Description

Transparent, light yellow solution with a characteristic strawberry odor.

Compound

Active substance: zidovudine 50.0 mg/5 ml.

Excipients: hydrogenated glucose syrup E965, glycerin, anhydrous citric acid, sodium benzoate, sodium saccharin E954, strawberry flavor, white sugar flavor, purified water.

Pharmacotherapeutic group

Antiviral agents for systemic use. Nucleoside and nucleotide reverse transcriptase inhibitors. CodeATX: J05AF01.

Pharmacological properties

Pharmacodynamics

Mechanism of action:

Zidovudine is an antiviral agent with high activity in vitro against retroviruses, including human immunodeficiency virus (HIV).

Zidovudine undergoes phosphorylation in both infected and intact cells to form monophosphate via cellular thymidine kinase. The subsequent phosphorylation of zidovudine monophosphate to zidovudine diphosphate and then to zidovudine triphosphate is catalyzed by cellular thymidylate kinase and nonspecific kinases, respectively. Zidovudine triphosphate acts as an inhibitor and substrate for viral reverse transcriptase. The formation of proviral DNA is blocked by the incorporation of zidovudine monophosphate into its chain, which leads to chain termination. The competition of zidovudine triphosphate for HIV reverse transcriptase is approximately 100 times stronger than for cellular human DNA polymerase a.

Clinical Virology:

Study of the relationship between HIV sensitivity to zidovudine in vitro and clinical response to therapy continues. Sensitivity tests in vitro were not standardized, so results may vary depending on methodological factors. Reduced sensitivity in vitro to zidovudine was observed in HIV isolates from patients receiving long-term courses of therapy with Retrovir. Available evidence suggests that in early HIV disease, the frequency and extent of decreased sensitivity in vitro are noticeably inferior to these indicators at the stage of progressive disease.

Reduced sensitivity due to the emergence of zidovudine-resistant strains limits the clinical benefit of zidovudine monotherapy. Endpoint data from clinical trials suggest that the use of zidovudine, especially in combination with lamivudine, but also with didanosine or zalcitabine, leads to a significant reduction in the risk of disease progression and mortality. The use of a protease inhibitor in combination with zidovudine and lamivudine, compared with the double combination, has been shown to provide additional benefit in terms of slowing disease progression and improving survival.

Research is underway in vitro to study the antiviral activity of combinations of antiretroviral drugs. Clinical studies and research in vitro zidovudine in combination with lamivudine showed that zidovudine-resistant virus isolates become sensitive to zidovudine while simultaneously acquiring resistance to lamivudine. In addition, there is clinical evidence that the use of a combination of zidovudine and lamivudine delays the emergence of zidovudine resistance in patients who have not previously received antiretroviral therapy.

In vitro, there was no antagonism of the antiviral activity of zidovudine in combination with other antiretroviral drugs (testing was carried out for abacavir, didanosine, lamivudine and interferon-α).

The development of resistance to thymidine analogues (zidovudine is one of them) has been well studied and occurs as a result of the gradual accumulation of up to 6 specific mutations in codons 41, 67, 70, 210, 215 and 219 of HIV reverse transcriptase. 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. These mutations of thymidine analogues individually do not cause high-level cross-resistance to other nucleosides, which allows the use of other reverse transcriptase inhibitors for further treatment of HIV infection.

Two types of mutations lead to the development of multiple drug resistance.

In one case, mutations occur in codons 62, 75, 77, 116 and 151 of HIV reverse transcriptase and in the second case we are talking about a T69S mutation with the insertion of 6 nitrogen base pairs in this position, which 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 therapeutic options for HIV infection.

The US clinical trial ACTGO76 reported that Retrovir was effective in reducing maternal-to-fetal transmission of HIV-1 (incidence rates: 23% placebo, 8% zidovudine) when administered (100 mg five times a day) in HIV-positive pregnant women (from the 14th to the 34th week of pregnancy), as well as in their infants (2 mg/kg every 6 hours) until they reach 6 weeks of age. In a shorter-term, 1998 CDC clinical trial in Thailand, use of a single drug, Retrovir (oral 300 mg twice daily), from 36 weeks of gestation through delivery, also showed a reduction in the incidence of familial transmission of HIV (incidence rates: 19 % - in the placebo group, 9% - in the zidovudine group). These data, as well as the published results of a study comparing zidovudine dosing regimens aimed at preventing familial transmission of HIV, suggest that shorter duration of maternal therapy (from 36 weeks of gestation) is inferior to longer duration of maternal therapy (from 14 weeks of gestation). 1st to 34th week) in terms of reducing perinatal HIV transmission.

Pharmacokinetics

Adults Suction

Zidovudine is well absorbed from the gastrointestinal tract; at all dose levels studied, bioavailability was 60-70%. In a bioequivalence study, the mean steady-state (CV%) Cmax, Cmin and AUC values ​​obtained in 16 patients receiving zidovudine tablets 300 mg twice daily were 8.57 (54%) µmol (2 .29 μg/ml), 0.08 (96%) μmol (0.02 μg/ml) and 8.39 (40%) h*μmol (2.24 h*μg/ml).

Distribution

In studies in which Retrovir was administered intravenously, the mean terminal plasma half-life was 1.1 hours, the mean total clearance was 27.1 ml/min/kg, and the apparent volume of distribution was 1.6 L/kg.

In adults, the average ratio of zidovudine concentrations in cerebrospinal fluid and plasma 2-4 hours after administration was about 0.5. Available data indicate that zidovudine crosses the placenta into the amniotic fluid and fetal blood. Zidovudine is detected in seminal fluid and breast milk.

Plasma protein binding is relatively low (34-38%), drug interactions due to displacement from binding sites seem unlikely.

Metabolism

Zidovudine is primarily eliminated by hepatic conjugation to form an inactive glucuronidated metabolite. Zidovudine 5'-glucuronide is the main final metabolite of zidovudine, determined in both plasma and urine and accounts for approximately 50-80% of the dose of the drug, which is excreted by the kidneys. 3'-amino-3'-deoxythymidine has been identified as a metabolite of zidovudine when administered intravenously.

Removal

The renal clearance of zidovudine is much higher than the clearance of creatinine, indicating a significant role of tubular secretion in its elimination.

Children

Suction

In children over 5-6 months of age, pharmacokinetic parameters are similar to those in adults. Zidovudine is well absorbed from the intestine; at all dose levels studied, bioavailability is 60-74% with an average value of 65%. After administration of a dose of zidovudine 120 mg/m2 and a dose of 180 mg/m2 as an oral solution, the maximum steady-state concentrations were 4.45 μmol (1.19 μg/ml) and 7.7 μmol (2.06 μg/ml), respectively. When used in children at doses of 180 mg/m2 four times a day, systemic exposure indicators were observed (24-hour AUC (area under the concentration-time pharmacokinetic curve) 40.0 h * μmol or 10.7 h * μg / ml) were similar to those in adults when used in doses of 200 mg six times a day (40.7 h*µmol or 10.9 h*µg/ml).

Distribution

When administered intravenously, the mean terminal plasma half-life was 1.5 hours, and the mean total clearance was 30.9 ml/min/kg.

In children, the average ratio of zidovudine concentrations in the cerebrospinal fluid and in plasma varied from 0.52 to 0.85 after 0.5-4 hours after oral administration and amounted to 0.87 after 1-5 hours after a 1-hour infusion. During long-term intravenous infusion, the average ratio of zidovudine concentrations in the cerebrospinal fluid and plasma at steady state was 0.24.

Metabolism

The main metabolite is 5"-glucuronide. When administered intravenously, 29% of the dose is excreted in the urine unchanged, 45% as glucuronide.

Removal

The renal clearance of zidovudine is much greater than the clearance of creatinine, indicating significant tubular secretion.

Pharmacokinetic data indicate that glucuronidation of zidovudine is reduced in neonates and infants, resulting in increased bioavailability, decreased clearance and a longer half-life in infants less than 14 days of age, after which pharmacokinetic parameters become similar to those in adults.

Pregnancy

The pharmacokinetic properties of zidovudine were studied in a study involving eight women in the third trimester of pregnancy. As the gestational age increased, no signs of drug accumulation were noted. The pharmacokinetic properties of zidovudine when used in pregnant and non-pregnant women are similar. Due to the passive penetration of the drug through the placenta, the plasma concentration of zidovudine in children at birth is the same as in their mothers at the time of birth.

Elderly patients

There are no data on the pharmacokinetics of zidovudine in elderly patients.

In patients with severe renal impairment, the clearance of zidovudine after oral administration was approximately 50% of that in healthy volunteers without renal impairment. Hemodialysis and peritoneal dialysis do not affect the excretion of zidovudine, while the excretion of inactive zidovudine glucuronide increases (see section "Method of administration and dosage").

There are limited data on the pharmacokinetics of zidovudine in patients with impaired liver function (see section "Method of administration and dosage").

Indications for use

Dosage forms of Retrovir for oral administration are indicated for use as part of combination antiviral therapy for HIV infection in adults and children.

Chemoprophylaxis with Retrovir is indicated for HIV-positive pregnant women (with a gestational age of more than 14 weeks) to prevent transplacental transmission of HIV from mother to fetus and for the primary prevention of HIV infection in newborns.

Directions for use and dosage

Retrovir is prescribed by doctors with experience in treating HIV infection.

Adults and adolescents weighing at least 30 kg:

Children weighing 9 kg or more, but less than 30 kg:

Children weighing 4 kg or more, but less than 9 kg:

Doses to prevent mother-to-fetus transmission of HIV:

Pregnant women over 14 weeks of pregnancy are recommended to prescribe Retrovir orally before the onset of labor at a dose of 500 mg/day (100 mg 5 times a day). During labor and delivery, Retrovir should be administered intravenously at a dose of 2 mg/kg body weight over one hour, followed by a continuous intravenous infusion at a rate of 1 mg/kg/h until the umbilical cord is clamped.

Newborns are prescribed Retrovir at a dose of 2 mg/kg body weight every 6 hours, starting in the first 12 hours after birth and continuing until 6 weeks of age (for example, a newborn weighing 3 kg should be administered 0.6 ml of oral solution every 6 hours). If it is impossible to administer the drug orally to newborns, Retrovir should be administered by intravenous infusion at a dose of 1.5 mg/kg body weight over 30 minutes every 6 hours.

Due to the need to administer the oral solution in small volumes, doses for newborns should be carefully calculated. For precise dosing, the kit for newborns includes a 1 ml syringe.

If a caesarean section is planned, the infusion should begin 4 hours before surgery. In case of false labor contractions, you should stop administering Retrovir by infusion and resume oral administration.

Dose adjustment for adverse reactions from hematopoiesis:

In patients whose hemoglobin level or neutrophil count decreases to clinically significant levels, zidovudine replacement should be considered. Other potential causes of anemia or neutropenia should be excluded. If alternative treatment options are not available, consider reducing the dose of Netrovir or stopping therapy (see sections "Contraindications" and "Precautions").

Elderly patients

The pharmacokinetics of zidovudine in patients over 65 years of age have not been studied and no specific data have been obtained. However, given the age-related decline in renal function and possible changes in peripheral blood parameters, in such patients it is necessary to exercise special caution when prescribing Retrovir and carry out appropriate monitoring before and during treatment with Retrovir.

Patients with impaired renal function

In severe renal impairment (creatinine clearance

Patients with liver dysfunction

Data obtained in patients with cirrhosis of the liver indicate that in patients with liver failure, accumulation of zidovudine may occur due to decreased glucuronidation, and therefore dose adjustment may be required, however, due to the large variability in zidovudine exposure in patients with impaired liver function from moderate to severe, it is not possible to give precise recommendations on the dosage regimen. If monitoring plasma zidovudine concentrations is not possible, the physician should pay special attention to clinical signs of intolerance to the drug, in particular adverse reactions from hematopoiesis (anemia, leukopenia, neutropenia) and, if necessary, adjust the dose and/or increase the interval between doses ( see section "Precautions"),

Contraindications

Dosage forms of Retrovir for oral use are contraindicated in patients with hypersensitivity to zidovudine or any other component of the drug.

Oral dosage forms of Retrovir are not indicated for patients with an abnormally low neutrophil count (less than 0.75 × 109/L) or abnormally low hemoglobin level (less than 75 g/L).

Retrovir is contraindicated for use in neonates with hyperbilirubinemia requiring treatment with methods other than phototherapy, as well as in neonates with transaminase levels greater than 5 times the upper limit of normal.

Side effect

Adverse reactions that occur during treatment with Retrovir are the same in children and adults.

The most serious adverse reactions include anemia (blood transfusion may be required), neutropenia and leukopenia. These reactions develop more often when using high doses (1200-1500 mg per day) and in patients with advanced stages of HIV infection (especially with low bone marrow reserve at the start of treatment) and in patients with a CD4 cell count of less than 100/mm3 . In this case, it may be necessary to reduce the dose or discontinue therapy (see section "Precautions").

Neutropenia was also observed more often in patients with reduced levels of neutrophils, hemoglobin and vitamin B12 at the time of initiation of therapy with Retrovir.

To assess the frequency of occurrence of adverse reactions, the following gradations were used: very often (≥ 1/10), often (≥ 1/100,

Coaspects of hematopoiesis and lymphatic system: often - anemia, neutropenia and leukopenia; uncommon – thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rarely - true erythrocyte aplasia; very rarely - aplastic anemia.

From the side of metabolism and nutrition: rarely - lactic acidosis in the absence of hypoxemia, anorexia.

Cosides of the central and peripheral nervous systems: very often - headache; often - dizziness; rarely - insomnia, paresthesia, drowsiness, decreased speed of thinking, convulsions.

Mental disorders: rarely - anxiety, depression.

Cosides cardiovascular systems: rarely - cardiomyopathy.

Coaspects of the respiratory system and chest organs: infrequently - shortness of breath; rarely - cough.

Cosides of the gastrointestinal tract: very often - nausea; often - vomiting, abdominal pain, diarrhea; infrequently - flatulence; rarely - pancreatitis; pigmentation of the oral mucosa, taste disturbance, dyspepsia.

Cosides of the liver and biliary tract: often - increased bilirubin levels and liver enzyme activity; rarely - liver dysfunction, such as severe hepatomegaly with steatosis.

Cosides of the skin and subcutaneous fat: uncommon - rash, itchy skin; rarely - pigmentation of nails and skin, urticaria, increased sweating.

Cosides of the musculoskeletal system: often - myalgia; infrequently - myopathy.

Cosides of the urinary system: rarely - frequent urination.

Cosides of the genitals and mammary gland: rarely - gynecomastia.

General and local reactions: often - malaise; uncommon - fever, generalized pain syndrome, asthenia; rarely - chills, chest pain, flu-like syndrome.

Results from both placebo-controlled and open-label clinical studies suggest that the incidence of nausea and other commonly reported adverse reactions decreases steadily during the first few weeks of use of Retrovir.

Adverse reactions that occur when using Retrovir to prevent transmission of HIV infection from mother to fetus

In the placebo-controlled clinical trial, the overall adverse clinical reactions and laboratory abnormalities observed in women in the Retrovir group and in the placebo group were similar. However, cases of mild and moderate anemia before childbirth were more likely to occur in the group of women receiving zidovudine.

In the same study, hemoglobin concentrations in children treated with Retrovir for this indication were slightly lower than in the placebo group, but no blood transfusion was required. The anemia resolved within 6 weeks after discontinuation of Retrovir. Other adverse clinical reactions and laboratory test abnormalities observed in the Retrovir group and the placebo group were similar. Data on possible long-term consequences of exposure to Retrovir as in utero, and after birth, are absent.

Cases of lactic acidosis (sometimes fatal), usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of zidovudine (see section "Precautions").

Treatment with zidovudine may be accompanied by loss of subcutaneous fat, which is most noticeable in the face, limbs and buttocks. Patients receiving Retrovir should be regularly questioned and examined for signs of lipodystrophy. If such signs are detected, Retrovir should be discontinued (see section "Precautions").

Weight gain and increases in blood lipids and glucose may occur during antiretroviral therapy (see Precautions section),

HIV-infected patients who are severely immunocompromised at the time of initiation of combination antiretroviral therapy (cART) may exhibit an inflammatory response to asymptomatic or residual opportunistic infections (see Precautions).

Cases of osteonecrosis have been reported, particularly in patients with established risk factors such as advanced HIV infection or long-term cART. The incidence of this adverse event is unknown (see section "Precautions").

Overdose

Symptoms

Apart from reported adverse effects such as fatigue, headache, vomiting and occasional hematological disturbances, no specific symptoms or signs of acute zidovudine overdose were identified. A case has been reported of ingestion of an unknown amount of zidovudine with subsequent serum drug concentrations consistent with an overdose of more than 17 g; however, no short-term clinical, biochemical and hematological complications were observed.

Treatment

Careful monitoring of toxicity in patients is necessary (see section “Side Effects”) and provision of the necessary supportive therapy.

Hemodialysis and peritoneal dialysis are not highly effective in removing zidovudine from the body, but they enhance the removal of its metabolite, zidovudine 5'-glucuronide.

Precautionary measures

Although effective viral suppression during antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission of HIV, a residual risk of transmission cannot be excluded. Precautions should be taken in accordance with national guidelines.

Retrovir is not a cure for HIV infection or AIDS. Patients receiving Retrovir or any other antiretroviral therapy may develop opportunistic infections and other complications of HIV infection.

The combined use of rifampicin or stavudine with zidovudine should be avoided (see section “Interaction with other drugs”).

Adverse reactions from the hematopoietic system

Anemia (usually observed after 6 weeks of starting Retrovir, but sometimes may develop earlier), neutropenia (usually developing after 4 weeks of starting treatment with Retrovir, but sometimes occurs earlier), leukopenia (usually secondary to neutropenia) may occur in patients receiving Retrovir. These reactions occur more often when using high doses of the drug (1200-1500 mg/day) and in patients with reduced bone marrow hematopoiesis before treatment, especially in advanced stages of HIV infection (see section “Side Effects”).

While taking the drug Retrovir, it is necessary to carefully monitor hematological parameters. In patients with an advanced clinical picture of HIV infection, it is usually recommended to monitor blood tests at least once every 2 weeks during the first 3 months of therapy, and then monthly. Taking into account the general condition of the patient, blood tests may be performed less frequently, for example, at intervals of 1-3 months.

If the hemoglobin content decreases to 75-90 g/l or the number of neutrophils decreases to 0.75-1.0 × 109/l, the daily dose of Retrovir can be reduced until blood counts are restored; alternatively, restoration of blood counts can be achieved by a short-term (2-4 weeks) break in treatment. Recovery of bone marrow function is usually observed within 2 weeks, after which Retrovir can be re-prescribed in a reduced dose. Despite reducing the Retrovir dose, severe anemia may require blood transfusions (see section “Contraindications”).

Lactic acidosis

Cases of lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, have been reported with the use of zidovudine. Early symptoms (symptomatic hyperlactatemia) include benign gastrointestinal symptoms (nausea, vomiting and abdominal pain), non-specific discomfort, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (in including motor weakness).

Lactic acidosis is characterized by high mortality; it may be associated with pancreatitis, liver failure, or kidney failure.

The development of lactic acidosis was observed, as a rule, after one to two or more months of therapy.

Zidovudine should be discontinued if there is symptomatic hyperlactatemia, metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing transaminase levels.

Zidovudine should be used with caution in patients (especially obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain drugs and alcohol). A separate risk group may include patients co-infected with the hepatitis C virus and receiving interferon alpha and ribavirin.

Patients at high risk should be closely monitored.

Mitochondrial dysfunction after in utero exposure

Nucleotide and nucleoside analogues can cause varying degrees of mitochondrial damage, which is most pronounced with stavudine, didanosine and zidovudine. Mitochondrial dysfunction has been reported in HIV-negative neonates exposed in utero and/or postnatally to nucleoside analogues; These reports primarily concerned zidovudine-containing regimens. The main adverse reactions were hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). As a rule, these adverse reactions were temporary. There have also been rare reports of delayed neurological disorders (hypertension, seizures, behavioral disturbances). It is currently unknown whether these side effects are reversible. The possibility of such reactions should be considered in any child exposed in utero to nucleoside or nucleotide analogues who experiences severe clinical manifestations of unknown etiology, especially neurological impairment. These data do not change existing recommendations for antiretroviral treatment during pregnancy to prevent vertical transmission of HIV.

Lipoatrophy

Treatment with zidovudine may be accompanied by loss of subcutaneous fat due to mitochondrial toxicity. The incidence and severity of lipoatrophy are related to the total accumulated dose. This fat loss, which is most noticeable in the face, limbs and buttocks, may be irreversible after switching to a treatment regimen that does not contain zidovudine. During therapy with zidovudine and zidovudine-containing drugs (Combivir and Trizivir), patients should be regularly monitored for signs of lipoatrophy. If the development of lipoatrophy is suspected, switching to alternative therapy is necessary.

Changes in body weight and metabolic parameters

Weight gain and increases in blood lipids and glucose levels may occur during antiretroviral therapy. These changes may be due in part to disease control and lifestyle choices. In some cases, there has been evidence that increases in blood lipids are associated with treatment, while there is no significant evidence that weight gain is associated with a specific treatment. Blood lipid and glucose monitoring should be performed in accordance with accepted HIV treatment guidelines. Lipid metabolism disorders should be treated according to the clinical picture.

Liver disease

The clearance rates of zidovudine in patients with mild hepatic impairment without cirrhosis are similar to those in healthy volunteers, so no dose adjustment of zidovudine is required. For patients with moderate to severe liver disease, it is not possible to make specific dosing recommendations due to the observed large variability in zidovudine exposure, and therefore the use of zidovudine in these patients is not recommended.

Patients with chronic hepatitis B or C who are receiving combination antiretroviral therapy are at increased risk of developing potentially fatal hepatic adverse events. If you are co-prescribing antiviral drugs for the treatment of hepatitis B or C, see also the instructions for their use.

In patients with pre-existing liver dysfunction, including chronic active hepatitis, the incidence of liver dysfunction increases during combination antiretroviral therapy. Such patients should be monitored in accordance with standard medical practice. If there are signs of worsening liver disease, consider suspending or discontinuing treatment in these patients (see Dosage and Administration). Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency, during initiation of cART, there may be an exacerbation of the inflammatory process against the background of an asymptomatic opportunistic infection or its residual effects, which can cause serious deterioration of the condition or aggravation of symptoms. Typically, such reactions were observed in the first weeks or months of cART initiation. The most significant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infection and Pneumocystis pneumonia (R.carinii). Any symptoms of inflammation must be immediately identified and treatment initiated if necessary. There have also been reports of autoimmune disorders (eg, cases of Graves' disease) secondary to immune reactivation; however, the timing of their onset is more variable and may occur many months after the start of treatment. Patients should be cautioned against the simultaneous use of drugs without a doctor's prescription (see section "Interaction with other drugs").

Patients with rare hereditary conditions of fructose intolerance should not take this medicine.

Use in elderly patients and in patients with impaired renal and liver function

See section "Method of administration and dosage".

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (including the use of corticosteroids, alcohol consumption, the presence of severe immunosuppression, increased body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV infection and/or on long-term cART. Patients should seek medical attention if they experience joint pain, aches, stiffness, or difficulty moving.

Co-infection with HIV and viral hepatitis WITH

Interaction with other drugs

Based on limited data, coadministration of zidovudine and rifampicin resulted in a 48%+34% reduction in zidovudine AUC. This may lead to partial or complete loss of effectiveness of zidovudine. The combined use of rifampicin and zidovudine should be avoided (see section "Precautions").

The combination of zidovudine and stavudine is antagonistic in vitro, so combined clinical use of these drugs should be avoided (see section "Precautions").

Probenecid increases the AUC of zidovudine by 106% (range 100 to 170%). Patients receiving both drugs should be closely monitored for hematologic toxicity.

There is a moderate increase (28%) in the maximum concentration of zidovudine (Cmax) when used simultaneously with lamivudine, but the overall exposure (AUC) does not change. Zidovudine has no effect on the pharmacokinetics of lamivudine.

With simultaneous use of Retrovir with phenytoin, the concentration of the latter in the blood plasma decreases, however, a high level was noted in one patient. Plasma concentrations of phenotoin should be monitored when using this combination.

Atovaquone: zidovudine does not affect the pharmacokinetic parameters of atovaquone. However, pharmacokinetic data indicate that atovaquone slows the transformation of zidovudine to its glucuronidated metabolite (zidovudine AUC at steady state increases by 33% and maximum glucuronide concentrations decrease by 19%). It is unlikely that the use of zidovudine at doses of 500 or 600 mg/day for three weeks concomitantly with atovaquone for the treatment of acute Pneumocystis pneumonia will lead to an increase in the incidence of adverse reactions associated with increased plasma concentrations of zidovudine. If longer-term combined use of these drugs is necessary, careful monitoring of the patient's clinical condition is recommended.

Valproic acid, fluconazole or methadone, when used concomitantly with zidovudine, increases the AUC of zidovudine with a corresponding decrease in its clearance. Because available data are limited, the clinical significance of these findings is unclear; However, if zidovudine is used concomitantly with valproic acid, fluconazole or methadone, patients should be closely monitored for possible signs of zidovudine toxicity. Worsening of ribavirin-induced anemia has been reported with the use of zidovudine as part of the HIV treatment regimen; the exact mechanism of this phenomenon is unclear. The simultaneous use of ribavirin and zidovudine is not recommended due to the increased risk of anemia (see section "Precautions"). Consideration should be given to replacing zidovudine as part of the cART regimen for existing anemia. This seems especially important in patients with a history of zidovudine-induced anemia.

The combination of Retrovir, especially in emergency treatment, with potentially nephrotoxic and myelotoxic drugs (for example, pentamidine for systemic use, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of developing adverse reactions to zidovudine If such a combination appears necessary, increased attention should be paid to monitoring renal function and hematological parameters; if necessary, the dose of drugs is reduced.

Limited data obtained from clinical studies did not reveal a significant increase in the risk of adverse reactions to zidovudine when used in combination with cotrimoxazole, pentamidine in the form of aerosol, pyrimethamine and acyclovir in prophylactic doses.

When using clarithromycin tablets, the absorption of zidovudine is reduced. This effect can be eliminated by separate administration of zidovudine and clarithromycin with an interval of at least 2 hours.

In the absence of compatibility studies, this medicinal product should not be mixed with other drugs.

Use during pregnancy and lactation

Pregnancy

In general, when making decisions about the use of antiretroviral drugs to treat HIV infection in pregnant women and to reduce the risk of vertical transmission of HIV to the newborn, data from animal studies as well as data from clinical studies in pregnant women should be taken into account. The use of zidovudine in pregnant women, as well as subsequent treatment in newborns, has been shown to reduce the incidence of mother-to-child transmission of HIV.

There is a large amount of data on the use of zidovudine in pregnant women (more than 3000 pregnancy outcomes when using the drug in the first trimester and more than 3000 pregnancy outcomes when using the drug in the second and third trimesters), indicating the absence of teratogenic toxicity. Retrovir can be used during pregnancy if clinically necessary. Based on the large amount of data obtained, it can be concluded that teratogenic effects in humans are unlikely.

An animal study found evidence of reproductive toxicity associated with zidovudine. The active ingredient in Retrovir may inhibit cellular DNA replication. One animal study showed that zidovudine is a transplacental carcinogen. The clinical significance of the findings is unclear. Zidovudine has been demonstrated to cross the placental barrier in humans.

Mitochondrial dysfunction: Nucleotide and nucleoside analogues have been demonstrated in vitro and in vivo to cause varying degrees of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative newborns whose mothers took nucleotide analogs during pregnancy and the perinatal period (see section "Precautions").

Fertility

Zidovudine does not affect fertility in male and female rats receiving 450 mg/kg/day orally. There is no data on the effect of Retrovir on the reproductive function of women. In men, taking Retrovir does not affect the number of sperm, their morphology and motility.

Lactation

Following administration of a single dose of 200 mg zidovudine to HIV-infected women, similar drug concentrations were observed in breast milk and serum. Women living with HIV should not breastfeed under any circumstances to avoid HIV transmission.

Impact on the ability to drive a car/other mechanisms

The effect of Retrovir on the ability to drive a car/use machines has not been studied. In addition, adverse effects on these abilities cannot be predicted based on the pharmacological properties of the drug. However, when deciding on the ability to drive a car/machines, one should keep in mind the patient’s clinical condition and the profile of adverse reactions to Retrovir.

Release form

Oral solution 50 mg/5 ml.

A yellow glass bottle, closed with a polyethylene cap, equipped with a tamper evident device. One bottle along with a plastic dosing syringe, adapter and instructions for use is placed in a cardboard box.

Termvalidity

2 years. After opening the bottle - 30 days.

Do not use after the expiration date stated on the package.

Storage conditions

At a temperature not exceeding 30 °C.

Keep out of the reach of children.

Conditions for dispensing from pharmacies

By doctor's prescription.

Manufacturer

GlaxoSmithKline Inc., Canada / GlaxoSmithKline Ink., Canada

7333, Mississauga Road, Mississauga, Ontario, L5N 6L4, Canada / 7333, Mississauga Road, Mississauga, Ontario, L5N 6L4, Canada.

For more information please contact

Representative office of GlaxoSmithKline Export Limited LLC (Great Britain) in the Republic of Belarus.

Minsk, st. Voronyanskogo 7A, office 400.

Tel.: + 375 17 213 20 16; fax + 375 17 213 18 66.

Disease class

Clinical and pharmacological group

• Not indicated. See instructions

Pharmacological action

• Antiviral

Pharmacological group

• Medicines for the treatment of HIV infection

Solution for infusion Retrovir (Retrovir)

Instructions for medical use of the drug

• Indications for use
• Release form
• Pharmacokinetics of the drug
• Contraindications for use
• Side effects
• Directions for use and doses
• Overdose
• Special instructions for use
• Storage conditions
• Best before date

Indications for use

Treatment of HIV infection as part of combination antiretroviral therapy in children and adults; reducing the frequency of transplacental transmission of HIV from mother to fetus.

Release form

solution for infusion 200 mg/20 ml; bottle (bottle) 20 ml, box (box) 5;

Pharmacokinetics

The mean T1/2, mean total clearance and volume of distribution are 1.1 hours, 27.1 ml/min/kg and 1.6 l/kg, respectively. The renal clearance of zidovudine is much greater than the clearance of creatinine, indicating its preferential elimination by tubular secretion. Zidovudine 5′-glucuronide is the main metabolite, determined in both plasma and urine and accounting for approximately 50–80% of the drug dose that is excreted through the kidneys. With intravenous administration of the drug, a metabolite 3′ amino? 3′-deoxytidymine is formed.

In children over 5–6 months of age, pharmacokinetic parameters are similar to those in adults. When taken orally, it is well absorbed from the intestine, bioavailability is 60–74% (on average 65%). After oral administration of Retrovir solution at a dose of 120 mg/m2 of body surface and 180 mg/m2, the average equilibrium maximum concentration is 4.45 and 7.7 μM (or 1.19 and 2.06 μg/ml). After intravenous infusion at a dose of 80 mg/m2, 120 mg/m2 and 160 mg/m2, it is 1.46, 2.26 and 2.96 mcg/ml, respectively. The average T1/2 and total clearance are 1.5 hours and 30.9 ml/min/kg, respectively. The main metabolite is a 5′-glucuronide. After intravenous administration, 29% of the drug dose is excreted unchanged in the urine and 45% of the dose is excreted as a glucuronide. In newborns younger than 14 days, there is a decrease in bioavailability, decreased clearance and prolongation of T1/2.

2–4 hours after oral administration in adults, there is no glucuronidation of zidovudine with a subsequent increase in its average concentration ratio of zidovudine in the cerebrospinal fluid and in plasma is 0.5, and in children after 0.5–4 hours it is 0.52–0.85 . There are no signs of accumulation of zidovudine in pregnant women, and its pharmacokinetics are similar to those in non-pregnant women. Zidovudine passes through the placenta and is detected in the amniotic fluid and fetal blood. The plasma concentration of zidovudine in children at birth is the same as in mothers during childbirth. It is found in semen and breast milk (after a single dose of 200 mg, the average concentration in milk corresponds to that in serum). Binding of the drug to plasma proteins is 34–38%.

In patients with severe renal impairment, the plasma concentration of zidovudine is increased by 50% compared to its concentration in patients without renal impairment. Systemic exposure of the drug (defined as the area under the concentration-time curve) was increased by 100%; T1/2 is significantly impaired. In renal failure, a significant accumulation of the main glucuronide metabolite is observed, but no signs of toxicity are observed. Hemo- and peritoneal dialysis do not affect the elimination of zidovudine, while the excretion of glucuronide is enhanced.

In case of liver failure, accumulation of zidovudine may be observed due to decreased glucuronidation (requires dose adjustment).

Use during pregnancy

Before 14 weeks of pregnancy, use is possible only if the expected effect of therapy exceeds the potential risk to the fetus. Breastfeeding should be stopped during treatment.

Contraindications for use

Hypersensitivity to the components of the drug, neutropenia (neutrophil count less than 0.75 109/l); decreased hemoglobin content (less than 75 g/l or 4.65 mmol/l), children's age (up to 3 months).

With caution: inhibition of bone marrow hematopoiesis, deficiency of vitamin B12 and folic acid, liver failure.

Side effects

From the hematopoietic system: >1/100-<1/10 - анемия, нейтропения, лейкопения;

>1/1000-<1/100 - тромбоцитопения, панцитопения (с гипоплазией костного мозга); <1/10000 - апластическая анемия.

From the metabolic side: >1/10000–1/1000 - lactic acidosis in the absence of hypoxemia and anorexia.

From the central and peripheral nervous system: >1/10 - headache; >1/100-<1/10 - головокружение; >1/10000-<1/1000 - бессонница, парестезии, сонливость, снижение скорости мышления, судороги, тревога, депрессия.

From the cardiovascular system: >1/10000-<1/1000 - кардиомиопатия.

From the respiratory system: >1/1000-<1/100 - одышка; >1/10000-<1/1000 - кашель.

From the gastrointestinal tract: >1/10 - nausea; >1/100-<1/10 - рвота, боли в верхних отделах живота, диарея; >1/1000-<1/100 - метеоризм; >1/10000-<1/1000 - пигментация слизистой оболочки полости рта, нарушение вкуса, диспепсия, панкреатит.

From the hepatobiliary system: >1/100-<1/10 - повышение уровня билирубина и активности ферментов печени; >1/10000-<1/1000 - выраженная гепатомегалия со стеатозом.

From the skin and its appendages: >1/1000-<1/100 - кожная сыпь (кроме крапивницы), кожный зуд; >1/10000-<1/1000 - пигментация ногтей и кожи, крапивница, повышенное потоотделение.

From the musculoskeletal system: >1/100-<1/10 - миалгия; >1/100-<1/100 - миопатия.

From the urinary system: >1/10000-<1/1000 - учащенное мочеиспускание.

From the endocrine system: >1/10000-<1/1000 - гинекомастия.

Others: >1/100-<1/10 - недомогание; >1/1000-<1/100 - лихорадка, болевой синдром различной локализации, астения; >1/10000-<1/1000 - озноб, боли в грудной клетке, гриппоподобный синдром.

With intravenous administration for 2–12 weeks, the most common occurrences are: anemia, leukopenia, neutropenia.

When preventing the transmission of HIV infection from mother to fetus in children, a decrease in hemoglobin levels is observed. Anemia disappears 6 weeks after completion of therapy.

Directions for use and doses

IV (solution for infusion), by slow infusion in a diluted form over 1 hour. The solution is administered only until patients are able to take the drug orally.

Breeding

The solution for intravenous infusion must be diluted before administration. The required dose (see below) of the solution is added to a 5% glucose solution for intravenous administration and mixed with it so that the final concentration of zidovudine is 2 mg/ml or 4 mg/ml. Such solutions remain stable for 48 hours at 5 °C and 25 °C.

Since there is no antimicrobial preservative in the Retrovir solution, dilution should be carried out under conditions of complete asepsis, immediately before administration; the unused part of the solution in the vial should be destroyed. If the solution becomes cloudy, it should be thrown away.

Adults and children over 12 years of age - 1–2 mg/kg every 4 hours. This dose with intravenous administration of Retrovir provides the same drug exposure as a dose of zidovudine 1.5 mg/kg or 3 mg/kg every 4 hours ( 600 or 1200 mg/day in patients weighing 70 kg) when taken orally. The effectiveness of the lower dose in the treatment or prevention of HIV-associated neurological complications and malignancies is unknown.

Children from 3 months to 12 years. Information on the use of Retrovir for intravenous infusion in children is insufficient. The drug was prescribed in various doses from 80 to 160 mg/m2 every 6 hours (320–640 mg/m2/day). Doses of the drug between 240–320 mg/m2 per day in 3–4 divided doses are comparable to doses from 360 mg/m2 to 480 mg/m2 per day in 3–4 oral doses, but how effective they are is currently not established.

Prevention of transmission of HIV infection from mother to fetus. Pregnant women, starting from 14 weeks of pregnancy until the onset of labor, are recommended to prescribe Retrovir orally. During childbirth, Retrovir is administered IV at a dose of 2 mg/kg as an infusion over 1 hour, and then as a continuous infusion at a dose of 1 mg/kg/hour until the umbilical cord is clamped.

Retrovir is administered orally to newborns from the first 12 hours after birth to 6 weeks. If oral administration is not possible, administer IV at a dose of 1.5 mg/kg as an infusion over 30 minutes every 6 hours.

For severe renal failure, a dose of 1 mg/kg 3–4 times daily intravenously is recommended. This dose is equivalent to the daily dose of 300–400 mg oral zidovudine recommended for this category of patients. Depending on the peripheral blood response and clinical effect, further dose adjustments may be required. For patients with end-stage renal disease on hemodialysis or peritoneal dialysis, a dose of zidovudine 100 mg every 6 to 8 hours is recommended.

Overdose

Symptoms: fatigue, headache, vomiting, changes in blood counts (very rare).

Treatment: symptomatic therapy. Hemo- and peritoneal dialysis are ineffective for removing zidovudine from the body, but enhance the excretion of its metabolite, glucuronide.

Interactions with other drugs

Lamivudine moderately increases the Cmax of zidovudine (by 28%), but does not change the AUC. Zidovudine has no effect on the pharmacokinetics of lamivudine. Probenecid reduces glucuronidation and increases T1/2 and AUC of zidovudine. Renal excretion of glucuronide and zidovudine is reduced in the presence of probenecid.

Ribavirin is an antagonist of zidovudine (their combination should be avoided).

Combination with rifampicin results in a decrease in AUC for zidovudine by 48±34% (the clinical significance of this change is unknown).

Zidovudine inhibits intracellular phosphorylation of stavudine; reduces the concentration of phenytoin in the blood (with simultaneous administration, monitoring of the level of phenytoin in plasma is necessary).

Paracetamol, aspirin, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, isoprinosine can interfere with the metabolism of zidovudine (competitively inhibit glucuronidation or suppress microsomal metabolism in the liver). Such combinations should be approached with caution.

The combination of Retrovir with nephrotoxic or myelotoxic drugs (especially in emergency care) - pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin - increases the risk of adverse reactions of Retrovir (monitoring of renal function is necessary, blood counts and dose reduction if necessary).

Radiation therapy enhances the myelosuppressive effect of zidovudine.

Precautions for use

In case of liver failure, if necessary, adjust the dose and/or increase the interval between doses.

If the hemoglobin level decreases to 75–90 g/l (4.65–5.59 mmol/l) or the number of leukocytes decreases to 0.75–1 109/l, change the dosage of the drug or discontinue it.

Particular care should be taken when treating elderly patients (age-related decline in renal function and changes in peripheral blood parameters should be taken into account).

Special instructions for use

The solution for infusion cannot be administered intramuscularly.

It is necessary to inform the patient about the dangers of using over-the-counter drugs simultaneously with Retrovir and that the use of Retrovir does not prevent HIV infection through sexual contact or contaminated blood. Appropriate safety precautions must be taken.

Retrovir does not cure HIV infection; patients remain at risk of developing a full-blown disease with immunosuppression and the occurrence of opportunistic infections and malignant neoplasms. For AIDS, Retrovir reduces the risk of developing opportunistic infections, but does not reduce the risk of developing lymphomas.

Pregnant women undergoing prevention of HIV transmission to the fetus should be informed about the risk of infection of the fetus despite the therapy.

Anemia (usually observed 6 weeks after the start of Retrovir use, but sometimes may develop earlier), neutropenia (usually develops 4 weeks after the start of treatment with Retrovir, but sometimes occurs earlier), leukopenia can occur in patients with an advanced clinical picture of HIV infection, receiving Retrovir, especially in high doses (1200–1500 mg/day), and having reduced bone marrow hematopoiesis before treatment.

During treatment with Retrovir in patients with an advanced clinical picture of HIV infection, it is necessary to monitor blood tests at least once every 2 weeks during the first 3 months of therapy, and then monthly. In the early stage of AIDS (when bone marrow hematopoiesis is still within normal limits), adverse reactions from the blood rarely develop, so blood tests are performed less frequently, once every 1–3 months (depending on the general condition of the patient).

If the hemoglobin content decreases to 75–90 g/l (4.65–5.59 mmol/l), the number of neutrophils decreases to 0.75–1.0 109/l, the daily dose of Retrovir should be reduced until blood counts are restored or Retrovir must be discontinued for 2–4 weeks. until blood counts are restored. Typically, the blood picture returns to normal after 2 weeks, after which Retrovir in a reduced dosage should be re-prescribed. In children with severe anemia, blood transfusions may be required (despite a reduction in the dose of Retrovir).

Lactic acidosis and severe hepatomegaly with steatosis can be fatal, both with mono- and multicomponent therapy with Retrovir. The risk of developing these complications increases in women. In all cases of clinical or laboratory signs of lactic acidosis or toxic liver damage, Retrovir should be discontinued.

When deciding whether to drive a car, you should take into account the likelihood of developing such adverse reactions as dizziness, drowsiness, lethargy, and convulsions.

The use of the drug to prevent the transmission of HIV from mother to fetus helps to reduce the frequency of HIV transmission from mother to fetus. The long-term consequences of this prophylaxis are unknown. The possibility of a carcinogenic effect cannot be completely excluded. Pregnant women should be informed about this.

Storage conditions

List B.: At a temperature not exceeding 30 °C.

Best before date

ATX classification:

J Antimicrobials for systemic use

J05 Antiviral drugs for systemic use

J05A Direct acting antivirals

J05AF Nucleosides - reverse transcriptase inhibitors

Catad_pgroup Antiviral for HIV

Retrovir solution - instructions for use

Registration number:

Trade name of the drug: Retrovir ® / Retrovir ® .

International nonproprietary name: zidovudine / zidovudine.

Dosage form:

solution for oral administration.

Compound
5 ml of the drug contains:

Description
Transparent light yellow solution with a characteristic strawberry odor.

Pharmacotherapeutic group
Antiviral (HIV) agent.

ATX code: J05AF01.

Pharmacological properties
Pharmacodynamics
Mechanism of action
Zidovudine is an antiviral drug, a thymidine analogue, highly active against retroviruses, including the human immunodeficiency virus (HIV).
Zidovudine undergoes phosphorylation in both infected and intact cells to form monophosphate via cellular thymidine kinase. The subsequent phosphorylation of zidovudine monophosphate to zidovudine diphosphate and then to zidovudine triphosphate is catalyzed by cellular thymidylate kinase and nonspecific kinases, respectively.
Zidovudine triphosphate acts as an inhibitor and substrate for viral reverse transcriptase. The formation of proviral DNA is blocked by the incorporation of zidovudine triphosphate into its chain, which leads to chain termination. The competition of zidovudine triphosphate for HIV reverse transcriptase is approximately 100 times stronger than for cellular human DNA polymerase.
Zidovudine acts additively or synergistically with a large number of antiretroviral drugs, such as lamivudine, didanosine, and interferon, suppressing HIV replication in cell culture.
The development of resistance to thymidine analogues (zidovudine is one of them) occurs as a result of the gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. Viruses acquire phenotypic resistance to thymidine analogues as a result of combined mutations at positions 41 and 215 or the accumulation of at least 4 of 6 mutations. These mutations do not cause cross-resistance to other nucleoside analogues, which allows the future use of other reverse transcriptase inhibitors for the treatment of HIV infection.
Two types of mutations lead to the development of multiple drug resistance.
In one case, mutations occur in positions 62, 75, 77, 116 and 151 of HIV reverse transcriptase, and in the second case we are talking about a T69S mutation with the insertion of 6 nitrogen base pairs in this position, which is accompanied by the appearance of phenotypic resistance to zidovudine, and also to other nucleoside reverse transcriptase inhibitors. Both types of these mutations significantly limit therapeutic options for HIV infection.
A decrease in the in vitro sensitivity of HIV isolates to zidovudine was observed during long-term treatment of HIV infection with zidovudine.
Currently, the relationship between sensitivity to zidovudine in vitro and the clinical effect of therapy has not been studied.
Research in vitro zidovudine in combination with lamivudine showed that zidovudine-resistant virus isolates become sensitive to zidovudine while simultaneously acquiring resistance to lamivudine. Clinical studies have demonstrated that the use of zidovudine in combination with lamivudine delays the emergence of zidovudine-resistant strains of the virus in patients who have not previously received antiretroviral therapy.

Pharmacokinetics
Suction
Zidovudine is well absorbed after oral administration, bioavailability is 60-70%. The mean values ​​of the maximum concentration at steady state (C ss max) and the minimum concentration at steady state (C ss min) in plasma when taking 5 mg/kg zidovudine every 4 hours were 7.1 and 0.4 µmol, respectively (or 1.9 and 0.1 µg/ml).
Bioequivalence
It has been shown that zidovudine oral solution is bioequivalent to zidovudine capsules in terms of area under the concentration-time pharmacokinetic curve (AUC).
Distribution
Plasma protein binding is relatively low, 34-38%.
Zidovudine penetrates into the cerebrospinal fluid, placenta, amniotic fluid, fetal blood, sperm and breast milk.
Metabolism
Zidovudine 5"-glucuronide is the main final metabolite of zidovudine, determined in plasma and urine and accounts for approximately 50-80% of the drug dose that is excreted by the kidneys.
Removal
The renal clearance of zidovudine is much greater than the clearance of creatinine, indicating the predominant elimination of zidovudine by tubular secretion.
Special patient groups
Children
In children over 5-6 months of age, pharmacokinetic parameters are similar to those in adults.
Zidovudine is well absorbed from the intestine, bioavailability is 60-74% with an average value of 65%. After taking zidovudine in doses of 120 mg/m2 and 180 mg/m2 as an oral solution, the maximum equilibrium concentration was 4.45 μM (1.19 μg/ml) and 7.7 μM (2.06 μg/ml ) respectively.
Pharmacokinetic data indicate that glucuronidation of zidovudine is reduced in neonates and infants, resulting in increased bioavailability. Decreased clearance and a longer half-life are recorded in infants younger than 14 days, then pharmacokinetic parameters become similar to those in adults.
Elderly patients
The pharmacokinetics of zidovudine in patients over 65 years of age have not been studied.

In patients with severe renal impairment, the maximum plasma concentration of zidovudine is increased by 50% compared to that in patients without renal impairment. Systemic exposure of zidovudine (AUC) increases by 100%, the half-life does not change significantly. When renal function is impaired, a significant accumulation of the main metabolite of zidovudine 5"-glucuronide is observed, but no signs of toxic effects are detected. Hemodialysis and peritoneal dialysis do not affect the excretion of zidovudine, while at the same time the excretion of zidovudine 5"-glucuronide is enhanced.

In case of liver failure, accumulation of zidovudine may be observed due to decreased glucuronidation, which requires dose adjustment of the drug.
Pregnancy
The pharmacokinetic parameters of zidovudine in pregnant women do not change, and there are no signs of zidovudine accumulation.
Plasma zidovudine concentrations in children at birth are the same as those in their mothers at the time of delivery.

Indications for use

Treatment of HIV infection as part of combination therapy;

treatment of HIV infection in pregnant women to reduce the frequency of transplacental transmission of HIV from mother to fetus. Contraindications

Hypersensitivity to zidovudine or any other component of the drug;

neutropenia (neutrophil count less than 0.75 * 10 9 /l);

decrease in hemoglobin content (less than 75 g/l or 4.65 mmol/l). Carefully

Elderly patients;

inhibition of bone marrow hematopoiesis;

anemia;

severe liver failure. Use during pregnancy and lactation
Fertility
There is no data on the effect of the drug Retrovir ® on the reproductive function of women. In men, taking Retrovir ® does not affect sperm composition, morphology and sperm motility.
Pregnancy
Zidovudine crosses the placenta. Retrovir ® can be used before 14 weeks of pregnancy only if the potential benefit to the mother outweighs the risk to the fetus.
Prevention of mother-to-fetus transmission of HIV
The use of the drug Retrovir ® after 14 weeks of pregnancy with its subsequent administration to newborns leads to a decrease in the frequency of vertical transmission of HIV.
The long-term consequences of using the drug Retrovir ® in children who received it in the prenatal or neonatal periods are unknown. The possibility of a carcinogenic effect cannot be completely excluded. Pregnant women should be informed about this.
Pregnant women considering the use of Retrovir ® during pregnancy to prevent vertical transmission of HIV should be informed of the risk of infection of the fetus, despite the therapy.
Lactation
Since zidovudine and HIV pass into breast milk, women should not breastfeed while taking Retrovir ®. Directions for use and doses
The drug Retrovir ® is intended for oral administration.
Adults and adolescents weighing at least 30 kg
The recommended dose is 500 or 600 mg per day, divided into two doses, as part of combination therapy. A dose of 1000 mg per day, divided into several doses, was used in clinical studies. The effectiveness of doses in the range below 1000 mg/day for the treatment or prevention of HIV-associated neurological dysfunction is unknown.
Children
Children weighing at least 9 kg but less than 30 kg
The recommended dose is 18 mg/kg per day, divided into two doses, as part of combination therapy. The effectiveness of doses in the range below 720 mg/m 2 /day (approximately 18 mg/kg twice daily) for the treatment of HIV-associated neurological dysfunction is unknown. The maximum daily dose should not exceed 600 mg (300 mg 2 times a day).
Children weighing at least 4 kg but less than 9 kg
The recommended dose is 24 mg/kg per day, divided into two doses, as part of combination therapy.
Elderly patients
The pharmacokinetics of zidovudine in patients over 65 years of age have not been studied. However, given the age-related decline in renal function and possible changes in peripheral blood parameters, in such patients it is necessary to exercise special caution when prescribing the drug Retrovir ® and carry out appropriate monitoring before and during treatment.
Patients with impaired renal function
For severe renal impairment, the recommended dose of Retrovir ® is 300-400 mg per day. Depending on the peripheral blood response and clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis do not have a significant effect on the elimination of zidovudine, but they accelerate the elimination of zidovudine 5"-glucuronide.
For patients with end-stage renal failure on hemodialysis or peritoneal dialysis, the recommended dose of Retrovir ® is 100 mg every 6-8 hours.
Patients with liver dysfunction
Data obtained in patients with liver cirrhosis indicate that in patients with liver failure, accumulation of zidovudine may occur due to decreased glucuronidation, and therefore dose adjustment may be required. If monitoring plasma zidovudine concentrations is not possible, the physician should pay special attention to clinical signs of intolerance to the drug and, if necessary, adjust the dose and/or increase the interval between doses of the drug.
Dose adjustment for adverse reactions from the hematopoietic system
Adequate correction of the dosage regimen - dose reduction or discontinuation of the drug Retrovir ® - may be required in patients with adverse reactions from the hematopoietic system (in case of a decrease in hemoglobin concentration to 75-90 g/l (4.65-5.59 mmol/l) or leukocyte count up to 0.75-1.0 * 10 9 /l).
Prevention of transmission of HIV infection from mother to fetus
The following 2 prophylaxis regimens have been shown to be effective in pregnant women

Pregnant women, starting from 14 weeks of pregnancy, are recommended to prescribe Retrovir ® orally before the onset of labor at a dose of 500 mg/day (100 mg 5 times a day). During childbirth, Retrovir ® is administered intravenously until the umbilical cord is clamped.

Pregnant women, starting from 36 weeks of pregnancy, are recommended to prescribe Retrovir ® at a dose of 600 mg/day (300 mg twice a day) orally until labor begins. Then every 3 hours, 300 mg of Retrovir ® orally from the onset of labor until delivery.
Newborns are prescribed Retrovir ® at a dose of 2 mg/kg body weight every 6 hours, starting in the first 12 hours after birth and continuing until 6 weeks of age. Newborns who cannot take Retrovir ® solution orally must be prescribed Retrovir ® intravenously.
Instructions for using the dosing syringe
The supplied dosing syringe and adapter are designed for precise dosing of Retrovir ®, oral solution.

1. Remove the cap from the bottle.
2. Insert the supplied adapter into the neck of the bottle while holding the bottle
3. Insert the dosing syringe into the hole in the adapter.
4. Turn the bottle over.
5. By pulling the plunger of the dosing syringe, measure out the exact amount of the first portion of the full dose of the drug prescribed to you.
6. Turn the bottle upside down and remove the syringe from the adapter.
7. Carefully place the syringe in the mouth, behind the cheek, swallow the drug, slowly pressing on the syringe plunger. Do not press the plunger too hard; the solution may splash into the back of the throat and cause choking.
8. Repeat procedures 3–7 until you receive the full dose.
9. Do not leave the syringe in the bottle; after use, thoroughly rinse the dosing syringe and adapter with clean water.
10. Close the bottle tightly with the cap.

Side effect
The profile of adverse events when taking zidovudine is similar in adults and children. The adverse events presented below are listed depending on the anatomical and physiological classification and frequency of occurrence. The frequency of occurrence is determined as follows: Often (≥1/10), often(≥1/100 and<1/10), infrequently(≥1/1000 and<1/100), rarely(≥1/10000 and<1/1000), very rarely (<1/10000, включая отдельные случаи). Категории частоты были сформированы на основании клинических исследований препарата и пострегистрационного наблюдения.
Frequency of occurrence of adverse events
From the hematopoiesis and lymphatic system
Common: anemia (which may require blood transfusions), neutropenia and leukopenia. Anemia occurs more often when taking high doses of the drug (1200-1500 mg/day) and in patients in the later stages of HIV infection, in particular when the concentration of CD4 lymphocytes is less than 100 cells/μl. As a result, dose reduction or discontinuation of therapy may be necessary. The incidence of neutropenia was higher in patients who had low neutrophil counts, hemoglobin levels, and serum vitamin B12 levels before treatment.
Uncommon: thrombocytopenia and pancytopenia (with bone marrow hypoplasia).
Rare: true erythrocyte aplasia.
Very rare: aplastic anemia.
Metabolism and nutrition
Common: hyperlactatemia.
Rarely: lactic acid, anorexia. Redistribution and/or accumulation of subcutaneous fat (the development of this phenomenon depends on many factors, including the combination of antiretroviral drugs).
From the central and peripheral nervous system
Very common: headache.
Common: dizziness.
Rarely: insomnia, paresthesia, drowsiness, decreased speed of thinking, convulsions.
From the mental sphere
Rarely: anxiety, depression.
From the cardiovascular system
Rarely: cardiomyopathy.
From the respiratory system, chest organs and mediastinum
Uncommon: shortness of breath.
Rarely: cough.
From the gastrointestinal tract
Very common: nausea.
Common: vomiting, abdominal pain, diarrhea.
Uncommon: flatulence.
Rarely: pigmentation of the oral mucosa, taste disturbance, dyspepsia.
From the liver, biliary tract and pancreas
Common: increased bilirubin levels and liver enzyme activity.
Rarely: liver damage, such as severe hepatomegaly with steatosis; pancreatitis.
From the skin and subcutaneous fat
Uncommon: rash, itchy skin.
Rarely: pigmentation of nails and skin, urticaria, increased sweating.
From the musculoskeletal system
Common: myalgia.
Uncommon: myopathy.
From the urinary system
Rarely: frequent urination.
From the endocrine system
Rare: gynecomastia.
General and local reactions
Often: malaise.
Uncommon: fever, generalized pain syndrome, asthenia.
Rarely: chills, chest pain, flu-like syndrome.
Adverse reactions that occur when using the drug Retrovir ® to prevent the transmission of HIV infection from mother to fetus
Pregnant women tolerate Retrovir ® well in recommended doses. In children, a decrease in hemoglobin levels is observed, which, however, does not require blood transfusions. Anemia disappears 6 weeks after completion of therapy with Retrovir ® . Overdose
Symptoms
Possible feeling of fatigue, headache, vomiting; very rarely: changes in blood parameters. There is one report of overdose with an unknown amount of zidovudine, where the concentration of zidovudine in the blood was 16 times the usual therapeutic concentration, however, there were no clinical, biochemical or hematological symptoms.
Treatment
Symptomatic therapy and supportive care. Hemodialysis and peritoneal dialysis are not highly effective in removing zidovudine from the body, but they enhance the removal of its metabolite, zidovudine 5"-glucuronide. Interaction with other drugs
Zidovudine is primarily excreted as an inactive metabolite, which is a glucuronide conjugate formed in the liver. Drugs with a similar route of elimination may potentially inhibit the metabolism of zidovudine.
Zidovudine is used in combination antiretroviral therapy together with other nucleoside reverse transcriptase inhibitors and drugs from other groups (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors).
The list of interactions listed below should not be considered exhaustive, but does include groups of drugs that require careful use with zidovudine.
Atovahon: Zidovudine does not affect the pharmacokinetic parameters of atovaquone. Atovachone slows down the transformation of zidovudine into its glucuronide derivative (the AUC of zidovudine at steady state increases by 33% and maximum glucuronide concentrations decrease by 19%). The safety profile of zidovudine at doses of 500 or 600 mg/day is unlikely to change when combined with atovaquone for three weeks for the treatment of Pneumocystis pneumonia. If longer-term combined use of these drugs is necessary, careful monitoring of the patient's clinical condition is recommended.
Clarithromycin: reduces the absorption of zidovudine. The interval between doses of zidovudine and clarithromycin should be at least 2 hours.
Lamivudine: There is a moderate increase in the maximum concentration of zidovudine (C max up to 28%) when used simultaneously with lamivudine, but the overall exposure (AUC) does not change. Zidovudine has no effect on the pharmacokinetics of lamivudine.
Phenytoin: with simultaneous use of the drug Retrovir ® with phenytoin, the concentration of the latter in the blood plasma decreases; the concentration of phenytoin in the blood plasma should be monitored when using this combination.
Probenecid: reduces glucuronidation and increases the mean half-life and AUC of zidovudine. Renal excretion of glucuronide and zidovudine itself is reduced in the presence of probenecid.
Rifampicin: the combination of Retrovir ® with rifampicin leads to a decrease in AUC for zidovudine by 48% ± 34%, but the clinical significance of this change is unknown.
Stavudin: Zidovudine can inhibit intracellular phosphorylation of stavudine. Therefore, it is not recommended to use stavudine concomitantly with zidovudine.
Other: acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, isoprinosine may interfere with the metabolism of zidovudine by competitive inhibition of glucuronidation or direct suppression of microsomal metabolism in the liver. The possibility of using these drugs in combination with Retrovir ® , especially for long-term therapy, should be approached with caution.
The combination of the drug Retrovir ®, especially in emergency treatment, with potentially nephrotoxic and myelotoxic drugs (for example, pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of developing adverse reactions to the drug Retrovir ®. Monitoring of kidney function and blood count is necessary, and if necessary, reduce the dose of drugs.
Since some patients, even despite therapy with Retrovir ® , may develop opportunistic infections, it is necessary to consider prescribing prophylactic antimicrobial therapy. Such prophylaxis includes co-trimoxazole, pentamidine aerosol, pyrimethamine and acyclovir. Limited data obtained from clinical studies did not reveal a significant increase in the risk of adverse reactions when using Retrovir ® together with these drugs. Special instructions and precautions for use
Treatment with Retrovir ® should be carried out by a physician experienced in treating HIV-infected patients. After opening the bottle, store for no more than 28 days at a temperature not exceeding 30°C.
Patients should be informed about the dangers of simultaneous use of Retrovir ® with over-the-counter drugs and that the use of Retrovir ® does not prevent HIV transmission through sexual contact or infected blood. Appropriate safety measures are required.
Emergency prevention in case of probable infection
According to international recommendations (Center for Disease Control and Prevention, USA, June 1998), if there is likely contact with HIV-infected material (blood, other liquids), it is urgently necessary to prescribe combination therapy with Retrovir ® within 1-2 hours from the moment of infection and Epivir ® . In case of a high risk of infection, a drug from the group of protease inhibitors should be included in the treatment regimen. Prophylactic treatment is recommended for 4 weeks. Despite the rapid initiation of treatment with antiretroviral drugs, the development of seroconversion cannot be ruled out.
Symptoms that are mistaken for adverse reactions to therapy with Retrovir ® may be a manifestation of the underlying disease or a reaction to taking other drugs used to treat HIV infection. The relationship between the developed symptoms and the effect of the drug Retrovir ® is often very difficult to establish, especially with an advanced clinical picture of HIV infection. In such cases, it is possible to reduce the dose of the drug or discontinue it.
Retrovir ® does not cure HIV infection, and patients remain at risk of developing opportunistic infections and malignancies due to immunosuppression. Retrovir ® reduces the risk of developing opportunistic infections. Data on the risk of developing lymphomas with the use of the drug are limited.
Adverse reactions from the hematopoietic system
Anemia (usually observed 6 weeks after starting treatment with Retrovir ® , but sometimes may develop earlier), neutropenia (usually develops 4 weeks after starting treatment with Retrovir ® , but sometimes occurs earlier), leukopenia may occur in the later stages of HIV infection in patients receiving Retrovir ® , especially in high doses (1200-1500 mg/day), and with reduced bone marrow hematopoiesis before treatment.
While taking Retrovir ® in patients with an advanced clinical picture of HIV infection, it is necessary to monitor hematological parameters at least once every 2 weeks during the first 3 months of therapy, and then monthly. In the early stages of HIV infection (with undepleted reserves of bone marrow hematopoiesis), undesirable reactions from the hematopoietic system rarely develop, so general blood tests can be performed less frequently, depending on the general condition of the patient (once every 1-3 months).
If the hemoglobin content decreases to 75-90 g/l (4.65-5.59 mmol/l) or the number of neutrophils decreases to 0.75-1.0 * 10 9 / l, the daily dose of Retrovir ® should be reduced to restoration of blood counts or Retrovir ® is canceled for 2-4 weeks until blood counts are restored. Typically, the blood picture returns to normal after 2 weeks, after which the drug Retrovir ® in a reduced dose can be re-prescribed. Despite reducing the dose of Retrovir ® , severe anemia may require blood transfusions.
Radiation therapy enhances the myelosuppressive effect of zidovudine.
Lactic acidosis and severe hepatomegaly with steatosis
These complications can be fatal both with monotherapy with Retrovir ® and when using Retrovir ® as part of combination therapy. Clinical signs of these complications may include weakness, anorexia, sudden unexplained weight loss, gastrointestinal symptoms, and respiratory symptoms (shortness of breath and tachypnea).
Caution should be exercised when prescribing the drug to patients, especially with risk factors for liver disease. The risk of developing these complications increases in women. Retrovir should be discontinued in all cases of clinical or laboratory signs of lactic acidosis or hepatotoxicity, which may include hepatomegaly with steatosis, even in the absence of increased transaminase activity.
Redistribution of subcutaneous fat tissue
Redistribution and/or accumulation of subcutaneous fat, including central obesity, increased fat on the back of the neck (“buffalo hump”), decreased subcutaneous fat on the face and extremities, enlarged mammary glands, increased serum lipids and blood glucose was noted both in combination and separately in some patients receiving combination antiretroviral therapy.
To date, all drugs in the protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor (NRTI) classes have been associated with one or more specific adverse events associated with a common syndrome often called lipodystrophy. However, data indicate that there are differences in the risk of developing this syndrome between specific representatives of therapeutic classes.
In addition, lipodystrophy syndrome has a multifactorial etiology, for example, factors such as stage of HIV infection, advanced age and duration of antiretroviral therapy play an important, possibly potentiating role.
The long-term consequences of this phenomenon are currently unknown. Clinical evaluation should include physical examination to assess for the presence of subcutaneous fat redistribution. A study of serum lipid and blood glucose concentrations should be recommended. Lipid disorders should be treated as clinically indicated.
Immune reconstitution syndrome
In HIV-infected patients with severe immunodeficiency, during the initiation of antiretroviral therapy, an exacerbation of the inflammatory process against the background of asymptomatic or residual opportunistic infection is possible, which can cause serious deterioration of the condition or aggravation of symptoms. Typically, such reactions have been described in the first weeks or months of starting antiretroviral therapy. The most significant examples? cytomegalovirus retinitis, generalized and/or focal mycobacterial infection and Pneumocystis pneumonia ( P. carinii). Any symptoms of inflammation must be immediately identified and treatment initiated if necessary.
Coinfection with HIV and viral hepatitis C
An increase in ribavirin-induced anemia has been reported in HIV-infected patients receiving concomitant zidovudine therapy, but the exact mechanism of this phenomenon is unknown. Therefore, the combined use of ribavirin and zidovudine is not recommended. The antiretroviral regimen should be changed to a regimen that does not contain zidovudine, especially in patients with a history of zidovudine-induced anemia. Impact on the ability to drive vehicles and machinery
The effect of Retrovir ® on the ability to drive a car or operate machinery has not been studied. However, an adverse effect on these abilities is unlikely based on the pharmacokinetics of the drug. However, when deciding whether to drive a car or move machinery, you should take into account the patient’s condition and the possibility of developing adverse reactions (dizziness, drowsiness, lethargy, convulsions). Release form
Oral solution, 50 mg/5 ml, 200 ml.
200 ml in a yellow glass bottle, closed with a polyethylene cap equipped with a tamper evident device. One bottle along with a plastic dosing syringe, adapter and instructions for use in a cardboard box. Best before date
2 years.
Do not use after the expiration date stated on the package. Storage conditions
At a temperature not higher than 30°C.
Keep out of the reach of children. Vacation conditions
On prescription. Manufacturer
"GlaxoSmithKline Inc."/ GlaxoSmithKline Ink. Canada, L5N 6L4, Ontario, Mississauga, Mississauga Road North, 7333/7333, Mississauga Road North, Mississauga, Ontario, L5N 6L4, Canada Name and address of the legal entity in whose name the registration certificate was issued
ViiV Healthcare UK Limited UK, TW8 9GS Middlesex, Brentford, Great West Road 980 / 980 Great West Road, Brentford, Middlesex TW8 9GS, United Kingdom For more information contact:
CJSC "GlaxoSmithKline Trading" 121614, Moscow, st. Krylatskaya, 17, bldg. 3, fl. 5, Business Park "Krylatsky Hills"

Retrovir is an antiviral pharmaceutical agent indicated for use in HIV infection.

Instructions for use Retrovir

What is the composition and release form of Retrovir?

The active ingredient in the antiviral drug Retrovir is zidovudine, the amount of which is 100 milligrams per capsule and 200 mg per vial. Excipients of the solution: hydrochloric acid and sodium hydroxide.

Retrovir also contains excipients: shellac, magnesium stearate, microcrystalline cellulose, corn starch, in addition, black iron oxide, ammonium hydroxide 28%, concentrated ammonium solution, propylene glycol, potassium hydroxide, and gelatin.

The drug Retrovir is available in white capsules with the designation “GSYJU” on the body, inside of which there is white powder. Supplied in blisters of 10 pieces. In addition, a transparent, slightly opalescent solution is produced, sold in 20 ml bottles. Sale is possible only after presentation of a prescription.

What is the effect of Retrovir?

An antiviral drug whose activity is directed against retroviruses, the most famous representative of which is the human immunodeficiency virus, abbreviated as HIV.

The mechanism of action of the drug is based on the ability of its active substance to disrupt the activity of the viral enzyme transcriptase, which is involved in the process of assembling virus particles. As a result, the process of formation of foreign DNA is disrupted, which slows down the progression of symptoms of the disease.

The disruption of the functioning of viral enzymes is due to the structural similarity of the active substance of the drug and thymidine triphosphate. Being integrated into the nucleic acid chain, zidovudine derivatives disrupt further processes of viral DNA assembly.

The use of Retrovir leads to partial normalization of the blood “formula”, which increases the patient’s body’s resistance to various dangerous factors, including infections.

It should be noted that the action of Retrovir is not completely selective. The active ingredient of the drug suppresses not only the assembly processes of viral particles, but also human DNA chains, although in significantly smaller quantities. The degree of influence on the patient's transcriptase is approximately 300 times lower.

The drug Retrovir is partially effective against other viruses: hepatitis B, Epstein-Barr virus and some others. The experiments also revealed insignificant antibacterial activity, suppressing the vital processes of individual representatives of the genus Enterobacteriaceae.

Absorption from the intestines is complete. The pharmaceutical drug introduced into the patient’s body quickly enters the systemic bloodstream. Zidovudine penetrates most tissue barriers. Metabolization processes are associated with liver activity. The half-life is about an hour. Metabolites of the active substance are excreted from the body in the urine.

What are Retrovir's indications for use?

Indications for Retrovir are:

Treatment of HIV infection as part of complex therapy;
Prevention of the development of HIV infection in the fetus if the mother is HIV-positive.

The use of the medicine is possible only after laboratory confirmation of the diagnosis. In addition, during the use of the drug, periodic assessment of the effectiveness of the measures taken is required.

What are Retrovir's contraindications for use?

The instructions for use do not allow the use of the drug Retrovir in the following cases:

A sharp decrease in the content of neutrophils in peripheral blood;
Decrease in hemoglobin content;
Individual intolerance.

Relative contraindications for Retrovir: elderly patient, renal failure, as well as severe inhibition of hematopoietic processes, in addition, severe anemic conditions.

What are Retrovir's uses and dosage?

The dosage of Retrovir is selected individually, taking into account the activity of the hematopoietic system, body weight and other factors. Capsules can be used without regard to meals in amounts of 500 to 600 milligrams per day. The frequency of administration is from 2 to 5 times.

The parenteral form of the drug Retrovir is administered intravenously in an amount of 1 to 2 milligrams per kilogram of the patient’s body weight, every 4 hours. The duration of therapeutic measures is determined by the attending physician, taking into account the effectiveness of the treatment.

What are the side effects of Retrovir?

The use of the drug Retrovir, both orally and intravenously, can lead to the following side effects: anemic conditions, hepatitis, flatulence (increased gas production), skin pigmentation, vomiting, diarrhea, swallowing disorders, anorexia, abdominal pain, headache, sleep disturbances, depression, weakness, lethargy, drowsiness. Other side effects of Retrovir are: inflammatory changes in the respiratory tract, urinary retention, heart pain, allergic skin rashes, anaphylactic reactions, metabolic disorders.

How to replace Retrovir, what analogues should I use?

Analogues of Retrovir include Zido-H, Viro-Z, Timazid, Retrovir AZiTi, Zidovirin, Zidovudine-Ferein, Zidovudine, Azidothymidine.

Conclusion

Treatment of HIV infection must be comprehensive. The patient should adhere to all the specialist’s recommendations: taking medications, nutritious nutrition, medical and protective regimen, course intake of multivitamins and multiminerals, regular observation in a medical institution.

Dosage form:  Solution for infusion. Compound:

Components
Active substance
Zidovudine
Excipients
Concentrated hydrochloric acid
Sodium hydroxide
Water for injections

Notes:

Concentrated hydrochloric acid or sodium hydroxide is used.

Description:

A transparent or slightly opalescent colorless solution, practically free of mechanical inclusions.

Pharmacotherapeutic group:Antiviral [HIV] agent. ATX:  

J.05.A.F.01 Zidovudine

Pharmacodynamics:

Mechanism of action

Zidovudine is an antiviral drug, a thymidine analogue, highly active in vitro against retroviruses, including the human immunodeficiency virus (HIV). undergoes phosphorylation in both infected and intact cells to form monophosphate via cellular thymidine kinase. The subsequent phosphorylation of zidovudine monophosphate to zidovudine diphosphate and then to zidovudine triphosphate is catalyzed by cellular thymidylate kinase and nonspecific kinases, respectively.

Zidovudine triphosphate acts as an inhibitor and substrate for viral reverse transcriptase. The formation of proviral DNA is blocked by the incorporation of zidovudine triphosphate into its chain, which leads to chain termination. The competition of zidovudine triphosphate for HIV reverse transcriptase is approximately 100 times stronger than for cellular human DNA polymerase a.

Antagonism between zidovudine and other antiretroviral drugs (, and) was not observed in vitro.

The development of resistance to thymidine analogues (is one of them) occurs as a result of the gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. 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. These mutations do not cause cross-resistance to other nucleoside analogues, which allows the future use of other reverse transcriptase inhibitors for the treatment of HIV infection.

Two types of mutations lead to the development of multiple drug resistance.

In one case, mutations occur in codons 62, 75, 77, 116 and 151 of HIV reverse transcriptase, and in the second case we are talking about a T69S mutation with the insertion of 6 nitrogen base pairs in this position, which is accompanied by the appearance of phenotypic resistance to zidovudine, and also to other nucleoside reverse transcriptase inhibitors (NRTIs). Both types of these mutations significantly limit therapeutic options for HIV infection.

A decrease in the in vitro sensitivity of HIV isolates to zidovudine was observed during long-term treatment of HIV infection with zidovudine. Available data indicate that in the early stages of HIV infection the frequency and extent of in vitro desensitization are significantly less than in later stages of the disease.

Currently, the relationship between sensitivity to zidovudine in vitro and the clinical effect of therapy has not been studied. In vitro susceptibility testing has not been standardized and results may vary depending on methodological factors.

In vitro studies of zidovudine in combination with lamivudine have shown that zidovudine-resistant virus isolates become susceptible to zidovudine while simultaneously acquiring resistance to lamivudine. Clinical studies have demonstrated that the use of zidovudine in combination with lamivudine delays the emergence of zidovudine-resistant viral strains in patients who have not previously received antiretroviral therapy (APT). is widely used as a component of combination APT together with other antiretroviral drugs of the same class (NRTIs) or other classes (HIV protease inhibitors (HIV PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs)).

Pharmacokinetics:

Suction

In patients who received an hourly infusion of the drug Retrovir at a dose of 1-5 mg/kg 3-6 times a day, the pharmacokinetics of zidovudine was dose-independent. The mean steady-state maximum (C ssmax) and minimum (C ssmin) plasma concentrations of zidovudine in adults after a 1-hour infusion of 2.5 mg/kg every 4 hours were 4.0 and 0.4 µmol, respectively (or 1.1 and 0 .1 µg/ml).

Distribution

In studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours, the mean total clearance was 27.1 mL/min/kg, and the apparent volume of distribution was 1.6 L/kg.

In adults, the mean ratio of zidovudine concentrations in cerebrospinal fluid to plasma 2 hours after dosing was approximately 0.5. Data show that it crosses the placenta and is found in amniotic fluid and fetal blood. has also been found in semen and breast milk.

Plasma protein binding is relatively low, 34-38%, so interactions with other drugs that affect the binding of zidovudine to plasma proteins are unlikely.

Metabolism

Zidovudine 5'-glucuronide is the main final metabolite of zidovudine, determined in plasma and urine and accounting for approximately 50-80% of the drug dose that is excreted by the kidneys. 3"-amino-3"-deoxythymidine (AMT) was identified as a metabolite of zidovudine after intravenous administration of the drug.

Removal

The renal clearance of zidovudine is much greater than the clearance of creatinine, indicating the predominant elimination of zidovudine by tubular secretion.

Special patient groups

Children

In children over 5-6 months of age, pharmacokinetic parameters are similar to those in adults. After intravenous administration of zidovudine at a dose of 80 mg/m2, 120 mg/m2 and 160 mg/m2 of body surface area, the C ssmax values ​​​​are 1.46 μg/ml, 2.26 μg/ml and 2.96 μg/ml, respectively. In children, the average ratio of the concentration of zidovudine in the cerebrospinal fluid and blood plasma varied from 0.52 to 0.85 0.5-4 hours after taking the drug orally and was 0.87 1-5 hours after a one-hour intravenous infusion. During intravenous infusion, the average ratio of drug concentrations in plasma and cerebrospinal fluid at steady state is approximately 0.24. When administered intravenously, the mean half-life and total clearance are 1.5 hours and 30.9 ml/min/kg, respectively. The main metabolite is zidovudine 5'-glucuronide. After intravenous administration, 29% of the drug dose is excreted unchanged through the kidneys, 45% of the dose is excreted as a glucuronide.

The renal clearance of zidovudine greatly exceeds the clearance of creatinine, indicating significant tubular secretion.

Pharmacokinetic data indicate that glucuronidation of zidovudine in

in newborns and infants is reduced, which leads to increased bioavailability. A decrease in clearance and a longer half-life are recorded in newborns younger than 14 days, then the pharmacokinetic parameters become similar to those in adults.

Elderly patients

The pharmacokinetics of zidovudine in patients over 65 years of age have not been studied.

Patients with impaired renal function

In patients with progressive renal impairment, the maximum plasma concentration of zidovudine is increased by 50% compared to that in patients with normal renal function. The systemic exposure of zidovudine (area under the concentration-time curve (AUC)) increases by 100%, the half-life does not change significantly. When renal function is impaired, a significant accumulation of the main metabolite of zidovudine 5'-glucuronide is observed, but no signs of toxic effects are detected.

Hemodialysis and peritoneal dialysis do not affect the excretion of zidovudine, while the excretion of zidovudine 5'-glucuronide is enhanced.

Patients with liver dysfunction

If liver function is impaired, accumulation of zidovudine may occur due to decreased glucuronidation, which may require dose adjustment of the drug, however, since only limited data are available, precise recommendations cannot be provided.

Pregnancy

The pharmacokinetics of zidovudine were studied in a study in 8 women during the last trimester of pregnancy. As pregnancy progressed, no signs of accumulation of zidovudine were observed. The pharmacokinetics of zidovudine were similar to those in non-pregnant adults. Plasma concentrations of zidovudine in infants at birth were similar to plasma concentrations in mothers, consistent with passive passage of zidovudine through the placenta.

Indications:

Severe manifestations of HIV infection in patients with AIDS when it is impossible to take Retrovir orally.

HIV infection in pregnant women, starting from the 14th week of gestation, and their newborn children to reduce the frequency of vertical transmission of HIV.

Contraindications:

Hypersensitivity to zidovudine or any other component of the drug;

Neutropenia (neutrophil count less than 0.75x 10 9/l);

Decreased hemoglobin content (less than 75 g/l or 4.65 mmol/l).

Carefully:

It is recommended to prescribe the drug with caution to patients under 3 months of age, because Limited data do not allow us to formulate clear recommendations on the dosage regimen of the drug for suppression of bone marrow hematopoiesis, deficiency of vitamin B12 and folic acid, and liver failure.

Pregnancy and lactation:

Fertility

There is no data on the effect of the drug Retrovir® on the reproductive function of women. In men, taking Retrovir® does not affect sperm composition, morphology and sperm motility.

Pregnancy

Zidovudine crosses the placenta. Retrovir can be used before 14 weeks of pregnancy only if the potential benefit to the mother outweighs the risk to the fetus. There have been reports of slight, transient increases in serum lactate concentrations, which may be due to mitochondrial dysfunction in neonates and infants exposed to NRTIs in utero or perinatal periods.

The clinical significance of transient increases in serum lactate concentrations is unknown. There are very rare reports of developmental delays, seizures and other neurological disorders (for example, increased muscle tone). However, a causal relationship between these events and intrauterine or perinatal exposure to NRTIs has not been established. These data do not affect the current recommendations for the use of APT during pregnancy to prevent vertical transmission of HIV.

Prevention of mother-to-fetus transmission of HIV

In the ACTG 076 trial, use of zidovudine after 14 weeks of pregnancy followed by neonatal administration resulted in a reduction in the incidence of vertical transmission of HIV (infection rate of 23% in the placebo group compared with 8% in the zidovudine group). Oral zidovudine therapy was started between 14 and 34 weeks of pregnancy and continued until the onset of labor. During childbirth it was administered intravenously. Newborns received it orally until 6 weeks of age. Newborns unable to take the drug orally were given by injection. In a study, zidovudine monotherapy administered orally to pregnant women starting at 36 weeks of pregnancy until delivery resulted in a significant reduction in the incidence of mother-to-fetus transmission of HIV (infection rate of 19% in the placebo group compared with 9% in the zidovudine group). In this study, mothers did not breastfeed their infants. The long-term effects of zidovudine in children exposed to it in utero or neonatal periods are unknown. Based on data on carcinogenicity and mutagenicity in animals, the possibility of carcinogenic effects in humans cannot be completely excluded. The significance of these data for infected and uninfected infants exposed to zidovudine is unknown. However, pregnant women considering the use of zidovudine during pregnancy should consider these data.

Breastfeeding period

From the hematopoiesis and lymphatic system

Common: anemia (which may require blood transfusions), neutropenia and leukopenia. Anemia occurs more often when taking high doses of the drug (1200-1500 mg/day) and in patients in the later stages of HIV infection, in particular when the concentration of CD4 lymphocytes is less than 100 cells/μl. As a result, dose reduction or discontinuation of therapy may be necessary. The incidence of neutropenia was higher in patients who had low neutrophil counts, hemoglobin levels, and serum vitamin B12 levels before treatment.

Uncommon: thrombocytopenia and pancytopenia (with bone marrow hypoplasia).

Rare: true erythrocyte aplasia.

Very rare: aplastic anemia.

Metabolism and nutrition

Common: hyperlactatemia.

Rarely: lactic acid, anorexia. Redistribution and/or accumulation of subcutaneous fat (the development of this phenomenon depends on many factors, including the combination of antiretroviral drugs).

From the central and peripheral nervous system

Very common: headache.

Common: dizziness.

Rarely: insomnia, paresthesia, drowsiness, decreased speed of thinking, convulsions.

From the mental sphere

Rarely: anxiety, depression.

From the cardiovascular system

Rarely: cardiomyopathy.

From the respiratory system, chest organs and mediastinum

Uncommon: shortness of breath.

Rarely: cough.

From the gastrointestinal tract

Very common: nausea.

Common: vomiting, abdominal pain, diarrhea.

Uncommon: flatulence.

Rarely: pigmentation of the oral mucosa, taste disturbance, dyspepsia.

From the liver, biliary tract and pancreas

Common: increased bilirubin levels and liver enzyme activity.

Rarely: liver damage, such as severe hepatomegaly with steatosis; pancreatitis.

From the skin and subcutaneous fat

Uncommon: rash, itchy skin.

Rarely: pigmentation of nails and skin, urticaria, increased sweating.

From the musculoskeletal system

Common: myalgia.

Uncommon: myopathy.

From the urinary system

Rarely: frequent urination.

From the endocrine system

Rare: gynecomastia.

General and local reactions

Often: malaise.

Uncommon: fever, generalized pain syndrome, asthenia.

Rarely: chills, chest pain, flu-like syndrome.

Adverse reactions that occur when using the drug Retrovir® to prevent transmission of HIV infection from mother to fetus

Pregnant women tolerate Retrovir® well in recommended doses. In children, a decrease in hemoglobin levels is observed, which, however, does not require blood transfusions. Anemia disappears 6 weeks after completion of therapy with Retrovir®.

Overdose:

Symptoms

Possible feeling of fatigue, headache, vomiting; very rarely - changes in blood parameters. There is one report of overdose with an unknown amount of zidovudine, where the concentration of zidovudine in the blood was 16 times the usual therapeutic concentration, however, there were no clinical, biochemical or hematological symptoms.

When used in clinical studies at the maximum dose of 7.5 mg/kg body weight infused every 4 hours for 2 weeks, one of 5 patients experienced anxiety, the remaining 4 patients did not develop any adverse reactions.

Treatment

Symptomatic therapy. Hemodialysis and peritoneal dialysis are not highly effective in removing zidovudine from the body, but enhance the removal of its glucuronide metabolite.

Interaction:

Zidovudine is primarily excreted as an inactive metabolite, which is a glucuronide conjugate formed in the liver. Drugs with a similar route of elimination can potentially inhibit the metabolism of zidovudine. used in combination APT together with other NRTIs and drugs from other groups (HIV II, NNRTIs).

The list of interactions listed below should not be considered exhaustive, but they are typical for drugs that require careful use with zidovudine.

Impact on the ability to drive vehicles. Wed and fur.:

The effect of Retrovir® on the ability to drive a car or operate machinery has not been studied. However, an adverse effect on these abilities is unlikely based on the pharmacokinetics of the drug. However, when deciding whether to drive a car or move machinery, you should take into account the patient’s condition and the possibility of developing adverse reactions (dizziness, drowsiness, lethargy, convulsions).

Release form/dosage:

Solution for infusion 10 mg/ml.

Package:

Solution for infusion of 200 mg/20 ml in a neutral light-protective glass bottle with a chlorobutyl rubber stopper and an aluminum cap with a plastic insert.

5 bottles each in a plastic blister pack together with instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature not exceeding 30°C in a place protected from light.

Keep out of the reach of children.

Best before date:

Do not use after the expiration date stated on the package.

Conditions for dispensing from pharmacies: On prescription Registration number: P N014790/01 Registration date: 19.12.2008 Owner of the Registration Certificate:ViiV Healthcare UK Limited Great Britain Manufacturer:   Representative office:  GlaxoSmithKline Trading, JSC Information update date:   25.10.2015 Illustrated instructions