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

Active substance: zidovudine	100 mg	200 mg
Excipients:
lactose monohydrate	40 mg	80 mg
microcrystalline cellulose	18 mg	36 mg
potato starch	40 mg	80 mg
magnesium stearate	2 mg	4 mg

Composition of hard gelatin capsule:

Titanium dioxide (E 171) - 4%, iron oxide yellow (E 172) - 0.63%, gelatin to 100%.

Description:

Capsules hard, gelatinous, opaque, white body, lid yellow; capsules №0 (dosage 200 mg), capsules №3 (dosage of 100 mg).

The contents of capsules are white or white powder with a yellowish tinge color, odorless.

Pharmacotherapeutic group:antiviral [HIV] agent

ATX: & nbsp

J.05.A.F.01 Zidovudine

Pharmacodynamics:

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. Competitive inhibitory activity,azidothymidine triphosphate with respect to HIV reverse transcriptase is approximately 100 times greater than that of human alpha-cell polymerase, thus, zidovudine does not affect the normal metabolism of the human body.

It was found that low concentrations of zidovudine also inhibit many strains Enterobacteriaceae in vitro, including strains of different types Shigella, Salmonella, Klebsiella, Enterobacter and Citrobacter, and Escherichia coli, while the bacteria rapidly develop resistance to zidovudine.

Activity in relation to Pseudomonas aeruginosa in vitro not installed.

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_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) 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 from impaired hepatic function The cumulation of zidovudine is possible due to a decrease in glucuronidation in the liver.

Data on the pharmacokinetics of zidovudine the pregnant women are limited, as well as the elderly patients.

Have children at the age of more than 5-6 months pharmacokinetic data of zidovudine are similar to those in 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 the drug is administered 200 mg 6 times a day, the maximum concentration (C_mOh) - 1,5 μg / ml of plasma, the minimum concentration (C_max) - 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 / m²). It accumulates in the seminal fluid, where its concentrations exceed those in the serum of 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; at a cirrhosis - varies depending on a degree of the expressed hepatic insufficiency, on the average, 2,4 ч; in children aged 2 weeks - 13 years - 1-1.8 hours, up to 14 days - 3 hours, in newborns, whose mothers received Timazid® - 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-glucopyranuronosylthymidine, T_1/2with normal kidney function - 1 hour, with renal failure - 8 hours, with anuria - 29-94 hours, with cirrhosis - varies from the degree of liver failure, on average, about 2.4 hours; is excreted by the kidneys and does not possess antiviral activity.

Unchanged zidovudine is excreted by the kidneys at 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),which increases the risk of toxic effects.

Indications:

Treatment of HIV infection as part of combined antiretroviral therapy in children and adults.

Prevention transmission of HIV from an infected mother to a child during pregnancy and childbirth.

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

Contraindications:

- Hypersensitivity to zidovudine or any component of the drug;

- leukopenia (the number of neutrophils is less than 0.75 x 10⁹/ l or 750 in μl);

- Anemia (hemoglobin (Hb) - below 75 g / l or 4.65 mmol / l);

- 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;

- deficiency of lactase;

lactose intolerance;

- glucose-galactose malabsorption;

- Children under 3 years of age with a body weight of less than 30 kg.

Carefully:

When treating Timazid®, patients with oppression of bone marrow hematopoiesis, deficiency of vitamin and folate, overweight, liver failure, hepatomegaly, hepatitis, or any known risk factors for liver disease should be carefully monitored in old age.

Pregnancy and lactation:

Zidovudine penetrates the placenta, found in breast milk.

The drug is not recommended for women until 14 weeks of pregnancy. Use the drug before 14 weeks of pregnancy is possible only if the potential benefit to the mother exceeds the risk to the fetus.

Women who use Timazid®, should not breastfeed.

Dosing and Administration:

Inside adults 600-800 mg per day in 3-4 divided doses. With CNS lesions, the daily dose of HIV is doubled.

Children older than 3 years, the drug is prescribed at a rate of 10-20 mg / kg per day.

At the expressed by-effects the dose can be lowered at of adults up to 300 mg per day and in children up to 5 mg / kg.

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

During pregnancy women who maintain pregnancy are recommended to take the drug at 100 mg 5 times a day, starting from the 14th week of pregnancy and until the birth.

Special dosage adjustment data in the elderly no.

Patients with severe renal insufficiency should prescribe the drug 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.

For Profilaktics infection individualsReceiving pricks and cuts when working with material contaminated with HIV as well as in other cases, parenteral risk of HIV infection, it is recommended to take the drug as soon as possible but not later than 72 hours after the possible infection of 200 mg 3 times a day for 4 weeks.

With a decrease in hemoglobin (Hb) by 25% from the initial and 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 below 7.5 g / dl or the number of neutrophils below 750 / μl.

With the development of anemia (decrease of Hb below 2 g / dL) or neutropenia, which are determined in two analyzes at 24-hour intervals, or a decrease in the platelet count to 50,000 / μL, the dose is reduced by 30%.

Termination of treatment in children required: with a decrease in Hb below 8 g / dL; with a decrease in the number of neutrophils to 750 / μL in two consecutive analyzes with an interval of 24 hours; at decrease in the number of platelets to 25,000 / μl or with progressive chronic renal failure (CRF). After stabilizing the hematological parameters, the treatment is resumed in smaller doses.

Side effects:

In the first days of taking the drug - dizziness, weakness, loss of appetite, diarrhea. Usually these phenomena subsequently disappear. Undesirable reactions arising in the treatment of Timazid®, similar in children and adults.

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, tremor, cramps; 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, hypercreatinemia.

From the endocrine system and metabolism: lactate-acidosis, gynecomastia.

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

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 secondary diseases associated with it, rather than the toxic effect of the drug.

Overdose:

In case of overdose, fatigue, headache, vomiting and very rarely changes on the part of blood counts are possible. 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.

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

Interaction:

Metabolism of zidovudine occurs in the liver with the formation of an inactive metabolite of glucuronide, which is excreted from the body. Drugs that have a pathway similar to zidovudine for excretion can inhibit the metabolism of zidovudine.

Below is a list of drugs that should be used with caution in combination with zidovudine, although it should not be considered exhaustive.

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

Lamivudine. There is a moderate increase in C_m_Oh (28%) of zidovudine when given with lamivudine, but the total exposure (AUC) is not impaired. Zidovudine does not affect the pharmacokinetics of lamivudine.

Stavudine. Zidovudine can suppress intracellular phosphorylation of stavudine.

Phenytoin. Reduces the concentration of phenytoin in the blood plasma, which requires monitoring of the level of phenytoin in the blood plasma with its simultaneous appointment with zidovudine.

Ribavirin. The nucleoside analog ribavirin antagonist antiviral activity of zidovudine in vitro, therefore, simultaneous use of these two drugs should be avoided.

Rifampicin. The combination of zidovudine with rifampicin leads to a decrease in AUC for zidovudine, but the clinical significance of this change is not known.

Probenicide. Reduces glucuronization and increases the average half-life and AUC of zidovudine.Renal excretion of glucuronide and zidovudine itself decreases in the presence of a probenicide.

Atovahon. Zidovudine does not affect the pharmacokinetic parameters of the atovahona. Atovahon slows the transformation of zidovudine into a glucuronide derivative (zidovudine AUC in the equilibrium state increases by 33% and 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 a longer combined use of these drugs is necessary, careful monitoring of the clinical condition of the patient is recommended.

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

Valproic acid, fluconazole, methadone reduce the clearance of zidovudine, which is why its systemic exposure is increased. Zidovudine increases concentration fluconazole.

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

Other drugs: 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.

The combination of zidovudine with potentially nephrotoxic and myelotoxic drugs, such as pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin, increases the risk of developing unwanted reactions to zidovudine. It is necessary to observe the function of the kidneys and the blood formula; if necessary, reduce the dose.

Special instructions:

To avoid complications, the drug is used under the supervision of a doctor.

Patients should be warned that they should not independently use other drugs, including OTC drugs, concomitantly with Timazide®, and that drug therapy does not reduce the risk of transmission of HIV to other people during sexual intercourse or blood transfusion.

Irregular intake of the drug may lead to the development of resistance to the virus and reduce the effectiveness of treatment.

During the treatment, peripheral blood is monitored: 1 every 2 weeks for the first 3 months of therapy, then 1 time per month.

Hematologic changes appear 4-6 weeks after the start of therapy (anemia and neutropenia develop more often when used at high doses of 1500 mg / day in patients with a decrease in T helper (T4), with untreated HIV infection (with a reduced reserve of bone brain before the start of therapy), neutropenia, anemia, vitamin B deficiency₁₂). With a decrease in Hb more than 25% or a decrease in the number of neutrophils by more than 50% compared with the original - a blood test is 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.

Radiation therapy increases the risk of toxic effects of zidovudine.

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

Studies have not been carried out, however, when deciding whether to control the car, mechanisms, one should keep in mind the patient's condition and the possibility of developing side effects on Timazid®, such as dizziness, drowsiness, inhibition, seizures.

Form release / dosage:

Capsules, 100 mg and 200 mg.

Packaging:

10 capsules of 100 mg or 5 capsules of 200 mg in a planar cell pack (blister) made of PVC and foil; 5 blisters for 5 capsules (25 capsules for 200 mg), or 5 blisters for 10 capsules (50 capsules for 100 mg), or 10 blisters for 10 capsules (100 capsules of 100 mg) with instructions for use in a pack of cardboard.

100 capsules of 100 mg or 50 capsules of 200 mg each in a polymer can. Bank with instructions for use in a pack of cardboard.

Storage conditions:

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

Keep away from 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:P N003506 / 01

Date of registration:28.10.2009 / 18.05.2012

Expiration Date:Unlimited

The owner of the registration certificate:AZT PHARMA KB, LLC AZT PHARMA KB, LLC Russia

Manufacturer: & nbsp

AZT PHARMA KB, LLC Russia

Information update date: & nbsp03.01.2017

Illustrated instructions

Instructions

Timazid® (Timazid®)