Zido-H - instructions for use, dose, side effects, contraindications

Description:The tablets covered with a film shell of white or almost white color, round, biconcave with engraving "H" on one side and "1" on the other.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.F.01 Zidovudine

Pharmacodynamics:

Zidovudine is a synthetic analogue 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 alpha polymerase of human cell DNA.

The development of resistance to thymidine analogues (zidovudine - one of them) occurs as a result of the gradual appearance of specific mutations in the 6 codons (41, 67, 79, 210, 215 and 219) of HIV reverse transcriptase. The viruses acquire phenotypic resistance to thymidine analogues as a result of combined mutations in codons 41 and 215 or the accumulation of at least 4 of 6 mutations. Mutations do not cause cross-resistance to other nucleosides, which allows other reverse transcriptase inhibitors to be used to treat HIV infection. Two types of mutations lead to the development of multiple drug resistance. In one case, the mutations occur in 62, 75, 77, 116, and 151 codons of HIV reverse transcriptase, in the second case, the T69S mutation with insertion into the 6th pair of nitrogenous bases corresponding to this position is accompanied by the appearance of phenotypic resistance to zidovudine , as well as to other nucleoside reverse transcriptase inhibitors. Both types of these mutations significantly limit the therapeutic possibilities for HIV infection.

Zidovudine is used in combined antiretroviral therapy along with other nucleoside reverse transcriptase inhibitors and preparations from other groups (protease inhibitors, nucleoside reverse transcriptase inhibitors). There is synergy or increased activity of zidovudine when combined with lamivudine, didanosine, alpha interferon. However, in vitro studies suggest that combination therapy with three drugs (nucleoside analogues or two nucleoside analogs and a protease inhibitor) is more effective than one or two drugs therapy in suppressing HIV-1. The use of zidovudine in combination with lamivudine delays the emergence of zidovudine-resistant strains of the virus if patients have not previously had antiretroviral therapy. 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:

Suction. 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. When administered internally at a dose of 300 mg twice a day, the equilibrium concentration in the plasma is 2 μg / ml.

Distribution. 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 defined in amniotic fluid and in fetal blood. 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.

Metabolism. Metabolised in the liver. The main end metabolite is 5'-glucuronide of zidovudine, which does not have antiviral activity, is determined in both plasma and urine and is approximately 50-80% of the dose of the drug that is excreted by the kidneys.

Excretion. Mean half-life (T_1/2) from the cells - 3,3 h, from the blood serum in adults - about 1 hour (0,8-1,2 h). About 20% of zidovudine excreted unchanged through the kidneys, about 75% - is metabolized with the formation of glucoronides and subsequent excretion through the kidneys. Systemic clearance - 1-2,2 l / h / kg, renal clearance - 0,29-0,39 l / h / kg. The renal clearance of zidovudine greatly exceeds the creatinine clearance, which indicates the excretion of a significant part of the drug with tubular secretion.

Pharmacokinetics in children

In children older than 5-6 months, pharmacokinetic parameters are similar to those in adults.

Pregnancy

Pharmacokinetic parameters of zidovudine in pregnant women do not change, there are no signs of cumulation of zidovudine. The concentration of zidovudine in the plasma in children at birth is the same as that of their mothers during childbirth.

Elderly patients

The pharmacokinetics of zidovudine in patients older than 65 years has not been studied.

Patients with impaired renal function

In patients with severe renal failure, the maximum zidovudine concentration in plasma is increased by 50%. In individuals with chronic renal failure (creatinine clearance (CK) 16-18 ml / min) T_1/2 - 1.4 hours.In renal insufficiency, there is a significant cumulation of the main metabolite, but there is no evidence of a toxic effect. Hemodialysis and peritoneal dialysis do not affect the excretion of zidovudine, while the removal of glucuronide is enhanced.

Patients with impaired liver function.

With hepatic insufficiency, cumulation of zidovudine may be observed due to reduced glucuronization (requires dose adjustment).

Indications:

Treatment of HIV infection in combination antiretroviral therapy in adults and children weighing more than 30 kg.
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 below 75 g / l or 4.65 mmol / l);
simultaneous reception with stavudine, doxorubicin, other drugs that reduce antiviral activity of zidovudine;
children with body weight less than 30 kg.

Carefully:

Inhibition of bone marrow hemopoiesis, deficiency of cyanocobalamin or folic acid, hepatic insufficiency, advanced age, obesity, hepatomegaly, hepatitis or any known 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. 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. Zidovudine It is not recommended to appoint women until the 36th week of pregnancy (for this dosage form).

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

Influence on childbearing function

There is no evidence of the effect of zidovudine on women's fertile function. In men, zidovudine intake does not affect the sperm composition, morphology and motility of spermatozoa.

Dosing and Administration:

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

Adults and children with a body weight of at least 30 kg: 600 mg per day in 2 divided 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

300 mg twice a day, from 36 weeks gestation to the onset of labor, then 300 mg every 3 hours until the child is separated from the mother (the umbilical cord intersection).

Prevention of occupational HIV infection

600 mg per day in 2 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 hepatic function

In liver failure, there may be a need for correction of the dosing regimen, but existing data are insufficient to develop recommendations for dosing. If monitoring of zidovudine in plasma is not possible, it is recommended that attention be paid to the signs of drug intolerance and, if necessary, to increase the interval between doses.

Patients with impaired renal function

When creatinine clearance is more than 10 ml / min, dosage regimen correction is not required. For severe renal dysfunction (creatinine clearance less than 10 ml / min), the recommended dose of zidovudine is 300 mg once a day.

Elderly patients

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 hematopoiesis: myelosuppression, anemia, neutropenia, leukopenia, thrombocytopenia, pancytopenia with bone marrow hypoplasia, aplastic or hemolytic anemia.

From the digestive system: nausea, vomiting, dyspepsia, dysphagia, anorexia, taste distortion, abdominal pain, diarrhea, flatulence, pigmentation or ulceration of the oral mucosa, hepatitis, hepatomegaly with steatosis, jaundice, increased bilirubin concentration and hepatic enzyme activity, pancreatitis.

From the nervous system: headache, dizziness, paresthesia, insomnia, drowsiness, weakness, lethargy, decreased mental performance, tremor, convulsions; feelings of 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 cardiovascular system: cardiomyopathy, fainting.

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

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

From 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.

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 dose-dependent side effects. A case is described when, after taking an unidentified dose of zidovudine, the concentration of the drug in the blood was 16 times higher than the therapeutic concentration, but there were no clinical, biochemical or hematological symptoms.

Treatment: symptomatic therapy. Hemodialysis and peritoneal dialysis are ineffective in eliminating zidovudine, but accelerate the excretion of its 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 pranobekc) 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.

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

Lamivudine moderately increases the maximum concentration of zidovudine (by 28%), but does not change the total exposure (AUC). Zidovudine does not affect the pharmacokinetics of lamivudine.

Probenecid 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. It is necessary to monitor the concentration of phenytoin in the blood plasma when using this combination.

Zidovudine increases the concentration of fluconazole.

Ribavirin Suppresses the phosphorylation of zidovudine to triphosphate (not recommended at the same time).

Zidovudine suppresses intracellular phosphorylation stavudine (simultaneous reception 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 have a fatal outcome, so when clinical or laboratory signs of lactic acidosis or toxic liver damage appear zidovudine should be canceled. Risk factors for lactic acidosis are female sex, obesity, long-term use of antiviral drugs that are nucleoside analogues.

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.

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 initiation of therapy (anemia and neutropenia develop more oftena background of high doses of zidovudine (1.2-1.5 g / day) in patients with a decrease in CD4 + cells, with HIV infection (with a reduced reserve of bone marrow 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 the baseline, a blood test is 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.

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 using simultaneously with zidovudine non-prescription drugs withoutpreliminary 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:

Film-coated tablets, 300 mg.

Packaging:

When manufacturing on Hetero Draga Limited, India: 60 tablets per can polymer, sealed with aluminum foil, with a screw cap, which has a device that prevents children from opening the can. Free space in the banks is filled with cotton absorbent medical cotton. In the jar, granulated silica gel is put in a paper bag. 1 jar along with instructions for use in a pack of cardboard.

When produced at OOO Makyz-Pharma, Russia: For 60 tablets in a jar of polymeric, ukuporennuyu cover. Free space in the banks filled with cotton absorbent medical absorbent or imported shock absorber. 1 jar along with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

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

Terms of leave from pharmacies:On prescription

Registration number:LS-001965

Date of registration:04.05.2012 / 08.08.2017

Expiration Date:Unlimited

The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India

Manufacturer: & nbsp

HETERO DRUGS Limited India

MAKIZ-PHARMA, LLC Russia

Information update date: & nbsp13.10.2017

Illustrated instructions

Instructions

Zido Hitch (Zido-H)