Timazid

General characteristics. Structure:

Active agent: zidovudine of 100 mg or 200 mg.

Excipients: lactose (sugar - milk), potato starch, cellulose microcrystallic, magnesium stearate.

Structure of capsules: the case - gelatin, titanium E171 dioxide; a cover - gelatin, titanium E171 dioxide, yellow quinolinic E104.

Pharmacological properties:

Pharmacodynamics. The zidovudine is an analog of thymidine and concerns to group of nukleozidny antiviral drugs. Has the high inhibiting activity concerning retroviruses, including the human immunodeficiency virus (HIV).

In the cells of the person infected with a virus the zidovudine is phosphorylated under the influence of a thymidinekinase to azidothymidinetriphosphate which is substrate inhibitor of the return transcriptase of retroviruses: at implementation of azidothymidinetriphosphate in a synthesizable chain of DNA of a virus, its further education it is blocked, reproduction of a virus stops what the therapeutic effect on decrease in concentration of HIV in the patient's blood is based on. The competitive inhibiting activity of azidothymidinetriphosphate concerning the HIV return transcriptase approximately by 100 times surpasses that for a DNA polymerase an alpha of cells of the person, thus the zidovudine does not exert impact on normal metabolism of a human body.

It is revealed that low concentration of a zidovudine inhibit also many strains of Enterobacteriaceae in vitro, including strains of different types of Shigella, Salmonella, Klebsiella, Enterobacter and Citrobacter, and also Escherichia coli (at the same time at bacteria resistance to a zidovudine quickly develops). Activity concerning Pseudomonas aeruginosa in vitro is not established. In very high concentration (1,9 mkg/ml (7 µmol/l)) suppresses Giardia lamblia though concerning other protozoa activity is absent.

Pharmacokinetics. The zidovudine is well soaked up from digestive tract, the maximum concentration (Cmax) in blood is reached in 30-90 minutes, bioavailability makes 63%. Gets through a blood-brain barrier (GEB) and it is found in cerebrospinal fluid (SMZh) in the concentration making 15-64% of an initial dose.

Well gets through a placenta owing to what its concentration in blood of an umbilical cord is comparable from that mother in blood. It is found in breast milk. Metabolism happens in a liver to formation of a glucuronide which is brought out of an organism by kidneys with urine.

At patients with abnormal liver functions cumulation of a zidovudine due to decrease in a glyukuronirovaniye in a liver is possible.

Data on zidovudine pharmacokinetics at pregnant women are limited, also as well as at elderly patients. At children 5-6 months are aged more senior pharmacokinetic data of a zidovudine are similar to those at adults.

Linkng of a zidovudine with proteins of plasma rather low (34-38%). Bioavailability at newborns aged up to 14 days - 89%, is more senior than 14 days of-61%. Reception with greasy food reduces the speed and extent of absorption.

At appointment in 200 mg of 6 times in days of Cmax - 1,5 mkg/ml of plasma, the minimum concentration (Cmin) - 0,1 mkg/ml of plasma. Gets through GEB, concentration in SMZh - 24% of concentration in a blood plasma is at children. Passes through a placenta (concentration in tissues of the central nervous system (CNS) at a 13 weeks fruit - 0,01 µmol/l that below effective antiviral concentration). Distribution volume at adults and children - 1,4-1,7 l/kg (42-52 l / кв.м). Collects in semen where its concentration exceed those in blood serum by 1,3-20,4 times, but does not influence removal of HIV with semen and therefore cannot prevent transfer of HIV sexually. An average elimination half-life (Т½) from cells - 3,3 h; from blood serum at adults - about 1 h (0,8-1,2 h), at a renal failure (the clearance of creatinine (CC) less than 30 ml/min.) - 1,4-2,9 h, at cirrhosis - vary depending on degree of manifestation of a liver failure, on average, 2,4 h; children at the age of 2 weeks-13 of years have 1-1,8 h, at newborns (whose mothers received a zidovudine)-13 h. The renal clearance - 27,1 ml/min., at children is 30,9 ml/min., exceeds KK. In a liver there is a conjugation to glucuronic acid; the main inactive metabolite - 3-азидо-3-дезокси-5-О-бета-D-глюкопирануроно-зилтимидин, T½ at normal function of kidneys of-1 h, at a renal failure - 8 h, at an anury - 29-94 h, at cirrhosis - varies depending on degree of a liver failure, on average, about 2,4 h; it is removed by kidneys and has no antiviral activity.

In not changed look it is brought by kidneys to 14-18%, children have 30%; in the form of glucuronides - 60-74%, at children are 45%. Does not kumulirut; at a chronic liver failure accumulation of metabolites is possible (conjugates with glucuronic acid) that increases risk of manifestation of toxic action.

Indications to use:

- treatment of HIV infection as a part of the combined anti-retrovirus therapy at children and adults;

- prevention of transfer of HIV infection from the infected mother to the child during pregnancy and childbirth;

- prevention of the infected persons who took injections and cuts during the work with the material contaminated by HIV.

Route of administration and doses:

Inside the adult on 0,6-0,8 g a day in 3-4 receptions. At defeats of TsNS HIV the daily dose is doubled. To children drug is more senior than 2 years appoint at the rate of 0,01-0,02 g/kg a day.

At the expressed side effects the dose can be lowered to 0,3 g a day at adults and at children from calculation to 0,005 g/kg.

Course of treatment - long, almost unlimited term. Breaks are possible it is aware of treatment up to 1 month.

In the antenatal period reception of the Zidovudine on 0,1 g of 5 times a day since 14th week of pregnancy before childbirth is recommended to the women keeping pregnancy.

Elderly people have no special data on change of a dosage.

Patients with the expressed renal failure should appoint the Zidovudine in lower doses. Further changes in a dosage have to correlate with hematologic parameters and clinical reaction to drug.

At a liver failure dose adjustment can be also required: the doctor should pay attention to signs of intolerance of drug and, if necessary, to increase intervals between introduction of doses.

For prevention of professional infection of HIV (work with the infected biological material), and also in other cases of parenteral risk of HIV infection, it is recommended to accept the Zidovudine on 0,2 g 3 times as soon as possible a day (no later than in 72 hours after possible infection) within 4 weeks.

At decrease in Hb by 25% from initial, numbers of neutrophils - a daily dose reduce by 50% of initial twice or temporarily cancel. After recovery of indicators the dose can be again increased to reference daily values. Treatment is stopped if Hb is less than 7,5 g/dl or the number of neutrophils are lower 750/mkl. At development of anemia (decrease in Hb by 2 g/dl) or a neutropenia which are defined in two analyses at an interval of 24 h or reduction of quantity of thrombocytes to 50000/mkl, the dose is lowered by 30%. The termination of treatment is required from children: at decrease in N it is lower than 8 g/dl; decrease in quantity of neutrophils to 500/mkl in two sequential analyses at an interval of 24 h; reduction of quantity of thrombocytes to 25000/mkl or at the progressing HPN. After stabilization of hematologic parameters treatment is resumed in smaller doses.

Features of use:

In order to avoid complications the Zidovudine is applied under control of the doctor.

Patients need to be warned that they should not use other drugs at the same time independently. Irregular administration of drug can lead to development of stability of a virus and decrease in efficiency of treatment.

Patients should be informed that therapy by the Zidovudine does not reduce risk of transfer of HIV to other people at sexual contacts or hemotransfusion.

During treatment carry out control of peripheral blood: 1 time in 2 weeks within the first 3 months of therapy, then - 1 time in month.

Hematologic changes appear in 4-6 weeks from the beginning of therapy (anemia and a neutropenia develop at use in high doses more often - 1500 mg/days are at patients with decrease in contents T-helperov (T4), with not treated HIV infection (at a reduced reserve of marrow prior to therapy), a neutropenia, anemia, deficit of B12 vitamin). At decrease in N more, than for 25% or reduction of number of neutrophils more, than for 50% in comparison with initial - blood tests carry out more often. At the patients receiving drug opportunistic infections, etc. HIV infection complications therefore they have to remain under observation of doctors can develop.

With care appoint to the patients who are engaged in potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

In the first days of reception of the Zidovudine - dizziness, weakness, appetite loss, diarrhea. Usually these phenomena disappear afterwards.

From bodies of a hemopoiesis: a miyelosupressiya, anemia, a neutropenia, a leukopenia, a lymphadenopathy, thrombocytopenia, a pancytopenia with a marrow hypoplasia, aplastic or hemolitic anemia.

From the alimentary system: nausea, vomiting, dyspepsia, a dysphagy, anorexia, a food faddism, an abdominal pain, diarrhea, a meteorism, abdominal distention, pigmentation or an ulceration of a mucous membrane of an oral cavity, hepatitis, a hepatomegalia with a steatosis, jaundice, a hyperbilirubinemia, increase in activity of "hepatic" enzymes, pancreatitis.

From a nervous system: headache, dizziness, paresthesias, sleeplessness, drowsiness, weakness, slackness, decrease in intellectual working capacity, tremor, spasms; alarm, depression, confusion of consciousness, mania.

From sense bodys: macular hypostasis, amblyopia, photophobia, вертиго, hearing loss.

From respiratory system: short wind, cough, rhinitis, sinusitis.

From CCC: cardiomyopathy, syncope.

From an urinary system: the speeded-up or complicated urination, a giperkreatininemiya.

From endocrine system and a metabolism: lactacidemia, gynecomastia.

From a musculoskeletal system: mialgiya, myopathy, spasm of muscles, miositis, рабдомиолиз, increase in activity of KFK, LDG.

From integuments: pigmentation of nails and skin, the increased sweating, Stephens-Johnson's syndrome, toxic an epidermal necrolysis.

Allergic reactions: skin rash, itch, small tortoiseshell, Quincke's disease, vasculitis, anaphylactic reactions.

Others: indisposition, dorsodynia and breasts, fever, grippopodobny syndrome, pain syndrome of various localization, fever, increase in activity of serumal amylase, development of consecutive infection, redistribution of fatty tissue.

Estimating portability of drug, it is necessary to consider that skin rashes, dizziness, weakness, a headache, anorexia, diarrhea, a mialgiya, anemia, thrombocytopenia, can be display of the HIV infection and the related secondary diseases but not toxic effect of drug.

Interaction with other medicines:

Metabolism of a zidovudine happens in a liver about formation of an inactive metabolite of a glucuronide which is brought out of an organism. The drugs having a way of removal, similar to a zidovudine, from an organism can inhibit metabolism of a zidovudine.

Drugs which need to be taken with caution in combination with a zidovudine (you should not consider the list exhaustive).

Fosfazid: along with stavudiny are direct competitors on the action mechanism that can lead to decrease of the activity concerning HIV.

Stavudin: the zidovudine can suppress intracellular phosphorylation of a stavudin.

Feniton: reduces concentration of a feniton in a blood plasma that demands observation of its level in a blood plasma at its simultaneous appointment with a zidovudine.

Rifampicin: the combination with a zidovudine leads it to decrease in AUC for a zidovudine, however clinical value of this change is not known.

Probenitsid: reduces a glyukuronization and raises an average elimination half-life and AUC of a zidovudine. Renal excretion of a glucuronide and the zidovudine decreases in the presence of a probenitsid.

Atovakhon: the zidovudine does not influence pharmacokinetic parameters of an atovakhon. In need of a long combination of these drugs observation of a clinical condition of the patient is recommended.

Klaritromitsin: reduces absorption of a zidovudine. The break between dosing has to make not less than 2 hours.

Paracetamol: increases the frequency of emergence of a neutropenia owing to oppression of metabolism of a zidovudine.

Other drugs: acetylsalicylic acid, codeine, morphine, indometacin, ketoprofen, Naproxenum, oxazepam, lorazepam, Cimetidinum, Clofibratum, dapsone, inosine can influence metabolism of a zidovudine by competitive inhibition of a glyukuronirovaniye and direct oppression of microsomal enzymes in a liver. Observation of function of kidneys and a blood count is necessary; if necessary reduce a dose.

Contraindications:

- hypersensitivity to drug;

- leukopenia;

- anemia (hemoglobin (N) is lower than 75 g/l);

- thrombocytopenia (thrombocytes less than 25 thousand in мкл);

- increase in aminotransferases and creatinine more than by 3 times of rather upper bound of norm;

- deficit of lactase;

- lactose intolerance;

- gdyukozo-galaktozny malabsorption;

- children are younger than 3 years with body weight less than 30 kg.

Overdose:

Symptoms: fatigue, headache, vomiting, disturbance of hematologic indicators. Most registered concentration of a zidovudine in blood of the patient made 49,4 mkg/ml (after intravenous administration of drug in a dose of 7,5 mg/kg each 4 hours within 2 weeks). After similar overdose any specific symptoms were not noted. In case of intoxications hemodialysis and peritoneal dialysis significantly strengthen removal of a glucuronic metabolite of a zidovudine.

Storage conditions:

At a temperature not above 25 °C in dry protected from light and the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules on 0,1 and 0,2g.

10 capsules on 0,1 g or 5 capsules on 0,2 g place in a blister strip packaging. 5 or 10 planimetric packagings on 0,1 g or 5 planimetric packagings on 0,2 g with the application instruction place in a pack from a cardboard.

100 capsules on 0,1 g or 50 capsules on 0,2 g place in banks polymeric. To bank together with the application instruction place in a pack from a cardboard.