Retrovir

General characteristics. Structure:

Active ingredient: Zidovudine of 200 mg 10 mg
Excipients: Acid the hydrochloric concentrated q.s q.s; Sodium q.s q.s hydroxide; Water for injections to 20 ml to 1 ml

Notes:
1. Acidum hydrochloricum concentrated or sodium hydroxide is used.

Pharmacological properties:

Pharmacodynamics. Action mechanism

Zidovudine ― antiviral drug, highly active in vitro concerning retroviruses, including the human immunodeficiency virus (HIV).

Process of phosphorylation of a zidovudine is carried out both in infected, and in not infected human body cells with formation of a zidovudine triphosphate (TF) which works as inhibitor and substrate for the HIV return transcriptase. Formation of pro-virus DNA is blocked by implementation zidovudina-TF in its chain that leads to break of a chain. The competition zidovudina-TF for the HIV return transcriptase is about 100 times stronger, than for an a-polymerase of cellular DNA of the person. The zidovudine works is additive or is synergistic with a large amount of anti-retrovirus drugs, such as ламивудин, диданозин, a-interferon, suppressing replication of HIV in culture of cells.

Development of resistance to thymidine analogs (a zidovudine ― one of them) results from gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of the HIV return transcriptase. Viruses gain phenotypical resistance to thymidine analogs as a result of the combined mutations in codons 41 and 215 or by means of accumulation, at least, of 4 of 6 mutations. These mutations of resistance to analogs of thymidine (MRAT) do not cause cross resistance to any other nukleozidny inhibitors of the return transcriptase (NIRT) that allows to apply other NIOT to further treatment of HIV infection.

Two types of mutations lead to development of multiple medicinal resistance. In one case of a mutation occur in 62, 75, 77, 116 and 151 codons of the HIV return transcriptase, in the second case it is about mutation T69S with an insert in the same position of 6 base pairs that is followed by emergence of phenotypical resistance to a zidovudine, and also to other registered nukleozidny inhibitors of the return transcriptase. Both types of these mutations considerably limit therapeutic opportunities at HIV infection.

Decrease in sensitivity to a zidovudine was observed at prolonged treatment of HIV infection by this drug. Now communication between sensitivity to a zidovudine in vitro and clinical effect of therapy is not studied. Use of a zidovudine in a combination with lamivudiny detains emergence of virus strains, resistant to a zidovudine, if to patients anti-retrovirus therapy was not carried out earlier.

Pharmacokinetics. Absorption
At the patients receiving within an hour Retrovir's infusion in a dose of 1-5 mg/kg on 3–6 times a day, the pharmacokinetics of a zidovudine had dozozavisimy character. Average equilibrium maximum (Cssmax) and minimum (Cssmin) of concentration of a zidovudine in a blood plasma at adults after infusion within 1 hour on 2,5 mg/kg each 4 h made 4,0 and 0,4 microns respectively (or 1,1 and 0,1 mkg/ml).

Distribution
Linkng of a zidovudine with proteins of plasma ― 34–38%. The average elimination half-life, average general clearance and volume of distribution made 1,1 hours, 27,1 ml/min. and 1,6 l/kg respectively. The zidovudine gets through a placenta and is defined in amniotic liquid and in fruit blood. The zidovudine is also defined in sperm and in breast milk.

Metabolism
5 glucuronide of a zidovudine are the main metabolite of a zidovudine, is defined both in plasma, and in urine and makes about 50-80% of a drug dose which is removed by kidneys.

3amino-3-dezoksitimidin (AMT) are a metabolite of a zidovudine which is formed at intravenous administration of drug.

Removal
The renal clearance of a zidovudine much more exceeds clearance of creatinine that indicates considerable removal of a zidovudine by means of canalicular secretion.

Special groups of patients

Children
At children 5–6 months are aged more senior pharmacokinetic indicators are similar to those at adults. After intravenous administration of a zidovudine in a dose of 80 mg/sq.m of a body surface, 120 mg/sq.m, 160 mg/sq.m of Cssmax value make respectively 1,46 mkg/ml, 2,26 mkg/ml and 2,96 mkg/ml. At intravenous administration the average elimination half-life and the general clearance make 1,5 h and 30,9 ml/min. respectively. The main metabolite is 5 ’-a zidovudine glucuronide. After intravenous administration of 29% of a dose of drug 45% of a dose ― in the form of a glucuronide are allocated through kidneys in not changed look.

Patients with a renal failure
At patients with a heavy renal failure the maximum concentration of a zidovudine in plasma increases by 50% in comparison with that at patients without renal failure. System exposure of a zidovudine (concentration − time", AUC is defined as the area under a pharmacokinetic curve ") increases by 100%; the drug elimination half-life considerably does not change. At a renal failure essential cumulation of the main metabolite of a zidovudine ― a glucuronide is observed, however signs of toxic action at the same time do not come to light. The hemodialysis and peritoneal dialysis do not influence allocation of a zidovudine, at the same time removal of a glucuronide amplifies.

Patients with an abnormal liver function
At a liver failure cumulation of a zidovudine owing to decrease in a glyukuronization can be observed that demands correction of a dose of drug.

Patients of advanced age
The zidovudine pharmacokinetics at patients is more senior than 65 years is not studied.

Pregnant women
Pharmacokinetic parameters of a zidovudine at pregnant women do not change in comparison with parameters at nonpregnant, signs of cumulation of a zidovudine are not noted.

Concentration of a zidovudine in plasma at children at the birth same, as at their mothers at the time of delivery.

Indications to use:

• Heavy displays of HIV infection at patients with AIDS at impossibility of oral administration of Retrovir.
• HIV infection at pregnant women, since 14th week of a gestation, and their newborn children for decrease in frequency of vertical transfer of HIV.

Route of administration and doses:

Drug Retrovir, solution for infusions, it is necessary to enter in a divorced look by slow intravenous infusion within one hour.

The drug CAN not be administered intramusculary.

Drug Retrovir, solution for infusions, it is necessary to apply only until patients are not able to take dosage forms for intake (capsules, solution to intake).

Cultivation
Drug Retrovir, solution for infusions, it is necessary to dissolve before introduction.

Necessary dose of solution of Retrovir add to 5% glucose solution for intravenous administration that final concentration of a zidovudine was equal 2 mg/ml or 4 mg/ml. The received solution is mixed. Solution remains chemically and physically stable within 48 hours at a temperature from 5 °C to 25 °C.

As in drug Retrovir, solution for infusions, is absent antimicrobic preservative, cultivation should be carried out in the conditions of a full asepsis, just before introduction, an unused part of solution in a bottle should be destroyed.

At opacification of solution to, in time or after cultivation it should be destroyed.

Adults and teenagers with body weight not less than 30 kg
Retrovir each 4 h appoint in a dose 1 mg/kg or 2 mg/kg. This dose at intravenous administration of Retrovir provides same AUC drug, as at Retrovir's reception inside in a dose of 1,5 mg/kg or 3 mg/kg each 4 h (the patient has 600 or 1200 mg/days with the body weight of 70 kg). Efficiency of lower doses for treatment or prevention of the HIV-associated neurologic dysfunction and malignant new growths is unknown.

Children aged from 3 months up to 12 years
Data on Retrovir's use, solution for infusion, intravenously children have not enough. The recommended range of doses makes from 80 to 160 mg/sq.m each 6 h (320–640 mg/sq.m/days). The daily dose of Retrovir making 240–320 mg/sq.m a day for 3–4 introductions is comparable to the dose recommended for use from 360 mg/sq.m to 480 mg/sq.m a day in 3–4 intakes. However now there are no data on efficiency of use of solution of Retrovir for intravenous administration in such low doses.

Children aged up to 3 months
It is recommended to be careful at purpose of an infusional dosage form to patients aged up to 3 months as limited data do not allow to formulate accurate recommendations about the drug dosing mode.

Prevention of transfer of HIV infection from mother to a fruit
Efficiency of two modes of a drug dosing Retrovir is proved:

1. To pregnant women, since the term of 14 weeks, Retrovir, capsules, in a dose of 500 mg (on 1 capsule of 100 mg five times a day) prior to childbirth is recommended to appoint drug. At the time of delivery and deliveries it is necessary to use drug Retrovir, solution for infusions, intravenously in a dose of 2 mg/kg within an hour with the subsequent long intravenous infusion in a dose of 1 mg/kg/h before crossclamping of an umbilical cord.

Further newborns should appoint drug Retrovir, solution for intake, in a dose of 2 mg/kg each 6 hours, beginning no later than 12 hours from the moment of the birth and to 6 weeks age. Children who are incapable to take the peroral forms need to administer the drug Retrovir, solution for infusions, intravenously in a dose of 1,5 mg/kg of body weight within 30 minutes each 6 hours.

2. To pregnant women, since 36th week of pregnancy, Retrovir, capsules, 300 mg (on 3 capsules of 100 mg) twice a day prior to childbirth and 300 mg (3 capsules of 100 mg) from the moment of the beginning of childbirth before delivery is recommended to appoint each 3 hours drug.

Patients with renal failures
At heavy renal failures the recommended Retrovir's dose, solution for infusions, makes 1 mg/kg 3–4 times a day that corresponds to the recommended daily dose of 300-400 mg a day at intake for patients of this group. Depending on reaction from peripheral blood and clinical effect further dose adjustment can be required. The hemodialysis and peritoneal dialysis do not exert significant impact on removal of a zidovudine, however accelerate removal of a glyukuronidny metabolite.

For the patients in an end-stage of a renal failure who are on a hemodialysis or peritoneal dialysis, the recommended Retrovir's dose makes 100 mg each 6–8 hours.

Patients with an abnormal liver function
The data obtained at patients with cirrhosis demonstrate that patients to a liver failure can have a cumulation of a zidovudine because of the lowered glyukuronization, in this regard dose adjustment can be required. If monitoring of concentration of a zidovudine in plasma is impossible, then the doctor should pay special attention to clinical signs of intolerance of drug and if necessary to carry out dose adjustment and/or to increase an interval between administrations of drug.

Dose adjustment at undesirable reactions from system of a hemopoiesis
Adequate correction of the mode of dosing ― reduction of a dose or Retrovir's cancellation can be required at patients in case of development of undesirable reactions from system of a hemopoiesis, in case of decrease in level of hemoglobin to 75–90 g/l (4,65–5,59 mmol/l) or quantities of neutrophils to 0,75-1,0 × 109/l.

Patients of advanced age
The zidovudine pharmacokinetics at patients is aged more senior than 65 years was not studied. However, considering age depression of function of kidneys and possible changes of indicators of peripheral blood, at such patients it is necessary to observe extra care at Retrovir's appointment and to carry out the corresponding observation to and during treatment by Retrovir.

Features of use:

The doctor having experience of maintaining HIV-positive patients has to carry out treatment by Retrovir.

Patients have to be informed on danger of simultaneous use of Retrovir with drugs of non-prescription dispensing and that Retrovir's use does not prevent HIV infection at sexual contact or through the infected blood. The appropriate measures of safety are necessary.

The emergency prevention at probable infection
According to the international recommendations, at probable contact with HIV-positive material (blood, other liquids), it is necessary urgently within 1-2 hours from the moment of infection to appoint a combination therapy a zidovudine and lamivudiny. In case of high risk of infection the scheme of treatment has to include drug from group of inhibitors of protease. Preventive treatment is recommended to be carried out within 4 weeks. Despite treatment quick start anti-retrovirus drugs, it is impossible to exclude development of seroconversion.

Symptoms which take for side reactions on Retrovir can be manifestation of a basic disease or reaction to reception of other drugs used for treatment of HIV infection. It is often very difficult to establish interrelation between the developed symptoms and Retrovir's action, especially at the developed clinical picture of HIV infection. In such cases the dose decline of drug or its cancellation is possible.

Retrovir does not cure of HIV infection and at patients the risk of development of the developed disease picture with suppression of immunity and developing of opportunistic infections and malignant new growths remains. At AIDS Retrovir reduces risk of development of opportunistic infections, but does not reduce risk of development of lymphoma. The pregnant women assuming Retrovir's use during pregnancy for prevention of transfer of HIV to a fruit have to be informed on risk of infection of a fruit, despite the carried-out therapy.

Use for children aged up to 3 months
Care at purpose of an infusional dosage form of Retrovir is recommended to patients aged up to 3 months since limited data do not allow to formulate accurate recommendations about the drug dosing mode.

Undesirable reactions from system of a hemopoiesis
Anemia (it is usually observed in 6 weeks from the beginning of use of Retrovir, but sometimes can develop earlier), neutropenia (usually develops in 4 weeks from an initiation of treatment Retrovir, but sometimes arises earlier), a leukopenia (usually secondary character owing to a neutropenia) can occur at the patients with the developed clinical picture of HIV infection who are receiving Retrovir, especially in high doses (1200 mg-1500 of mg/days), and having a reduced marrowy hemopoiesis prior to treatment.

During Retrovir's reception at patients with the developed clinical picture of HIV infection it is necessary to control blood tests at least once a week within the first 3 months of therapy, and then monthly. In an early stage of AIDS (when a marrowy hemopoiesis within norm) side reactions from blood develop seldom therefore blood tests are made less often depending on the general condition of the patient, once in 1-3 months.

If the hemoglobin content decreases to 75-90 g/l (4,65-5,59 mmol/l), the quantity of neutrophils decreases to 0,75-1.0x109/l, the daily dose of Retrovir has to be reduced before recovery of indicators of blood; or Retrovir is cancelled for 2-4 weeks before recovery of indicators of blood. Usually the picture of blood is normalized in 2 weeks then Retrovir in the reduced dose can be appointed repeatedly. Despite Retrovir dose decline, at the expressed anemia hemotransfusions can be required.

Lactic acidosis and the expressed hepatomegalia with a steatosis.
These complications can have a fatal outcome both at mono - and at multicomponent therapy by a zidovudine. Weakness, anorexia, unexpected loss in weight, symptoms from a GIT, respiratory symptoms (диспноэ and a tachypnea) can be clinical signs of these complications. The warning of risk of such states has to be made at each purpose of a zidovudine, but it is especially important to warn patients with risk factors of diseases of a liver. The risk of development of these complications increases at women. The zidovudine should be cancelled in all cases of emergence of clinical or laboratory signs of lactic acidosis or toxic damage of a liver.

Redistribution of a hypodermic fatty tissue
Redistribution / accumulation of a hypodermic fatty tissue, including the general obesity, increase in a fatty layer in a neck behind ("a buffalo hump"), loss of a fatty layer on the periphery, on a face, a gynecomastia, increase in serumal lipids and glucose in blood was noted as in a complex, and separately at some patients receiving is combined anti-retrovirus therapy.

Though so far was considered that all drugs from a class of the protease inhibitors (PI) and nukleozidny inhibitors of the return transcriptase (NIRT) were associated with one or more specific undesirable phenomena connected with the general syndrome which is often called by a lipodystrophy, new data show that there is a difference in risk of development of this syndrome between specific representatives of therapeutic classes.

In addition, a syndrome of a lipodystrophy has a multifactor etiology; for example such factors as the HIV infection stage, advanced age of the patient and duration of anti-retrovirus therapy, play important, perhaps exponential role.

Long-term effects of these phenomena are unknown now.

Clinical inspection has to include physical survey for assessment of existence of redistribution of a hypodermic fatty tissue. It is necessary to recommend a research of level of serumal lipids and glucose of blood. Lipidic disturbances it is necessary to treat according to clinical indications.

Immunity recovery syndrome

At HIV-positive patients with a heavy immunodeficiency during the beginning of anti-retrovirus therapy is (APT), the aggravation of inflammatory process against the background of a symptomless or slow opportunistic infection is possible that can become the reason of a serious aggravation of symptoms or aggravation of symptomatology. Usually such reactions were described in the first weeks or months of the beginning of APT. The most significant examples it is a Cytomegaloviral retinitis, a generalized and/or focal mikobakterialny infection and pneumocystic pneumonia (P. carinii). Any symptoms of an inflammation it is necessary to reveal and begin immediately treatment, when necessary.

Radiation therapy strengthens myelosuppressive action of a zidovudine.

Influence on ability to manage cars/mechanisms
Retrovir's influence on ability to manage cars / mechanisms was not studied. However, adverse influence on these abilities is improbable, proceeding from drug pharmacokinetics. Nevertheless, at the solution of a question of an opportunity to manage cars / mechanisms, it must be kept in mind a condition of the patient and a possibility of development of side reactions (dizziness, drowsiness, block, spasms) at Retrovir's reception.

Side effects:

The undesirable reactions arising at treatment by Retrovir identical at children and adults.

For assessment of frequency of emergence of undesirable reactions the following gradation are used: very often (> 1/10), it is frequent (> 1/100, <1/10) sometimes (> 1/1000, <1/100), is rare (> 1/10000, <1/1000), is very rare (<1/10000).

From system of a hemopoiesis: often - anemia (which can demand hemotransfusions), a neutropenia and a leukopenia developed at use of high doses of Retrovir (for example, 1200-1500 mg/days within clinical trials) and at patients with HIV infection in far come stage (especially at patients with a reduced reserve of marrow is prior to treatment), is preferential at decrease in number of CD4 lymphocytes lower than 100 cells/mm3. In these cases the dose decline of Retrovir or his cancellation can be required. Frequency of development of a neutropenia increases at patients at whom decrease in quantity of neutrophils, a hemoglobin content and B12 vitamin in serum in an initiation of treatment was observed. Sometimes - thrombocytopenia and a pancytopenia (with a marrow hypoplasia); seldom - an erythrocyte aplasia; very seldom - aplastic anemia.

Disbolism: often – a giperlaktatemiya; seldom - lactic acidosis, anorexia; redistribution/accumulation of a hypodermic fatty tissue (development of this phenomenon depends on many factors, including on a combination of anti-retrovirus drugs).

From the central and peripheral nervous system: very often - a headache; often - dizziness; seldom - sleeplessness, paresthesias, drowsiness, reduction of speed of thinking, a spasm, alarm and a depression.

From cardiovascular system: seldom - a cardiomyopathy.

From respiratory system: sometimes - an asthma; seldom - cough.

From digestive tract: very often – nausea; often - vomiting, pains in upper parts of a stomach, diarrhea; sometimes - a meteorism; seldom - pigmentation of a mucous membrane of an oral cavity, taste disturbance, dyspepsia.

From a liver and a pancreas: often - increase in level of bilirubin and activity of enzymes of a liver; seldom - the expressed hepatomegalia with a steatosis; pancreatitis.

From skin and its appendages: sometimes - skin rash (except a small tortoiseshell), a skin itch; seldom – pigmentation of nails and skin, a small tortoiseshell, the increased sweating.

From a musculoskeletal system: often – a mialgiya; sometimes - a myopathy.

From an urinary system: seldom - the speeded-up urination.

From endocrine system: seldom: gynecomastia.

Others: often - an indisposition; sometimes - fever, a generalized pain syndrome, an adynamy; seldom - a fever, thorax pains, a grippopodobny syndrome.

There is an experience of purpose of solution of Retrovir for intravenous administration over 2 weeks up to 12 weeks. The most frequent undesirable effects at the same time were anemia, a leukopenia, a neutropenia, sometimes local reactions.

The undesirable reactions arising at Retrovir's use for prevention of transfer of HIV infection from mother to a fruit.
Pregnant women well transfer Retrovir in the recommended doses. At children decrease in a hemoglobin content which, however, does not demand carrying out hemotransfusions is observed. Anemia disappears in 6 weeks, after completion of therapy by Retrovir.

Interaction with other medicines:

The zidovudine is preferential removed in the form of the inactive metabolite representing the glyukuronidny conjugate which is formed in a liver. The drugs having a similar way of removal potentially can inhibit metabolism of a zidovudine.

The zidovudine is applied in the combined anti-retrovirus therapy together with other nukleozidny inhibitors of the return transcriptase and drugs from other groups (protease inhibitors, nenukleozidny inhibitors of the return transcriptase).

The list of the interactions which are listed below should not be considered exhaustive, however they are characteristic of drugs which demand careful use together with a zidovudine.

Lamivudin: moderate increase in Cmax (28%) of a zidovudine at simultaneous use with lamivudiny is observed, however, the general exposure (AUC) at the same time does not change. The zidovudine does not exert impact on pharmacokinetics of a lamivudin.

Phenytoinum: at simultaneous use of Retrovir with Phenytoinum concentration of the last in a blood plasma decreases; it is necessary to control concentration of Phenytoinum in a blood plasma at use of this combination.

Probenetsid: reduces a glyukuronization and increases an average elimination half-life and AUC of a zidovudine. Removal by kidneys of a glucuronide and the zidovudine decreases in the presence of a probenetsid.

Atovakhon: the zidovudine does not influence pharmacokinetic parameters of an atovakhon. Atovakhon slows down transformation of a zidovudine in glyukuronidny derivative (AUC of a zidovudine in an equilibrium state increases by 33% and the maximum concentration of a glucuronide decrease by 19%). Change of a profile of safety of a zidovudine in doses of a zidovudine of 500 or 600 mg/days at the combined use with atovakhony within three weeks is improbable. In need of more prolonged combined use of these drugs careful 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.

Ribavirin: the nukleozidny analog рибавирин is an antagonist of a zidovudine, and their combination should be avoided.

Rifampicin: Retrovir's combination with rifampicin leads to decrease in AUC for a zidovudine for 48%±34%, however clinical value of this change is not known.

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

Valproic acid, флуконазол, methadone reduce clearance of a zidovudine because of what its system exposure increases.

Others: acetylsalicylic acid, codeine, methadone, morphine, indometacin, ketoprofen, Naproxenum, oxazepam, lorazepam, Cimetidinum, Clofibratum, dapsone, изопринозин can break metabolism of a zidovudine by competitive inhibition of a glyukuronization or direct suppression of microsomal metabolism in a liver. To a possibility of use of these drugs in a combination with Retrovir, especially at long therapy, it is necessary to approach with care. Retrovir's combination, especially at emergency treatment, with potentially nefrotoksichny and miyelotoksichny drugs (for example, pentamidine, dapsone, Pyrimethaminum, co-trimoxazole, Amphotericinum, flutsitoziny, gantsikloviry, interferon, Vincristinum, vinblastine, doxorubicine) increases risk of development, undesirable reactions on Retrovir. Observation of function of kidneys and a blood count is necessary; if necessary reduce doses of drugs.

Contraindications:

• Hypersensitivity to a zidovudine or any other component of drug;
• Neutropenia (number of neutrophils less than 0,75 x 10 9/l);
• Decrease in a hemoglobin content (less than 75 g/l or 4,65 mmol/l).

Use at pregnancy and a lactation

Fertility
There are no data on Retrovir's influence on fertility of women. At men Retrovir's reception does not influence composition of sperm, morphology and mobility of spermatozoa.

Pregnancy
The zidovudine gets through a placenta. Before the 14th week of a gestation Retrovir it is possible to apply only if the potential advantage for mother exceeds risk for a fruit.

There are messages on slight, passing increase of concentration of a lactate in blood serum which can be caused by dysfunction of mitochondrions at the newborns and babies who were exposed to pre-natal or perinatal exposure by nukleozidny inhibitors of the return transcriptase. The clinical importance of passing increase in concentration of a lactate in blood serum is unknown. There are very rare messages on cases of an arrest of development, convulsive attacks and other neurologic disturbances, for example a spasticity. Nevertheless, relationship of cause and effect between these phenomena and pre-natal or perinatal exposure by nukleozidny inhibitors of the return transcriptase is not established. These data do not influence the present recommendations about use of anti-retrovirus therapy for pregnant women about prevention of a vertical way of transfer of HIV.

Prevention of transfer of HIV from mother to a fruit
Retrovir's use after 14 weeks of pregnancy with the subsequent appointment at newborns leads it to decrease in transmission frequency of HIV from mother to a fruit (frequency of developing of an infection when using placebo ― 23% in comparison with frequency when using a zidovudine ― 8%).

The remote effects of use of Retrovir for the children receiving it in the pre-natal or neonatal periods are unknown. It is impossible to exclude a possibility of cancerogenic influence completely. Pregnant women have to be informed on it.

Lactation
Because the zidovudine and HIV get into breast milk, the women accepting Retrovir are not recommended to nurse.

With care
Purpose of drug with care is recommended to patients aged up to 3 months since limited data do not allow to formulate accurate recommendations about the drug dosing mode, at oppression of a marrowy hemopoiesis, deficit of B12 vitamin and folic acid, a liver failure.

Overdose:

Symptoms
The feeling of fatigue, headache, vomiting are possible; very seldom - changes from blood indicators. There is one message on overdose by unknown quantity of a zidovudine when concentration of a zidovudine in blood exceeded usual therapeutic concentration by 16 times, nevertheless, at the same time clinical, biochemical or hematologic symptoms were absent.

At use within clinical trials of the maximum doses – 7,5 mg/kg of body weight infusionally each 4 hours within 2 weeks, at one of 5 patients the concern was observed, at the remained 4 patients no undesirable reactions developed.

Treatment
Symptomatic therapy. The hemodialysis and peritoneal dialysis have no high performance for removal of a zidovudine from an organism, but strengthen removal of its metabolite of a glucuronide.

Storage conditions:

At a temperature not above 30 °C in the place protected from light. To store in the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for infusions of 10 mg/ml.
Solution for infusions on 200 mg / 20 ml in a bottle of neutral light-protective glass with a chlorbutyl rubber bung and an aluminum cap with a plastic insert.
On 5 bottles in a plastic blister strip packaging together with the application instruction place in a cardboard box.