How should Retrovir be given to a newborn? Prophylactic use of antiretroviral drugs in newborns

in glass bottles of 200 ml (with dosing adapter); 1 bottle in a cardboard box.

10 pcs in blister; There are 10 blisters in a cardboard pack.

in dark glass bottles of 20 ml; There are 5 bottles in a cardboard pack.

Description of the dosage form

Oral solution: transparent, pale yellow in color with strawberry aroma.

Capsules: hard, gelatinous, opaque, white with Wellcome written in black ink, a unicorn symbol and the code "Y9C100". The cap and body of the capsules are secured with transparent blue gelatin tape. The contents of the capsules are white or almost white powder.

Solution for infusion: a transparent, colorless or light yellow sterile aqueous solution, practically free of mechanical impurities.

Characteristic

Antiretroviral drug.

pharmachologic effect

pharmachologic effect- antiviral.

It is integrated into the viral DNA chain and blocks its formation, promoting its termination. The drug competes for HIV reverse transcriptase approximately 100 times stronger than for human cellular DNA alpha polymerase.

Pharmacodynamics

Active against retroviruses, including human immunodeficiency virus. Zidovudine is phosphorylated in virus-affected and unaffected cells to monophosphate (MP) derivatives by cellular thymidine kinase. Further phosphorylation of zidovudine-MP to zidovudine di- and triphosphate is catalyzed by cellular thymidine kinase and nonspecific kinases, respectively.

Pharmacokinetics

When taken orally, it is well absorbed from the intestine, bioavailability is 60-70%. In adults, the average equilibrium maximum and minimum concentrations after oral administration of Retrovir solution at a dose of 5 mg/kg every 4 hours are 7.1 and 0.4 μM (or 1.9 and 0.1 μg/ml), respectively; after taking Retrovir capsules at a dose of 200 mg every 4 hours - 4.5 and 0.4 µM (or 1.2 and 0.1 µg/ml), respectively; after infusion for an hour, 2.5 mg/kg every 4 hours - 4.0 and 0.4 μM (or 1.1 and 0.1 μg/ml).

The average half-life, average 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. 5"-glucuronide of zidovudine is the main metabolite, determined both in plasma and urine and constitutes approximately 50-80% of the dose of the drug, which is excreted through the kidneys. With intravenous administration of the drug, the metabolite 3" amino-3"-deoxytidimine 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 5"-glucuronide. After intravenous administration, 29% of the drug dose is excreted unchanged in the urine and 45% of the dose is excreted in the form of glucuronide. In newborns under 14 days of age, a decrease in bioavailability, a decrease in clearance and an extension of T1/2 are observed.

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 - 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%; T 1/2 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).

Clinical pharmacology

The development of resistance to thymidine analogues (including zidovudine) occurs as a result of the gradual appearance 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. The mutations do not cause cross-resistance to other nucleosides, which makes it possible to use other reverse transcriptase inhibitors to treat 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; in the second case, we are talking about a T69S mutation with an insertion at the position of the 6th pair of nitrogenous bases corresponding to this position, which is accompanied by the appearance of phenotypic resistance to zidovudine , as well as other nucleoside reverse transcriptase inhibitors. Both types of these mutations significantly limit therapeutic options for HIV infection. A decrease in sensitivity to zidovudine was observed during long-term treatment of HIV infection with Retrovir. At present, the relationship between sensitivity to zidovudine has not yet been studied in vitro and clinical effect of therapy. The use of zidovudine in combination with lamivudine delays the emergence of zidovudine-resistant strains of the virus if patients have not previously received antiretroviral therapy.

Zidovudine is used in combination antiretroviral therapy together with other nucleoside reverse transcriptase inhibitors and drugs from other groups (protease inhibitors, nucleoside reverse transcriptase inhibitors.)

Indications of the drug Retrovir ®

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.

Contraindications

Hypersensitivity to the components of the drug, neutropenia (neutrophil count less than 0.75 10 9 /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 B 12 and folic acid, liver failure.

Use during pregnancy and breastfeeding

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.

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 side of metabolism:>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.

Interaction

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.

Directions for use and doses

Inside(capsules, oral solution). Adults and children over 12 years old. The recommended dose is 500-600 mg/day in 2-3 doses in combination with other antiretroviral drugs. The effectiveness of a daily dose of less than 1000 mg for the treatment and prevention of HIV-associated complications has not been established.

Children from 3 months to 12 years. The daily dose is 360-480 mg/m2 in 3-4 doses in combination with other antiretroviral drugs. The effectiveness of a daily dose of less than 720 mg/m2 (180 mg/m2 every 6 hours) for the treatment and prevention of neurological complications of HIV infection has not been established. The maximum dose should not exceed 200 mg every 6 hours.

Prevention of transmission of HIV infection from mother to fetus. Two prevention schemes are effective.

1. Pregnant women - 500 mg/day (100 mg 5 times a day), starting from 14 weeks of pregnancy until the onset of labor. During childbirth - IV until a clamp is applied to the umbilical cord.

Newborns - 2 mg/kg every 6 hours, starting from the first 12 hours after birth until 6 weeks. If it is not possible to take it orally, it is prescribed intravenously.

2. Pregnant women - 300 mg 2 times a day from 36 weeks before the onset of labor, and then every 3 hours until the end of labor.

For severe renal failure, a dose of 300-400 mg/day is recommended. Depending on the peripheral blood response and clinical effect, further dose adjustments may be made. For patients with end-stage renal failure on hemo- or peritoneal dialysis, 100 mg every 6-8 hours.

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 doses are comparable to doses from 360 mg/m2 to 480 mg/m2 per day in 3-4 doses when taken orally, but how effective they are is currently not installed.

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 zidovudine 300-400 mg taken orally 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.

Precautionary measures

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 10 9 / 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

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 10 9 / l, the daily dose of Retrovir should be reduced until the indicators are restored blood or Retrovir must be discontinued for 2-4 weeks. until blood counts are restored. Usually 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.

Manufacturer

SmithKline Beecham Pharmaceuticals, UK.

Storage conditions for the drug Retrovir ®

In a dry place, protected from light, at a temperature of 15-25 °C.

Keep out of the reach of children.

Shelf life of the drug Retrovir ®

oral solution 50 mg/5 ml - 2 years.

capsules 100 mg - 5 years.

solution for infusion 200 mg/20 ml - 3 years.

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

Active substance: zidovudine 50.0 mg/5 ml.

Excipients: hydrogenated glucose syrup (mannitol solution), glycerin, anhydrous citric acid, sodium benzoate, sodium saccharin, strawberry flavor, white sugar flavor, purified water.

Transparent, light yellow solution with a characteristic strawberry odor.

Pharmacotherapeutic group: antiviral [HIV] agent.

ATX code: J05AF01.

Pharmacodynamics

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 α-polymerase.

Zidovudine acts additively or synergistically with a large number of antiretroviral drugs, such as lamivudine, didanosine, α-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 positions (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. The mutations do not cause cross-resistance to other nucleosides, which makes it possible to use other reverse transcriptase inhibitors to treat 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.

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 strains of the virus in patients who have not previously received antiretroviral therapy.

Suction

Zidovudine is well absorbed after oral administration, bioavailability is 60-70%. The average concentrations at steady state maximum (Css rnax) and minimum (Cssmin) 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 ).

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 both 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 its preferential elimination by tubular secretion. .

Special patient groups

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%. Following doses of zidovudine 120 mg/m2 oral solution and 180 mg/m2, the maximum steady-state concentrations were 4.45 μmol (1.19 μg/ml) and 7.7 μmol (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 (defined as the area under the concentration-time curve) 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 adjustment of the drug dose.

Pregnancy

The pharmacokinetic parameters of zidovudine in pregnant women do not change; There are no signs of accumulation of zidovudine.

Treatment of HIV infection as part of combination therapy.

Treatment of HIV infection in pregnant women to reduce the incidence of transplacental transmission of HIV from mother to fetus.

Neutropenia (neutrophil count less than 0.75 x 109/L);

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

CAREFULLY

Elderly patients

Inhibition of bone marrow hematopoiesis

Severe liver failure

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 HIV transmission from mother to fetus

The use of 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 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

Women should not breastfeed while taking Retrovir.

Effect on fertility

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

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. Effectiveness of doses in the range below 1000 mg/day. for the treatment or prevention of HIV-associated neurological dysfunction is unknown.

Children weighing at least 9 kg but less than 30 kg:

The recommended dose is 18 mg/kg/day, divided into two doses, as part of combination therapy. The effectiveness of doses in the range below 720 mg/m2/day (approximately 18 mg/day) for the treatment of HIV-associated neurological dysfunction is unknown. The maximum daily dose should not exceed 600 mg, divided into two doses.

Children weighing at least 4 kg but less than 9 kg:

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 Retrovir and carry out appropriate monitoring before and during treatment with Retrovir.

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.

Dose adjustment for adverse reactions from the hematopoietic system

Adequate correction of the dosage regimen - dose reduction or withdrawal of Retrovir may be required in patients with adverse reactions from the hematopoietic system, in the event of a decrease in hemoglobin level to 75-90 g/l (4.65-5.59 mmol/l) or the number of leukocytes up to 0.75-1.0 x 109/l.

Prevention of transmission of HIV infection from mother to fetus

The following 2 prophylaxis regimens have been shown to be effective for 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 from the first 12 hours after birth and continuing until the age of 6 weeks. Newborns who cannot take Retrovir solution orally must be given Retrovir intravenously.

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

From the hematopoiesis and lymphatic system: often - anemia (which may require blood transfusions), neutropenia and leukopenia. The incidence of neutropenia increases in patients who have had a decrease in the number of neutrophils, hemoglobin and vitamin B12 in the serum at the beginning of treatment. Sometimes - thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rarely - true erythrocyte aplasia; very rarely - aplastic anemia.

From the side of metabolism and nutrition: often - hyperlactatemia; rarely - lactic acidosis, anorexia. Redistribution/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 often - headache; often - 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 and chest organs: sometimes - shortness of breath; rarely - cough.

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

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

From the skin and its appendages: sometimes - rash, itching; rarely - pigmentation of nails and skin, urticaria, increased sweating.

From the musculoskeletal system: often - myalgia; sometimes - myopathy.

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

Adverse reactions that occur when using 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 Retrovir therapy.

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. At a 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 reactions.

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, 5"-zidovudine glucuronide.

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.

Atovaquone: Zidovudine does not affect the pharmacokinetic parameters of atovaquone. Atovaquone 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 is unlikely to change at doses of zidovudine 500 or 600 mg/day when combined with atovaquone for three weeks. If longer-term combined use of these drugs is necessary, careful monitoring of the patient's clinical condition is recommended.

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

Phenytoin: with simultaneous use of Retrovir with phenytoin, the concentration of the latter in the blood plasma decreases; Plasma concentrations of phenotoin should be monitored when using this combination.

Stavudine: Zidovudine may inhibit the intracellular phosphorylation of stavudine. Therefore, it is not recommended to use stavudine concomitantly with zidovudine.

Others: 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 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 Retrovir. Monitoring of kidney function and blood count is necessary; if necessary, reduce the dose of drugs.

Since some patients may develop opportunistic infections even despite Retrovir therapy, prophylactic antimicrobial therapy should be considered. Such prophylaxis includes cotrimoxazole, pentamidine aerosol, pyrimethamine, and acyclovir. Limited data obtained from clinical studies did not reveal a significant increase in the risk of adverse reactions when Retrovir was used together with these drugs.

Treatment with Retrovir should be carried out by a physician experienced in treating HIV-infected patients.

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 infection through sexual contact or infected blood. Appropriate safety measures are required.

Emergency prevention in case of possible infection

According to international recommendations, in case of probable contact with HIV-infected material (blood, other liquids), it is necessary to urgently prescribe combination therapy with Retrovir and Epivir within 1-2 hours from the moment of infection. 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 Retrovir therapy may be a manifestation of the underlying disease or a reaction to taking other drugs used to treat HIV infection. The relationship between developed symptoms and the effect of 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 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.

Adverse reactions from the hematopoietic system

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 Retrovir treatment, but sometimes occurs earlier), leukopenia can occur in patients with an advanced clinical picture of HIV infection receiving Retrovir, especially in high doses (for example, 1200 mg-1500 mg/day in clinical trials), 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 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), undesirable reactions from the hematopoietic system rarely develop, so blood tests are 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), the number of neutrophils decreases to 0.75-1.0x109 / l, the daily dose of Retrovir should be reduced until blood counts are restored; or Retrovir is discontinued for 2-4 weeks until blood counts are restored. Usually the blood picture returns to normal after 2 weeks, after which Retrovir in a reduced dose can be re-prescribed. Despite reducing the Retrovir dose, severe anemia may require blood transfusions.

Lactic acidosis and severe hepatomegaly with steatosis

These complications can be fatal both with Retrovir monotherapy and with Retrovir used as part of multicomponent therapy. Clinical signs of these complications may include weakness, anorexia, unexpected 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 levels).

Redistribution of subcutaneous fat tissue

Redistribution/accumulation of subcutaneous fat, including central obesity, an increase in the fat layer on the back of the neck (“buffalo hump”), a decrease in the fat layer on the periphery, on the face, breast enlargement, increased serum lipids and blood sugar were noted as a complex, 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 members of the therapeutic classes.

In addition, lipodystrophy syndrome has a multifactorial etiology; for example, factors such as stage of HIV infection, older 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. Serum lipid and blood sugar testing should be recommended. Lipid disorders should be treated as clinically indicated.

In HIV-infected patients with severe immunodeficiency during initiation of antiretroviral therapy (APT), exacerbation of the inflammatory process may occur due to asymptomatic or residual opportunistic infection, 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 APT. The most significant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infection, and Pneumocystis pneumonia (P. carinii). Any symptoms of inflammation should be identified immediately and treatment initiated when necessary.

Co-infection with HIV and viral hepatitis C

Exacerbation of ribavirin-induced anemia has been reported in HIV-infected patients receiving concomitant zidovudine therapy, the mechanism 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.

INFLUENCE 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. However, adverse effects on these abilities are unlikely based on the pharmacokinetics of the drug. However, when deciding on the ability to drive a car/machines, one should keep in mind the patient’s condition and the possibility of developing adverse reactions (dizziness, drowsiness, lethargy, convulsions) to Retrovir.

Oral solution 50 mg/5 ml.

Yellow glass bottle, closed with a polyethylene cap, with

tamper evident device. One bottle along with a plastic dosing syringe, adapter and instructions for use is placed in a cardboard box.

At a temperature not exceeding 30 °C. Keep out of the reach of children.

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

By doctor's prescription.

Self-medication may be harmful to your health. You should consult your doctor and also read the instructions before use.

apteka.103.by

RETROVIR

From the hematopoietic system: myelosuppression, anemia, neutropenia, leukopenia, lymphadenopathy, thrombocytopenia, pancytopenia with bone marrow hypoplasia, aplastic or hemolytic anemia.

From the digestive system: nausea, vomiting, dyspepsia, dysphagia, anorexia, taste perversion, abdominal pain, diarrhea, flatulence, bloating, pigmentation or ulceration of the oral mucosa, hepatitis, hepatomegaly with steatosis, jaundice, hyperbilirubinemia, increased liver activity enzymes, pancreatitis, increased serum amylase activity.

From the nervous system: headache, dizziness, paresthesia, insomnia, drowsiness, weakness, lethargy, decreased mental performance, tremor, convulsions; anxiety, depression, confusion, mania.

From the senses: macular edema, amblyopia, photophobia, vertigo, hearing loss.

From the respiratory system: shortness of breath, cough, rhinitis, sinusitis.

From the cardiovascular system: cardiomyopathy, fainting.

From the urinary system: frequent or difficult urination, hypercreatininemia.

From the endocrine system and metabolism: lactic acidosis, gynecomastia.

From the musculoskeletal system: myalgia, myopathy, muscle spasm, myositis, rhabdomyolysis, increased activity of CPK, LDH.

Dermatological reactions: pigmentation of nails and skin, increased sweating, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Allergic reactions: skin rash, itching, urticaria, angioedema, vasculitis, anaphylactic reactions.

Other: malaise, back and chest pain, fever, flu-like syndrome, pain of various localizations, chills, development of secondary infection, redistribution of adipose tissue.

www.vidal.ru

Retrovir for infusion - official instructions for use

REGISTRATION NUMBER: P No. 014790/01.

Trade name of the drug: Retrovir

International nonproprietary name:

zidovudine

Dosage form:

solution for infusion

Description: transparent or slightly opalescent, colorless or light yellow solution, practically free of mechanical inclusions.

Notes:

1. Concentrated hydrochloric acid or sodium hydroxide is used.

Pharmacotherapeutic group:

Antiviral [HIV] agent.

ATX code: J05A F01.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Zidovudine is an antiviral drug that is highly active in vitro against retroviruses, including the human immunodeficiency virus (HIV).

The process of phosphorylation of zidovudine occurs in both infected and uninfected cells of the human body to form zidovudine triphosphate (TF), which acts as an inhibitor and substrate for HIV reverse transcriptase. The formation of proviral DNA is blocked by the introduction of zidovudine-TF into its chain, which leads to chain termination. The competition of zidovudine-TF for HIV reverse transcriptase is approximately 100 times stronger than for human cellular DNA a-polymerase. Zidovudine acts additively or synergistically with a large number of antiretroviral drugs, such as lamivudine, didanosine, a-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 codons 41 and 215 or through the accumulation of at least 4 of the 6 mutations. These thymidine analogue resistance (MRAT) mutations do not cause cross-resistance to any other nucleoside reverse transcriptase inhibitors (NRTIs), allowing the use of other NRTIs 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; in the second case, we are talking about a T69S mutation with an insertion of 6 nitrogen base pairs in the same position, which is accompanied by the appearance of phenotypic resistance to zidovudine, and also to other registered nucleoside reverse transcriptase inhibitors. Both types of these mutations significantly limit therapeutic options for HIV infection.

A decrease in sensitivity to zidovudine was observed with long-term treatment of HIV infection with this drug. Currently, the relationship between sensitivity to zidovudine in vitro and the clinical effect of therapy has not been studied. The use of zidovudine in combination with lamivudine delays the emergence of zidovudine-resistant strains of the virus if patients have not previously received antiretroviral therapy.

Pharmacokinetics

Absorption In patients who received an hourly infusion of Retrovir at a dose of 1–5 mg/kg 3–6 times a day, the pharmacokinetics of zidovudine was dose-dependent. The mean steady-state maximum (Cssmax) and minimum (Cssmin) 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 μM, respectively (or 1.1 and 0.1 µg/ml).

Distribution: Zidovudine binding to plasma proteins is 34–38%. The mean half-life, mean total clearance, and volume of distribution were 1.1 hours, 27.1 mL/min/kg, and 1.6 L/kg, respectively. Zidovudine crosses the placenta and is detected in the amniotic fluid and fetal blood. Zidovudine is also detected in semen and breast milk.

Metabolism Zidovudine 5'-glucuronide is the main metabolite of zidovudine, determined in both plasma and urine and accounts for approximately 50–80% of the drug dose that is excreted by the kidneys.

3'amino-3'-deoxythymidine (AMT) is a metabolite of zidovudine, which is formed when the drug is administered intravenously.

Excretion The renal clearance of zidovudine is much greater than the clearance of creatinine, indicating significant 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 body surface, 120 mg/m2, 160 mg/m2, the Cssmax values ​​are 1.46 μg/ml, 2.26 μg/ml and 2.96 μg/ml, respectively. 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.

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

Patients with impaired liver function In case of liver failure, accumulation of zidovudine may be observed due to decreased glucuronidation, which requires adjustment of the drug dose.

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

Pregnant women The pharmacokinetic parameters of zidovudine in pregnant women do not change compared to the parameters in non-pregnant women; there are no signs of accumulation of zidovudine.

Plasma zidovudine concentrations in children at birth are the same as those in their mothers at the time of delivery.

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 0.75 x 109/l);
• Decreased hemoglobin content (less than 75 g/l or 4.65 mmol/l).

Use during pregnancy and lactation

Fertility There is no data on the effect of Retrovir on the fertility of women. In men, taking Retrovir does not affect sperm composition, morphology and sperm motility.

Pregnancy Zidovudine crosses the placenta. Before the 14th week of gestation, Retrovir can be used 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 in utero or perinatal to nucleoside reverse transcriptase inhibitors. 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 such as muscle spasticity. However, a cause-and-effect relationship between these events and intrauterine or perinatal exposure to nucleoside reverse transcriptase inhibitors has not been established. These data do not affect the current recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Prevention of transmission of HIV from mother to fetus The use of Retrovir after 14 weeks of pregnancy with its subsequent administration to newborns leads to a decrease in the frequency of HIV transmission from mother to fetus (infection rate when using placebo - 23% compared to the frequency when using zidovudine - 8%).

The long-term consequences of using 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.

Lactation Due to the fact that zidovudine and HIV pass into breast milk, women taking Retrovir are not recommended to breastfeed.

With caution It is recommended to prescribe the drug with caution to patients under the age of 3 months, 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.

Method of administration and dosage The drug Retrovir, solution for infusion, should be administered in a diluted form by slow intravenous infusion over one hour.

The drug CANNOT be administered intramuscularly.

Retrovir, solution for infusion, should be used only until patients are able to take oral dosage forms (capsules, oral solution).

Dilution The drug Retrovir, solution for infusion, must be diluted before administration.

The required dose of Retrovir solution is added to a 5% glucose solution for intravenous administration so that the final concentration of zidovudine is 2 mg/ml or 4 mg/ml. The resulting solution is stirred. The solution remains chemically and physically stable for 48 hours at temperatures from 5 °C to 25 °C.

Since the drug Retrovir, solution for infusion, does not contain an antimicrobial preservative, 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 before, during or after dilution, it should be destroyed.

Adults and adolescents weighing at least 30 kg Retrovir is prescribed at a dose of 1 mg/kg or 2 mg/kg every 4 hours. This dose, when Retrovir is administered intravenously, provides the same AUC of the drug as when Retrovir is taken orally at a dose of 1.5 mg /kg or 3 mg/kg every 4 hours (600 or 1200 mg/day in a patient weighing 70 kg). The effectiveness of lower doses for the treatment or prevention of HIV-associated neurological dysfunction and malignancies is unknown.

Children aged 3 months to 12 years There is insufficient information on the use of Retrovir, solution for infusion, intravenously in children. The recommended dose range is 80 to 160 mg/m2 every 6 hours (320 to 640 mg/m2/day). The daily dose of Retrovir, amounting to 240–320 mg/m2 per day for 3–4 administrations, is comparable to the recommended dose of 360 mg/m2 to 480 mg/m2 per day for 3–4 oral doses. However, there is currently no data on the effectiveness of using Retrovir solution for intravenous administration in such low doses.

Children under 3 months of age Caution is recommended when prescribing the infusion dosage form to patients under 3 months of age, as limited data do not allow the formulation of clear recommendations on the dosage regimen of the drug.

Prevention of transmission of HIV infection from mother to fetus The effectiveness of two dosage regimens of the drug Retrovir has been proven:

1. Pregnant women, starting from 14 weeks, are recommended to prescribe the drug Retrovir, capsules, at a dose of 500 mg (1 capsule 100 mg five times a day) before the onset of labor. During labor and delivery, it is necessary to use the drug Retrovir, solution for infusion, intravenously at a dose of 2 mg/kg over an hour, followed by a continuous intravenous infusion at a dose of 1 mg/kg/h until the umbilical cord is clamped.

Next, newborns should be prescribed Retrovir, oral solution, at a dose of 2 mg/kg every 6 hours, starting no later than 12 hours from birth until 6 weeks of age. Children who are unable to take oral forms should be given Retrovir, a solution for infusion, intravenously at a dose of 1.5 mg/kg body weight over 30 minutes every 6 hours.

2. Pregnant women, starting from the 36th week of pregnancy, are recommended to prescribe the drug Retrovir, capsules, 300 mg (3 capsules of 100 mg) twice a day until the onset of labor and 300 mg (3 capsules of 100 mg) every 3 hours from the onset of labor until delivery.

Patients with impaired renal function In severely impaired renal function, the recommended dose of Retrovir, solution for infusion, is 1 mg/kg 3-4 times a day, which corresponds to the recommended daily dose of 300-400 mg per day when taken orally for patients in this group. 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 the glucuronide metabolite.

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 impaired liver function Data obtained in patients with cirrhosis indicate that in patients with hepatic impairment, accumulation of zidovudine may occur due to reduced 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 drug administrations.

Dose adjustment in case of undesirable reactions from the hematopoietic system Adequate correction of the dosage regimen - dose reduction or discontinuation of Retrovir may be required in patients in case of undesirable reactions from the hematopoietic system, in the event of a decrease in hemoglobin level to 75–90 g/l (4.65– 5.59 mmol/l) or the number of neutrophils up to 0.75–1.0 × 109/l.

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 Retrovir and carry out appropriate monitoring before and during treatment with Retrovir.

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

To assess the incidence of adverse reactions, the following gradations were used: very often (>1/10), often (>1/100, 1/1000, 1/10000, From the hematopoietic system: often - anemia (which may require blood transfusions), neutropenia and leukopenia developed with the use of high doses of Retrovir (for example, 1200-1500 mg / day in clinical studies) and in patients with advanced HIV infection (especially in patients with reduced bone marrow reserve before treatment), mainly with a decrease CD4 lymphocyte count below 100 cells/mm3. In these cases, a reduction in the dose of Retrovir or its discontinuation may be necessary. The incidence of neutropenia increases in patients who have had a decrease in the number of neutrophils, hemoglobin and vitamin B12 in the serum at the beginning of treatment. Sometimes - thrombocytopenia and pancytopenia (with bone marrow hypoplasia); rarely - erythrocyte aplasia; very rarely - aplastic anemia.

Metabolic disorders: often – hyperlactatemia; rarely - lactic acidosis, anorexia; redistribution/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 often - headache; often - dizziness; rarely - insomnia, paresthesia, drowsiness, decreased speed of thinking, convulsions, anxiety and depression.

From the cardiovascular system: rarely - cardiomyopathy.

From the respiratory system: sometimes - shortness of breath; rarely - cough.

From the gastrointestinal tract: very often – nausea; often - vomiting, pain in the upper abdomen, diarrhea; sometimes - flatulence; rarely - pigmentation of the oral mucosa, taste disturbance, dyspepsia.

From the liver and pancreas: often - increased bilirubin levels and liver enzyme activity; rarely - severe hepatomegaly with steatosis; pancreatitis.

From the skin and its appendages: sometimes - skin rash (except urticaria), itching; rarely - pigmentation of nails and skin, urticaria, increased sweating.

From the musculoskeletal system: often – myalgia; sometimes - myopathy.

From the urinary system: rarely - frequent urination.

From the endocrine system: rarely: gynecomastia.

Other: often - malaise; sometimes - fever, generalized pain syndrome, asthenia; rarely - chills, chest pain, flu-like syndrome.

There is experience in prescribing Retrovir solution for intravenous administration over 2 weeks up to 12 weeks. The most common undesirable effects were anemia, leukopenia, neutropenia, and sometimes local reactions.

Adverse reactions that occur when using 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 Retrovir therapy.

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 with other drugs and other types of interactions 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.

Zidovudine is used in combination antiretroviral therapy together with other nucleoside reverse transcriptase inhibitors and drugs from other groups (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).

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

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

Phenytoin: with simultaneous use of Retrovir with phenytoin, the concentration of the latter in the blood plasma decreases; Plasma concentrations of phenytoin 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.

Atovaquone: Zidovudine does not affect the pharmacokinetic parameters of atovaquone. Atovachone slows down the transformation of zidovudine into a glucuronide derivative (the AUC of zidovudine at steady state increases by 33% and maximum glucuronide concentrations decrease by 19%). The safety profile of zidovudine is unlikely to change at doses of zidovudine 500 or 600 mg/day when combined with atovaquone for three weeks. 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 dosing should be at least 2 hours.

Ribavirin: The nucleoside analogue ribavirin is an antagonist of zidovudine and their combination should be avoided.

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.

Stavudine: Zidovudine may inhibit the intracellular phosphorylation of stavudine.

Valproic acid, fluconazole, and methadone reduce the clearance of zidovudine, which increases its systemic exposure.

Others: acetylsalicylic acid, codeine, methadone, morphine, 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 with long-term therapy, should be approached with caution. The combination of 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 Retrovir. Monitoring of kidney function and blood count is necessary; if necessary, reduce the dose of drugs.

Special instructions Treatment with Retrovir should be carried out by a physician experienced in caring for HIV-infected patients.

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 infection through sexual contact or through infected blood. Appropriate safety measures are required.

Emergency prophylaxis in case of probable infection According to international recommendations, in case of probable contact with HIV-infected material (blood, other liquids), it is urgently necessary to prescribe combination therapy with zidovudine and lamivudine within 1-2 hours from the moment of infection. 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 Retrovir may be a manifestation of an underlying disease or a reaction to taking other drugs used to treat HIV infection. The relationship between developed symptoms and the effect of 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 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 considering the use of Retrovir during pregnancy to prevent transmission of HIV to the fetus should be informed of the risk of infection of the fetus, despite the therapy.

Use in children under 3 months of age Caution is recommended when prescribing the infusion dosage form of Retrovir 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.

Adverse reactions from the hematopoietic system 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 Retrovir treatment, but sometimes occurs earlier), leukopenia (usually secondary to neutropenia ) may occur in patients with an advanced clinical picture of HIV infection, receiving Retrovir, especially in high doses (1200 mg-1500 mg/day), and having reduced bone marrow hematopoiesis before treatment.

While taking Retrovir in patients with an advanced clinical picture of HIV infection, it is necessary to monitor blood tests at least once a week 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, 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), the number of neutrophils decreases to 0.75-1.0x109/l, the daily dose of Retrovir should be reduced until blood counts are restored; or Retrovir is discontinued for 2-4 weeks until blood counts are restored. Usually the blood picture returns to normal after 2 weeks, after which Retrovir in a reduced dose can be re-prescribed. Despite reducing the Retrovir dose, severe anemia may require blood transfusions.

Lactic acidosis and severe hepatomegaly with steatosis. These complications can be fatal with both mono- and multicomponent zidovudine therapy. Clinical signs of these complications may include weakness, anorexia, unexpected weight loss, gastrointestinal symptoms, and respiratory symptoms (dyspnea and tachypnea). A warning about the risk of these conditions should be given whenever zidovudine is prescribed, but it is especially important to warn patients with risk factors for liver disease. The risk of developing these complications increases in women. Zidovudine should be discontinued in all cases of clinical or laboratory signs of lactic acidosis or liver toxicity.

Redistribution of subcutaneous fat Redistribution/accumulation of subcutaneous fat, including general obesity, increased fat in the back of the neck (“buffalo hump”), loss of fat in the periphery, on the face, gynecomastia, increased serum lipids and blood glucose were noted both in combination and separately in some patients receiving combination antiretroviral therapy.

Although it was previously thought that all drugs in the protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor (NRTI) classes were associated with one or more specific adverse events associated with a common syndrome often called lipodystrophy, new data demonstrate that there is a difference 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 of the patient, and duration of antiretroviral therapy play an important, possibly potentiating, role.

The long-term consequences of these phenomena are currently unknown.

Clinical evaluation should include physical examination to assess for the presence of subcutaneous fat redistribution. Serum lipid and blood glucose testing should be recommended. Lipid disorders should be treated as clinically indicated.

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency during initiation of antiretroviral therapy (APT), an exacerbation of the inflammatory process against the background of an asymptomatic or indolent opportunistic infection may occur, 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 APT. The most significant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infection, and Pneumocystis pneumonia (P. carinii). Any symptoms of inflammation should be identified immediately and treatment initiated when necessary.

Radiation therapy enhances the myelosuppressive effect of zidovudine.

Effect on the ability to drive a car/machines The effect of Retrovir on the ability to drive a car/machines has not been studied. However, adverse effects on these abilities are unlikely based on the pharmacokinetics of the drug. However, when deciding on the ability to drive a car/machines, you should keep in mind the patient’s condition and the possibility of developing adverse reactions (dizziness, drowsiness, lethargy, convulsions) when taking Retrovir.

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

Keep out of the reach of children.

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The drug "Retrovir" - instructions for use, description and reviews

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.

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

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. 5"-glucuronide of zidovudine is the main metabolite, determined both in plasma and urine and constitutes approximately 50–80% of the dose of the drug, which is excreted through the kidneys. With intravenous administration of the drug, a metabolite 3" amino-3"-deoxytidymine is formed. 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 surface body and 180 mg/m2, the level of average equilibrium maximum concentration is 4.45 and 7.7 μM (or 1.19 and 2.06 μg/ml).After IV infusion at a dose of 80 mg/m2, 120 mg/m2 and 160 mg/m2 it is respectively 1.46, 2.26 and 2.96 mcg/ml. Average T1/2 and total clearance are 1.5 hours and 30.9 ml/min/kg, respectively. The main metabolite is 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).

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.

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.

From the hematopoietic system: >1/100-1/1000-1/10 - headache; >1/100-1/10000-1/10000-1/1000-1/10000-1/10 - nausea; >1/100-1/1000-1/10000-1/100-1/10000-1/1000-1/10000-1/100-1/100-1/10000-1/10000-1/100-1 /1000-1/10000-

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 observed. 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. HIV-infected women are not recommended to 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

Retrovir solution(Solutio Retrovir)

international and chemical name: zidovudine; 3-azido-3-deoxythymidine;

Basic physical and chemical characteristics: colorless, transparent, or pale yellow solution, practically free of visible impurities;

Compound 1 ml of solution contains 10 mg of zidovudine;

other components: concentrated hydrochloric acid, sodium hydroxide, water for injection.

Release form of the medicinal product. Solution for intravenous infusion.

Pharmacotherapeutic group. Direct acting antiviral drugs. ATC code J05A F01.

Action of the medicine.

Pharmacodynamics.

Zidovudine is an antiviral drug active against retroviruses, including human immunodeficiency virus (HIV).

Once in the cell, the drug undergoes a series of sequential transformations that are catalyzed by cell enzymes. At the last stage, zidovudine triphosphate is formed, which blocks the synthesis of viral DNA as a result of competitive interactions with HIV reverse transcriptase.

Research in vitro show that a triple combination of nucleoside analogues or two nucleoside analogues with a protease inhibitor is more effective in inhibiting HIV-induced cytopathic effects than a single drug or combinations of two drugs.

Pharmacokinetics.

When administered intravenously, the average half-life is 1.1 hours, the average total clearance is 27.1 ml/minute/kg, the volume of distribution is 1.61/kg. The clearance of zidovudine significantly exceeds the clearance of creatinine, which is evidence that tubular secretion is an essential mechanism of elimination. Zidovudine crosses the placenta and is found in amniotic fluid and fetal blood. Plasma protein binding is relatively low (34 – 38%).

Indications for use. Retrovir for intravenous infusion is indicated for the short-term treatment of serious manifestations of HIV infections in patients who cannot take oral forms of the drug.

Retrovir is also prescribed for the treatment of HIV-positive pregnant women (pregnancy more than 14 weeks) as well as newborn infants, since Retrovir has been shown to reduce the risk of transplacental transmission of HIV.

Method of use and dose.

Retrovir therapy should be started by a doctor who has experience in treating HIV infection.

Retrovir for intravenous infusion should be administered by slow intravenous infusion of a diluted solution over at least one hour.

Retrovir for intravenous infusion cannot be administered internally.

Diluted: the solution is prepared aseptically immediately before use.

Use in adults and adolescents over 12 years of age: 1-2 mg zidovudine/kg body weight every 4 hours. The effectiveness of lower doses for the treatment and prevention of neurological disorders associated with HIV infection is unknown.

Retrovir is prescribed for intravenous infusion only until the time when Retrovir can be used for oral use (tablets or oral solution).

3 months - 12 years: Information on the use of Retrovir for intravenous administration in children is limited. Doses have been used ranging from 80 to 160 mg/m2 body surface every 6 hours (320–640 mg/m2 per day).

Children under 3 months of age: Limited available data make it impossible to recommend specific dosages for this age group.

Maternal-fetal transmission warnings:

The following dosage regimen of Retrovir has been found to be effective:

The recommended dose for pregnant women (more than 14 weeks pregnant) is 500 mg/day orally (100 mg 5 times daily) until labor begins. During childbirth, Retrovir is prescribed intravenously at a dose of 2 mg/kg body weight over 1 hour, followed by intravenous infusion at 1 mg/kg/hour. until the umbilical cord is crossed.

For newborn infants, Retrovir is prescribed at a dose of 2 mg/kg body weight orally every 6 hours, starting from the first 12 hours after birth until 6 weeks of age. Newborns who cannot be given the drug per os are prescribed Retrovir intravenously at a dose of 1.5 mg/kg body weight over 30 minutes every 6 hours.

Kidney failure

In patients with severe renal failure, an adequate dose would be

1 mg/kg IV 3-4 times daily (equivalent to an oral dose of 300-400 mg for this group of patients). Further dose adjustments may be required based on hematologic parameters or clinical response to treatment.

Hemodialysis and peritoneal dialysis do not have a significant effect on the excretion of zidovudine, but increase the excretion of zidovudine glucuronide. For patients with end-stage renal disease who are on hemodialysis or peritoneal dialysis, the recommended dose is 100 mg every 6 or 8 hours.

Liver failure

In patients with liver cirrhosis, accumulation of zidovudine is observed as the degree of glucuronidation decreases. Dose adjustment may be necessary, but no clear recommendations can be made from the examination for insufficiency of these data. If zidovudine plasma levels are not monitored, monitor for signs of intolerance and adjust the dose or increase the interval between doses.

Dose adjustment in patients with hematological adverse reactions

In patients whose hemoglobin level decreases in the range from 7.5 g/dl (4.65 mmol/l) to 9 g/dl (5.59 mmol/l) or the number of neutrophils - in the range from 0.75 x 10 9 /l to 1.0 x 10 9 /l, a dose reduction or interruption in treatment with Retrovir may be necessary.

Elderly patients

The pharmacokinetics of zidovudine in patients over 65 years of age have not been studied, so there are no special data. However, this group of patients requires special attention, since renal function deteriorates with age and hematological parameters change. Appropriate monitoring before and during the use of Retrovir is recommended.

Side effect.

The nature of the side effects in children and adults is similar.

During treatment with Retrovir, side effects are observed, which can also be manifestations of the underlying disease in combination with other medications used to treat it. Therefore, the relationship between these effects and the use of Retrovir is difficult to assess, especially in complicated cases characteristic of the advanced stage of HIV disease. It would be justified to reduce the dose or discontinue Retrovir to treat side effects.

To determine the frequency of side effects, the following classification is used: very often ³1/10, often ³1/100 and<1/10, не часто ³1/1000 и <1/100, редко ³1/10, 000 и <1/1000, очень редко<1/10, 000.

Side effects from the blood and lymphatic system:

Anemia (which may require blood transfusions), neutropenia and leukopenia. This occurs more frequently at higher doses (1200–1500 mg/day) and in patients with advanced HIV infection (especially those with low pretreatment bone marrow reserve), including patients with a CD4 cell count of less than 100/ mm 3. In this case, dose reduction or discontinuation of zidovudine therapy may be necessary. Neutropenia occurs more often in patients who, at the beginning of Retrovir therapy, have reduced levels of neutrophils, hemoglobin and vitamin B 12 in plasma.

Uncommon: thrombocytopenia and pancytopenia with bone marrow hypoplasia. Rare: true erythrocyte aplasia.

Metabolic reactions and reactions. food related:

Rarely: lactic acidosis without hypoxemia, anorreaction.

Psychiatric reactions:

Rare: anxiety and depression.

Neurological reactions:

Very common: headache.

Common: dizziness.

Rarely: insomnia, paresthesia, drowsiness, loss of mental acuity, convulsions.

Cardiovascular reactions:

Respiratory, chest and mediastinum:

Uncommon: shortness of breath.

Rarely: cough.

Gastroenterological:

Very common: nausea.

Common: vomiting, abdominal pain and diarrhea.

Not often: flatulence.

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

Hepatobiliary:

Common: increased levels of liver enzymes and bilirubin.

Rare: hepatic dysfunction such as severe hepatomegaly with steatosis.

Skin and subcutaneous tissues:

Uncommon: rash and itching.

Rarely: pigmentation of nails and skin, sweating.

Musculoskeletal:

Often: myalgia.

Uncommon: myopathies.

Lungs and urinary system:

Rare: frequent urination.

Reproductive system and mammary glands:

Rarely: gynecomastia.

General reactions and reactions at the injection site:

Often: malaise.

Uncommon: fever, generalized pain and asthenia.

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

Data on the use of Retrovir for intravenous administration for more than 2 weeks are limited, but some patients received treatment for 2 weeks. The most common side effects were anemia, neutropenia and leukopenia. Local reactions did not occur frequently

According to clinical studies using oral Retrovir, the incidence of nausea and other side effects, which are common, consistently decreases over time after the first weeks of treatment with Retrovir.

Side effects when preventing maternal-fetal transmission:

In a placebo-controlled study, Retrovir at recommended doses was well tolerated by pregnant women. The incidence of side effects was the same as in the placebo group.

According to the same study, hemoglobin levels in infants who were treated with Retrovir were slightly lower than those in the placebo group, but blood transfusion was not necessary. The anemia resolved 6 weeks after completion of treatment with Retrovir. Other side effects and changes in laboratory data were similar in the placebo group and the group treated with Retrovir. The long-term effects of the drug on the fetus and infant are unknown.

Special warnings.

Patients should be warned against simultaneous independent use of other medications.

Patients should be advised that treatment cannot prevent transmission of HIV to others through sexual contact or exposure to contaminated blood. Therefore, it is necessary to use appropriate safety measures.

Retrovir does not cure HIV infection, and the patient remains at risk of developing diseases associated with immune suppression, including opportunistic infections and neoplasms. Although it has been established that the risk of developing opportunistic infections is reduced, there is insufficient data on the development of tumors, including lymphomas. According to the treatment data for patients with an advanced stage of HIV disease, the risk of developing lymphoma in them is the same as in patients who were not treated with Retrovir. In patients with early stage HIV disease during long-term treatment with Retrovir, the risk of developing lymphoma is unknown.

Pregnant women who are considering treatment with Retrovir in order to prevent HIV transmission to the child should be aware that in some cases, despite treatment, HIV transmission can occur.

Hematological adverse reactions

In patients with an advanced stage of HIV disease during treatment with Retrovir, one can expect the development of anemia (usually no earlier than 6 weeks from the start of treatment, but rarely occurs earlier), neutropenia (usually no earlier than 4 weeks after the start of treatment, but sometimes earlier) and leukopenia ( which is secondary to ). This occurs more frequently with high doses (1200–1500 mg/day) and in patients with low pretreatment bone marrow reserve, especially in advanced HIV disease.

Hematological parameters should be carefully monitored. When Retrovir is administered intravenously, blood tests should be done at least once a week.

When the hemoglobin level decreases from 7.5 g/dl (4.65 mmol/l) to 9 g/dl (5.59 mmol/l) or the number of neutrophils ranges from 0.75 x 10 9 / l to 1 , 0 x 10 9 /l, dose reduction may be necessary until signs of bone marrow regeneration appear; Another way to speed up recovery is a short (2 - 4 weeks) break in treatment with Retrovir. Bone marrow regeneration usually occurs within 2 weeks, after which Retrovir therapy can be started again in reduced doses. Data on the use of intravenous Retrovir for more than 2 weeks are limited. In case of significant anemia, reducing the dose of Retrovir does not eliminate the need for blood transfusions.

Lactic acidosis/severe hepatomegaly with steatosis

Cases of lactic acidosis and severe hepatomegaly with steatosis, including deaths, have been observed when treating HIV infection with antiretroviral nucleoside analogues alone or in combination, including zidovudine. Most of these cases were observed in women. The drug should be prescribed with caution to every patient, but especially to patients with risk factors for developing liver disease. If clinical or laboratory signs of lactic acidosis or hepatotoxicity appear, treatment with Retrovir should be discontinued.

Contraindications. Hypersensitivity to zidovudine or other components of the drug.

Retrovir is contraindicated in patients with an abnormally low neutrophil count (less than 0.75 x 109/L) or abnormally low hemoglobin level (less than 7.5 g/dL or 4.65 mmol/L).

Interaction with other drugs. Zidovudine is eliminated mainly by conjugation in the liver to an inactive glucuronide metabolite. Active substances that are also eliminated by hepatic metabolism, especially through glucuronidation, can potentially delay the metabolism of zidovudine. The interactions described below are not exhaustive, but represent classes of medications that should be used with caution when prescribing.

Lamivudine: a moderate increase in C max (28%) of zidovudine is observed when used concomitantly with lamivudine, but the total concentration (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin: Low levels of phenytoin have been reported in the blood of some patients receiving Retrovir, although high levels were detected in one patient. These data suggest that phenytoin levels should be carefully monitored when both drugs are used concomitantly.

Probenicide: Based on limited data, probenecid increases the mean half-life and area under the concentration/time curve of zidovudine by decreasing glucuronidation. Renal excretion of glucuronide (possibly zidovudine itself) is reduced in the presence of probenecid.

Ribavirin: The nucleoside analogue ribavirin is an antagonist in vitro of the antiviral activity of zidovudine, so their simultaneous administration should be avoided.

Rifampicin: Limited data indicate that concomitant use of zidovudine and rifampicin reduces the AUC of zidovudine by 48% ± 34%, but the clinical significance of this phenomenon is unknown.

Stavudin: Zidovudine may inhibit the intracellular phosphorylation of stavudine when both medications are administered simultaneously. Therefore, stavudine is not recommended to be combined with zidovudine.

Other interactions: other active substances, including aspirin, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone and isoprinosine (the list is not limited to these drugs), can affect the metabolism of zidovudine through competitive inhibition of glucuronidation or direct inhibition of hepatic microsomal metabolism. Therefore, you need to keep in mind the possibility of interactions when prescribing these medications, especially for chronic treatment, in combination with Retrovir.

Concomitant use, mostly in acute cases, with potentially nephrotoxic or myelosuppressive drugs (for example, systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vinblastine and doxorubicin) may also increase the risk of side effects from Retrovir. When concomitant use of these medications is necessary, carefully monitor renal function and hematologic parameters and, if necessary, reduce the dose of one or more drugs.

Since some patients receiving Retrovir may suffer from opportunistic infections, prophylactic administration of antimicrobial agents may be appropriate. Such prophylaxis may include co-trimoxazole, aerosolized pentamidine, pyrimethamine, and acyclovir. Limitations from clinical studies indicate that when used simultaneously with these drugs, there is no increase in the incidence of adverse reactions to Retrovir.

Overdose.

There is experience using high doses of 7.5 mg/kg body weight of intravenous Retrovir every 4 hours for 4 weeks in 5 patients. One patient experienced a feeling of anxiety, and 4 patients experienced no adverse events.

There are no specific symptoms or signs of acute overdose of zidovudine, except for those listed in the side effects section (fatigue, headache, vomiting, isolated cases of hematological changes). Following the patient's reported consumption of an unknown amount of zidovudine, blood levels of zidovudine were more than 16 times normal therapeutic levels, but no clinical, biochemical, or hematologic sequelae were observed.

In case of overdose, it is necessary to carefully examine the patient to determine signs of intoxication and prescribe appropriate supportive therapy.

Hemodialysis and peritoneal dialysis have a limited effect on the elimination of zidovudine, but accelerate the elimination of its glucuronide metabolite.

Features of use.

Pregnancy

Zidovudine has been found to cross the placenta in humans. According to limited data on the use of Retrovir during pregnancy, Retrovir should be used before 14 weeks of pregnancy only when the potential benefit to the mother outweighs the possible risk to the fetus.

Transmission from mother to fetus

In the ACTG076 study, the use of Retrovir in pregnant women over 14 weeks' gestation and subsequent treatment of their newborns resulted in a significant reduction in maternal-to-fetal transmission of HIV (23% in the placebo group compared with 8% in the Retrovir-treated group). Oral therapy with Retrovir was started between 14 and 34 weeks of pregnancy and long-term until the onset of labor. During childbirth, Retrovir was administered intravenously. Newborns received Retrovir upon reaching 6 weeks of age. For newborns who could not take Retrovir orally, it was prescribed intravenously.

There is no long-term data on the effect of Retrovir on the fetus and infant. Based on data from carcinogenicity and mutagenicity studies in animals, the risk of carcinogenesis in humans cannot be excluded. The significance of these data in relation to infected and uninfected infants treated with Retrovir is unknown. However, pregnant women who decide to be treated with Retrovir should know about this.

Lactation

Health experts recommend that women living with HIV avoid breastfeeding their babies if possible to avoid transmitting HIV. After administration of a single dose of zidovudine 200 mg to HIV-infected women, the average concentration of the drug in breast milk and blood serum was approximately the same. Given that zidovudine and the virus pass into breast milk, mothers who take Retrovir are not recommended to breastfeed their children.

Fertility

There is no data on the effect of Retrovir on female fertility. It has been established that Retrovir does not affect the number, morphology and motility of sperm in men.

Impact on the ability to drive a car and other mechanisms

Based on the pharmacological data of the active substance, there is no possibility of any harmful effect on the ability to drive a car and other mechanisms. Despite this, the general condition of the patient and the side effect profile of the drug should always be taken into account when deciding whether to perform these activities.

Storage conditions and periods.

Store at temperatures below 30°C, protected from light and out of reach of children. Shelf life – 3 years.