresthesia, insomnia, drowsiness, weakness, lethargy, decreased mental performance, tremors, convulsions; anxiety, depression, confusion, mania.

From the sense organs: macular edema, amblyopia, photophobia, vertigo, hearing loss.

From the respiratory system: shortness of breath, cough, rhinitis, sinusitis.

From the side of the cardiovascular system: cardiomyopathy, fainting.

From the urinary system: rapid or difficult urination, hypercreatininaemia.

From the endocrine system and metabolism: lactic acidosis, gynecomastia.

From the side of the musculoskeletal system: myalgia, myopathy, muscle spasm, myositis, rhabdomyolysis, increased activity of creatine phosphokinase, lactate dehydrogenase.

From the skin: pigmentation of nails and skin, increased sweating, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Allergic reactions: skin rash, itching, hives, angioedema, vasculitis, anaphylactic reactions.

Other: malaise, back and chest pain, fever, flu-like syndrome, pain syndrome of various locations, chills, increased serum amylase activity, development of secondary infection, redistribution of adipose tissue.

It should be borne in mind that skin rashes, dizziness, weakness, headache, anorexia, diarrhea, anemia, myalgia, thrombocytopenia can be a manifestation of HIV infection itself and secondary diseases associated with it.

Overdose:

Symptoms: fatigue, headache, vomiting, violation of hematological parameters.

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

Interaction:

Stavudine reduces the effectiveness of zidovudine in vitro, so their simultaneous use is not recommended.

Nucleoside analogues that disrupt DNA replication, such as ribavirin, can in vitro reduce the antiviral activity of zidovudine.

Simultaneous use of such drugs with zidovudine is not recommended.

Simultaneous use of zidovudine and doxorubicin is not recommended due to mutual weakening of activity of each of the drugs in vitro.

Simultaneous application with ganciclovir, interferon alfa, ribavirin, other drugs that inhibit bone marrow hematopoiesis, incl. cytostatics can enhance the hematotoxicity of zidovudine.

Special instructions:

Treatment with zidovudine should be under the supervision of a doctor who has experience in the treatment of HIV infection. 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, increasing the subsequent dose is not recommended.

The frequency of side effects is associated with the dose and duration of the drug, increases in the late stages of the disease.

Dizziness, weakness, loss of appetite, diarrhea, some other side effects that appear at the beginning of treatment, can subsequently decrease and disappear.

Lactic acidosis and hepatomegaly with steatosis can be pronounced and lead to death, so when clinical or laboratory signs of lactic acidosis, or toxic liver damage 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 during the first 3 months of therapy, then - once a month.

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

It is necessary to perform systematic biochemical monitoring of the functional state of the liver: in the first 3 months of treatment - every 2 weeks, then at least once a month.

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

During the treatment should be monitored changes in 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.

With extreme caution, the drug should be prescribed to patients with renal and hepatic insufficiency, as well as elderly patients; in these cases, correction of the dosing regimen is recommended depending on the dynamics of the drug concentration in the blood. Caution should be exercised when concomitant administration of zidovudine and drugs,able to change its metabolism in the liver.

Zidovudine should not be prescribed with other medicines containing zidovudine.

In patients receiving zidovudine as part of combined antiviral therapy, there may be a syndrome of reactivation of immunity, which may require medical intervention. Zidovudine can cause redistribution / accumulation of fatty tissue, in particular, central obesity, the accumulation of fatty tissue in the dorso-cervical region ("buffalo" hump), thinning of fatty tissue in the limb or face area, breast augmentation, "Cushingoid" face.

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 10, 25 capsules in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1, 3, 4, 5 contour squares with the instruction for use are placed in a pack of cardboard.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-007182/10

Date of registration:27.07.2010 / 31.05.2017

Expiration Date:Unlimited

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Information update date: & nbsp13.10.2017

Illustrated instructions

Instructions

Zidovudine (Zidovudine)