Zidovudine

General characteristics. Structure:

Active ingredient: 100 mg of a zidovudine in 1 capsule.

Excipients: potato starch, кросповидон, cellulose microcrystallic, povidone, magnesium stearate.

Capsule: gelatin, titanium dioxide.

Pharmacological properties:

Pharmacodynamics: Antiviral drug with high activity against retroviruses including a human immunodeficiency virus, is an analog of thymidine and concerns to group of nukleozidny inhibitors of the return transcriptase. Selectively inhibits replication of virus DNA due to competitive blockade of the return transcriptase. The zidovudine triphosphate has structural similarity to thymidinetriphosphate, owing to similarity competes with it for embedding in the growing chains of a virus RNA-dependent DNA polymerase (the return transcriptase), suppressing thereby replication of retrovirus DNA.

Getting to a cell (both in infected, and in intact), with the participation of respectively cellular thymidinekinases, a timidilatkinaza and a nonspecific kinase it is phosphorylated with education mono - di - and trifosfatny connection. A zidovudine triphosphate is inhibitor, and also substrate for effect of reverse transcriptase of a virus; mediates formation of virus DNA on a matrix of virus RNA.

Increases quantity of CD4 of cells (indicators of the immune status), increases ability of an organism to infection resilience.

Ability to inhibit the HIV return transcriptase 100-300 times higher, than ability to suppress a DNA polymerase an alpha of the person.

The zidovudine is active concerning a virus of hepatitis B and Epstein-Barre's virus in vitro; however when using as monotherapy at patients with hepatitis B and AIDS it slightly suppresses replication of a virus of hepatitis B.

It is revealed that low concentration of a zidovudine of in vitro inhibit also many strains of Enterobacteriaceae, 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 of in vitro concerning Pseudomonas aeruginosa is not established. In very high concentration (1,9 mkg/ml) suppresses Giardia lamblia though concerning other protozoa activity is absent.

Pharmacokinetics: Pharmacokinetic parameters of a zidovudine at children are more senior than 3 months and at adults are similar. Absorption - high, bioavailability - 60-70%, at newborns aged up to 14 days is 89%, 14 days - 61% are more senior. Reception with greasy food reduces the speed and extent of absorption. Communication with proteins of plasma rather low - 34-38%. Time of achievement of the maximum concentration (TCmax) after intake in blood serum - 30-90 min., in spino-brain liquid - 1 h after the end of infusion.

At appointment inside in a dose of 300 mg 2 times a day equilibrium concentration in plasma makes 2 mkg/ml. Distribution volume at adults and children – 1,4-1,7 l/kg (42-52 l / кв.м). Gets into the majority of fabrics and liquids of an organism, through a placenta and the blood-brain barrier (BBB). Concentration in cerebrospinal fluid (SMZh) makes 15-64% of concentration in plasma. Children have a concentration in SMZh – 24% of content in plasma. Is defined in amniotic liquid and in fruit blood; concentration of a zidovudine in plasma at children at the birth same, as at mothers at the time of delivery. It is found in breast milk. Collects in semen where its concentration exceed those in blood serum by 1,3-20,4 times, but does not influence allocation of HIV with semen and therefore cannot prevent transfer of HIV sexually.

In a liver there is a conjugation of a zidovudine to glucuronic acid. The main inactive metabolite - 3-азидо-3-дезокси-5-О-бета-D-глюкопирануронозилтимидин which elimination half-life (T½) at normal function of kidneys - 1 h, at a renal failure - 8 h, at an anury - 29-94 h, at cirrhosis - vary depending on degree of a liver failure and averages about 2,4 h. The conjugate is removed by kidneys and has no antiviral activity.

In not changed look it is removed by kidneys of 14-18% of a zidovudine, children have 30%; in the form of glucuronides - 60-74%, at children are 45%. Does not kumulirut. T1/2 from cells is 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 the cirrhosis (C) of T1/2 vary depending on degree of manifestation of a liver failure, averaging 2,4 h; at newborns (whose mothers received a zidovudine) - 13 h. At children aged from 2 weeks up to 13 years of T1/2 makes 1-1,8 h.

The renal clearance – 27,1 ml/min., at children is 30,9 ml/min., exceeds KK that indicates removal of a considerable part of drug by means of canalicular secretion.

At the chronic renal failure (CRF) accumulation of metabolites is possible (conjugates with glucuronic acid) that increases risk of manifestation of toxic action. At sick CPUs and a liver failure cumulation owing to decrease in intensity of linkng with glucuronic acid is possible.

Indications to use:

In a combination with other anti-retrovirus means it is applied to treatment of HIV infection at adults and children (more than 14 kg are more senior than 3 years with body weight); prevention of professional infection of the persons who took injections and cuts during the work with the HIV-contaminated material and transplacental HIV infection of a fruit.

Route of administration and doses:

Inside, without chewing, with enough liquid, irrespective of meal.

Adults and children with body weight not less than 30 kg: on 600 mg a day in 2-3 inclusion in combinations with other anti-retrovirus drugs.

Children of 3 years with the body weight of 14-20 kg: 300 mg a day in 2 receptions (2 capsules in the morning and 1 evening).

Children with the body weight of 20-30 kg: 400 mg a day in two steps.

At decrease in a hemoglobin content by 25% of initial contents, number of neutrophils by 50% from initial the daily dose is reduced twice or temporarily cancelled. After recovery of indicators the dose can be again increased to reference daily values. Treatment should be stopped if the hemoglobin content is less than 75 g/l or the number of neutrophils are lower than 0,75Õ109/l.

Prevention of professional infection of HIV: 600 mg a day in 2-3 receptions within 4 weeks. Chemoprophylaxis of parenteral transfer of HIV is recommended to be begun no later than in 72 hours after possible infection.

Prevention of transplacental transfer of HIV: on 100 mg of 5 times a day, since 14th week of pregnancy, or on 300 mg 2 times a day, since 36th week of pregnancy prior to patrimonial activity, then on 300 mg each 3 hours until separation of the child from mother (crossing of an umbilical cord).

Patients with an abnormal liver function: at the expressed disturbance of functions of a liver there can be a need for correction of the mode of dosing (a dose of introduction or an interval between receptions of doses).

Patients with a renal failure: at KK more than 10 ml/min. of correction of the mode of dosing are not required. At smaller KK the recommended dose of a zidovudine makes 300-400 mg/days, but when progressing HPN further dose adjustment can be required.

Patients of advanced age: changes of the mode of dosing are not required, however, it is necessary to consider involute izmeneniyafunktion of kidneys, other systems and bodies.

Features of use:

Use at pregnancy and during breastfeeding: The zidovudine gets through a placenta. It is not recommended to appoint to women till 14th week of pregnancy. In need of purpose of drug till 14th week of pregnancy it is necessary to correlate carefully estimated advantage estimated advantage for mother and potential risk for a fruit. In case of use of drug in the period of a lactation it is necessary to stop breastfeeding

Treatment by a zidovudine has to take place under observation of the doctor. Irregular administration of drug can lead to development of stability of a virus and decrease in efficiency of treatment. At the admission of reception it is not recommended to increase the subsequent dose.

Frequency of development of side effects is connected with a dose and duration of use of drug, increases at late stages of a disease.

Dizziness, weakness, the appetite loss, diarrhea, some other by-effects appearing in an initiation of treatment can decrease and disappear afterwards.

Lactic acidosis and hepatomegalia with a steatosis can be expressed and lead to a lethal outcome therefore at emergence of clinical or laboratory signs of lactic acidosis or toxic damage of a liver the zidovudine should be cancelled.

During treatment it is necessary to carry out systematic control of a picture of peripheral blood: 1 time in 2 weeks within the first 3 months of therapy, then – once a month.

Hematologic changes appear usually in 4-6 weeks from the beginning of therapy (anemia and a neutropenia usually develop against the background of high doses of a zidovudine (1,2-1,5 g/days) at patients with reduced quantity of CD4+ of cells, with heavy HIV infection (at considerable oppression of a marrowy hemopoiesis prior to therapy). At decrease in hemoglobin more than for 25% or reduction of number of neutrophils is more white than for 50% in comparison with the beginning of therapy blood test is carried out more often.

It is necessary to make systematic biochemical control of a functional condition of a liver: in the first 3 months of treatment – each 2 weeks, then – at least 1 time a month.

At co-administration of a zidovudine and any of the drugs possessing nefro-or myelotoxic action, it is necessary to control carefully function of kidneys and hematologic indicators.

In the course of treatment it is necessary to control changes in the immune status of patients. At the patients receiving drug opportunistic infections and other complications of HIV infection can develop.

Anti-retrovirus therapy does not prevent transfer of HIV at sexual contact and through the infected blood.

With extra care it is necessary to appoint drug sick with a renal and liver failure, and also the elderly patient; in these cases correction of the mode of dosing depending on dynamics of concentration of drug in blood is recommended. It is necessary to be careful at the co-administration of a zidovudine and drugs capable to change his metabolism in a liver. Use of drug for pregnant women is possible in case the expected advantage for mother exceeds potential risk for a fruit. In need of use in the period of a lactation it is necessary to stop breastfeeding.

Influence on ability to driving of motor transport and to control of mechanisms: During treatment it is necessary to be careful during the driving of motor transport and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

From system of blood and the hemopoietic bodies: a miyelosupressiya, anemia, a neutropenia, a leukopenia, thrombocytopenia, a pancytopenia with a marrow hypoplasia, aplastic anemia.

From the alimentary system: nausea, vomiting, dyspepsia, anorexia, a food faddism, abdominal pains, diarrhea, a meteorism, pigmentation of a mucous membrane of an oral cavity, a hepatomegalia with a steatosis, increase in blood of activity of "hepatic" enzymes, concentration of bilirubin, pancreatitis, increase in activity of serumal amylase.

From the central and peripheral nervous system: headache, dizziness, paresthesias, sleeplessness, drowsiness, weakness, slackness, decrease in intellectual working capacity, feeling of alarm, depression, adynamy, spasms.

From respiratory system: short wind, cough.

From cardiovascular system: cardialgias, cardiomyopathy.

From an urinary system: increase of an urination, giperkreatininemiya.

From endocrine system and a metabolism: lactic acidosis in the absence of an anoxemia, a gynecomastia.

From a musculoskeletal system: mialgiya, myopathy.

Allergic reactions: skin rash, itch, small tortoiseshell.

From skin and hypodermic cellulose: pigmentation of nails and skin, the increased sweating.

Others: fever, indisposition, development of consecutive infection, food faddism, fever, pain syndrome of various localization.

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

Interaction with other medicines:

Combined use of paracetamol with a zidovudine increases the frequency of emergence of a neutropenia, apparently, owing to oppression of metabolism of a zidovudine (both drugs glyukuronirutsya).

The drugs inhibiting enzymes of a microsomal oxidation in a liver (acetylsalicylic acid, morphine, codeine, indometacin, valproic acid, ketoprofen, Naproxenum, oxazepam, lorazepam, Cimetidinum, Clofibratum) also change metabolism of a zidovudine, by inhibition of activity of glucuronidase or direct inhibition of microsomal metabolism in a liver in this connection concentration of a zidovudine in plasma increases.

Simultaneous treatment by the drugs possessing nephrotoxic action or suppressing function of marrow (dapsone, pentamidine, Pyrimethaminum, Amphotericinum In, флуцитозин, ганцикловир, Vincristinum, vinblastine, doxorubicine, interferon an alpha, co-trimoxazole), increases risk of toxic action of a zidovudine.

Probenitsid and other inhibitors of canalicular secretion extend T ½ zidovudines. The zidovudine increases concentration of a flukonazol.

Synergism at use is noted by other antiviral drugs HIV, (lamivudiny) concerning replication, in culture of cells. Ribavirin suppresses phosphorylation of a zidovudine to triphosphate therefore their joint use is not recommended.

Stavudin kazyvat antagonistic action to a zidovudine therefore their combined use is undesirable.

Rifampicin reduces concentration of a zidovudine in plasma that can lead to decrease in efficiency of the last therefore it is not recommended to apply them at the same time.

Absorption of a zidovudine decreases at a concomitant use with tablets of a klaritromitsin in this connection it is recommended to use drugs with an interval not less, than 2 hours.

In need of performing anti-virus antiherpetic therapy it is possible to apply an acyclovir.

Contraindications:

Hypersensitivity to a zidovudine or any component of drug, a neutropenia/leukopenia (number of neutrophils below 750/mkl), anemia (a hemoglobin content less than 7,5 g/dl or 4,65 mmol/l), the thrombocytopenia (reduction of quantity of thrombocytes to 25000/mkl) expressed to HPN, a heavy liver failure. Children up to 3 years and with body weight less than 14 kg. Deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.

With care: Oppression of a marrowy hemopoiesis, deficit of cyanocobalamine or folic acid, liver failure, advanced age, obesity, hepatomegalia, hepatitis or any known risk factors of diseases of a liver.

Overdose:

Symptoms: strengthening of manifestations of the described by-effects.

Treatment: gastric lavage, absorbent carbon, symptomatic therapy. The hemodialysis and peritoneal dialysis are ineffective at removal of a zidovudine, but accelerate elimination of a glucuronic metabolite.

Storage conditions:

In the dry place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 10 capsules in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 3, 5, 10 blister strip packagings together with the application instruction place in a pack from a cardboard.