Viro-Zet - 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 chain of the virus, its formation is blocked, the virus is stopped, and the therapeutic effect for reducing the concentration of HIV 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 human alpha cell polymerase,t.o. 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 Oitrobacter, 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 or 7 μmol / L) Giardia lamblia is inhibited, although there is no activity for other protozoa.

Pharmacokinetics:

Zidovudine is well absorbed from the gastrointestinal tract, the maximum concentration (C_mOh) 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) in concentrations 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.

In patients with impaired hepatic function, cumulation of zidovudine is possible due to a decrease in: glucuronidation in the liver.

Data on the pharmacokinetics of zidovudine in pregnant women are few, 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%). Admission with fatty foods reduces the rate and degree of absorption.

When administered inside 200 mg 6 times a day C_mOh - 1.5 μg / ml of plasma, the minimum concentration (C_min) - 0.1 μg / ml of plasma. In children, the concentration in the CSF is 24% of the concentration in the blood plasma. 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. The 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 severe renal failure - 8 hours, with anuria - 29-94 hours, with cirrhosis - varies depending on the severity of liver failure, an average of 2.4 hours; in children aged 2 weeks. up to 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 QC. In the liver, conjugation with glucuronic acid occurs; the basic inactive metabolite is 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranurono-zilthymidine; is excreted by the kidneys and does not possess antiviral activity.

14-18% of the drug in unchanged form is excreted by the kidneys, 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:

Viro-Zet is used in adults and children older than 3 years to treat HIV infection in the stage:
- acute infection
- incubation
- primary clinical manifestations
- with a decrease in CD4 fraction of T-lymphocytes less than 400-500 in mm³,
In pregnant women with HIV, Viro-Zet can be prescribed in the course of progression of secondary diseases or when the number of CD4-lymphocytes is less than 0.2 x 10⁹/ l. In other cases, the course of Viro-Zetom treatment may be interrupted before the first trimester of pregnancy expires.
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 750 in μl);
Anemia (hemoglobin below 7.5 g / dL);
Thrombocytopenia (platelets less than 25 thousand in μl);
Increase of aminotransferases and creatinine more than 3 times relative to the upper limit of the norm;
Children younger than 3 years.

Carefully:

Inhibition of bone marrow hematopoiesis, deficiency of cyanocobalamin (vitamin B₁₂) or folic acid, hepatic insufficiency, advanced age, obesity, hepatomegaly, hepatitis, or any known risk factors for liver disease. In the treatment of Viro-Zetoma, such patients require careful observation.

Pregnancy and lactation:

If it is necessary to prescribe the drug during pregnancy, you should carefully correlate the intended benefit to the mother and the potential risk to the fetus. Viro-Zet is not recommended for women until 14 weeks of pregnancy.

Women who use Viro-Z are not recommended to breast-feed.

Dosing and Administration:

Inside.

Adults on 0,6-0,8 g per day in 3-4 reception. In HIV lesions, the CNS daily dose is doubled.

Children over 3 years: 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 the rate of 0.005 g / kg.

The course of treatment is a long unlimited. Possible interruptions in treatment up to 1 month.

In the antenatal period, women who are pregnant, are recommended to take Viro-Zeta 0.1 g 5 times a day, starting from the 14th week of pregnancy before childbirth.

Special dosage adjustment data for old people no.

Patients with severe renal insufficiency should be prescribed Viro-Zet at lower doses. Further changes in dosage are carried out depending on the parameters of the peripheral blood and on the obtained clinical effect.

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.

For prevention of occupational HIV infection when working with infected biological material, as well as in cases of risk of parenteral HIV infection,it is recommended as soon as possible (no later than 72 hours after possible infection) to start taking Viro-Zet by 0.2 g 3 times a day for 4 weeks.

With a 25% reduction in hemoglobin and a 50% decrease in the number of neutrophils, the daily dose is reduced by a factor of 2 or the drug is temporarily withdrawn. After the restoration of these parameters, the dose can be increased again to the original daily values. Treatment is discontinued if the hemoglobin is less than 7.5 g / dL or the neutrophil count is below 750 / μL. If anemia develops (hemoglobin reduction by 2 g / dl) or neutropenia, which is determined in two blood tests done at 24-hour intervals, or a decrease in the platelet count to 50,000 / μL, the dose is reduced by 30%. Discontinuation of treatment in children is required with a hemoglobin level below 8 g / dL, a reduction in the number of neutrophils to 500 / μl in two consecutive blood tests done at 24-hour intervals, a decrease in the platelet count to 25,000 / mm3, or with progressive chronic renal failure. After the stabilization of blood values, Viro-Zet treatment is resumed in smaller doses.

Side effects:

To estimate the incidence of undesired reactions, the following grades are used: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1 / 10000,<1/1000), very rarely (<1/10000), the frequency is unknown (insufficient data to estimate the frequency of development).

On the part of the hematopoiesis system: often - anemia, neutropenia, leukopenia, infrequently - thrombocytopenia, pancytopenia with bone marrow hypoplasia, rarely - erythrocyte aplasia, very rarely - aplastic anemia, frequency unknown - granulocytopenia.

From the side of metabolism: often - hyperlactatemia, rarely - lactic acidosis in the absence of hypoxemia, anorexia, redistribution / accumulation of subcutaneous fat, frequency unknown - hypertriglyceridemia, hyperglycemia, lipodystrophy.

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

From the psychic sphere: rarely - anxiety, depression.

From the cardiovascular system: rarely - cardiomyopathy, the frequency is unknown - cardialgia.

From the respiratory system: infrequently - shortness of breath, rarely - cough.

From the digestive system: very often - nausea, often - vomiting, abdominal pain, diarrhea, infrequent - flatulence, rarely - taste distortion, pigmentation of the oral mucosa, dyspepsia.

From the hepatobiliary system and the pancreas: often - increase of bilirubin in the blood plasma, increased activity of "liver" transaminases, rarely - pancreatitis, hepatic steatosis, hepatomegaly, the frequency is unknown - increased activity of serum amylase.

From the skin: seldom - rash, pruritus, rarely - pigmentation of nails and skin, urticaria, increased sweating.

From the immune system: frequency unknown - diffuse toxic goiter, immune reactivation syndrome.

From the musculoskeletal system: often - myalgia, infrequently - myopathy.

From the excretory system: rarely - frequency of urination, frequency unknown - hypercreatininaemia.

Other undesirable phenomena: often - malaise, weakness, rarely - fever, generalized pain, fatigue, rarely - fever, gynecomastia, chest pain, flu-like symptoms, the frequency is unknown - asthenic syndrome, secondary infection, mitochondrial toxicity, mycobacterial infection.

Assessing the tolerability of the drug, it should be noted that the skin rashes, dizziness, weakness, headache, anorexia, diarrhea, myalgia, anemia, thrombocytopenia, may be a manifestation of HIV infection itself and secondary diseases associated with it, and not the toxic effect of AZT.

The incidence of neutropenia was higher in those patients whose neutrophil count, hemoglobin content and vitamin B12 plasma levels were low at the beginning of zidovudine therapy.

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. In case of adverse reactions, it is advisable to continue treatment with Viro-Zet and prescribe other drugs to correct complications. With a pronounced toxic effect, Viro-Zet is canceled before the restoration of the affected systems.

Overdose:

The maximum recorded concentration of zidovudine in the patient's blood is 49.4 μg / ml (after intravenous administration of the drug at a dose of 7.5 mg / kg every 4 hours for 2 weeks). Specific symptoms of overdose are not recorded. In case of intoxication, hemodialysis and peritoneal dialysis significantly increase the excretion of the glucuronic metabolite of zidovudine.

Interaction:

Do not use Viro-Zet in combined treatment regimens with phosphazide and stavudine, as these drugs are direct competitors of zidovudine in the mechanism of action,which can lead to a decrease in its 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.

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, α-interferon, amphotericin-B, co-trimoxazole, vinblastine, vincristine, ganciclovir, dapsone, sulfadiazine and other sulfonamides in combination with zidovudine increase myelotoxicity of each other.

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

Radiation therapy increases the risk of toxic effects of zidovudine.

Zidovudine increases the concentration of fluconazole.

There is synergistic effect with other HIV drugs (especially lamivudine) on 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, Viro-Zet should be used under medical supervision.

Patients should be warned that when taking Viro-Zeta they should not use other drugs without consulting a doctor. 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 Viro-Zet therapy does not reduce the risk of HIV transmission to other people during sexual intercourse or transfusion of infected blood.

During treatment, blood tests are prescribed once every 2 weeks. during the first 3 months. therapy, then - once a month.

Changes in the parameters of peripheral blood appear after 4-6 weeks; from the beginning of therapy.Anemia and neutropenia develop more often when zidovudine is used in high doses - 1500 mg / day. in patients with a decrease in T-helper (T4), with untreated HIV infection (with a reduced reserve of bone marrow before the start of therapy), neutropenia, anemia, vitamin B deficiency₁₂. 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. Against the background of Viro-Zetom therapy, opportunistic infections and other complications of HIV infection can develop, so patients should be under the supervision of doctors.

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

A special study of the effect of zidovudine on the ability to drive and move vehicles has not been carried out. Pharmacological properties of the drug indicate a low probability of such an effect. However, when assessing this ability, one should take into account the patient's condition and the nature of the side effects, if any.

Form release / dosage:

The tablets covered with a film cover on 300 mg.

Packaging:

For 60 tablets in a vial of high density polyethylene with a screw cap and a protective film of foil under the lid; 1 bottle with instructions for use in a cardboard box.

For 10 tablets in a blister of PVC / PVDNH; for 3, 6 or 10 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

Shelf life (for blisters). 2 years. Do not use after the expiry date printed on the package.

Shelf life (for vials). 3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-006462/09

Date of registration:13.08.2009 / 16.03.2015

Expiration Date:Unlimited

The owner of the registration certificate:Ranbaxy Laboratories LimitedRanbaxy Laboratories Limited India

Manufacturer: & nbsp

RANBAXY LABORATORIES, Ltd. India

Representation: & nbspRABBAYS LABORATORY LIMITEDRABBAYS LABORATORY LIMITED

Information update date: & nbsp19.02.2017

Illustrated instructions

Instructions

Viro-Zet (Viro-Z)