Whenever possible, postnatal prophylaxis should begin within the first 6 hours after birth. Zidovudine is administered orally or, in the presence of gastrointestinal disorders, intravenously. In Germany, oral standard prophylaxis was shortened from six to two (four) weeks (Vocks-Hauck, 2001).
Prevention at increased risk of perinatal HIV transmission (multiple births, preterm births)
In multiple births, neonates are recommended to be given prophylaxis with zidovudine for 4 weeks in the absence of additional risk factors. Premature newborns should receive nevirapine in addition to zidovudine: one dose if the mother received nevirapine at the time of delivery, or two doses if the mother did not receive nevirapine. If less than an hour has elapsed between the mother taking NVP and the birth of the baby, the baby should receive the first dose of NVP within the first 48 hours after birth (Stringer, 2003). If the mother was taking non-virapine as part of a combination ART regimen, the neonatal dose should be doubled to 4 mg/kg due to possible enzyme induction. In addition, neonates should receive extended preterm zidovudine prophylaxis (see above) for four (Ferguson, 2008) to six (CDC, 2008a) weeks.
Prevention at extremely high risk of perinatal HIV transmission
In neonates with additional risk factors, combination prophylaxis with zidovudine plus lamivudine is recommended. Very high risk factors are premature rupture of amniotic fluid, amnionitis, high maternal viral load before delivery, lack of prevention of perinatal HIV transmission, cutting injury to the baby during caesarean section, and aspiration of hemorrhagic amniotic fluid from the baby's gastrointestinal tract or airways. In the presence of additional risk factors, it is recommended to prescribe combined prophylaxis of zidovudine and lamivudine, as well as two doses of nevirapine, to newborns. However, there are very few data on the pharmacokinetics of antiretroviral drugs in neonates.
Prevention in cases where the mother did not receive PMTCT during pregnancy and childbirth
Combination prophylaxis with zidovudine plus lamivudine should be initiated within the first 6 to 12 hours after birth. In addition, perinatal prophylaxis with nevirapine is recommended. If the mother is diagnosed with HIV only after delivery, combined prophylaxis started within 48 hours of birth is much more effective than monoprophylaxis started only after the third day (vertical transmission rate 9.2% vs. 18.4%; Wade , 1998). However, even late initiation of zidovudine prophylaxis is better than no prophylaxis at all (risk of perinatal infection 18.4% versus 26.6%) (see Table 15.6). Even very late initiation of postnatal prophylaxis (> 3 days) will be beneficial.
Further Research on HIV Prevention in Newborns
An overview of neonatal pharmacokinetic studies is shown in Table 15.7 (Ronkavilit, 2001 and 2002; Mirochnik, 2005; Blum, 2006; Chadwick, 2008; Hirt, 2008). To continuously improve antiretroviral treatment of HIV infection in pregnancy and antiretroviral prevention of perinatal transmission of HIV, all clinical data must be carefully recorded. The United States has an Antiretroviral Pregnancy Registry that helps track any possible teratogenic effects of antiretrovirals based on reports of malformations. Table 15.7. Research on antiretroviral prophylaxis in newborns Abbreviation Trade nameAverage daily doseMost Common Side EffectsResearch AZT Retrovir® 2 mg/kg 4 times a day 2 mg/kg 2 times a day; then 2 mg/kg 3 times a day - preterm<35 недель гестации с 15-го дня; недоношенным <30 недель гестации с 29-го дняАнемия, нейтропения Митохондриопатия при применении в комбинации с ламивудином(P)ACTG 076, 316, 321, 353, 354, 358; HIVNET 012 III PACTG 331(PI)3TC Эпивир®2 мг/кг 2 раза в сутки новорожденным (в возрасте <30 дней)Нарушения со стороны ЖКТ, рвота, в комбинации с другими препаратами - токсическое повреждение митохондрий. Нельзя применять у недоношенныхPACTG 358FTC Эмтрива1 мг/кг сразу после рождения или 2 мг/кг через 12 часов после рождения; 3 мг/кг (новорожденным в возрасте <3 мес)Нарушения со стороны ЖКТ МитохондриопатияANRS12109 Исследование фармако-кинетики GileadddI Видекс®50мг/м2 2 раза в сутки, начиная с 14-го дня жизниДиарея, панкреатит, в комбинации с другими препаратами - токсическое повреждение митохондрийPACTG 239, 249; HIV-NATd4T Зерит®0,5 мг/кг 2 раза в сутки (новорожденным в возрасте <30 дней)В комбинации с другими препаратами - токсическое повреждение митохондрийPACTG 332, 356; HIV-NATABC Зиаген®2-4 мг/кг однократно (в возрасте <1 мес) и 8 мг/кг 2 раза в сутки (в возрасте >1 month) Hypersensitivity reaction, mitochondriopathy, lactic acidosis PACTG 321TDF Virid 4 mg/kg immediately after birth, and on days 3 and 5 13 mg/kg postpartum (under study) Osteopenia, nephrotoxicity NCT00120471, HPTN 057; ANRS12109NVP Viramune® 2-4 mg/kg once daily for 14 days or 120 mg/m2 once, then 3.5-4 mg/kg twice daily or 120 mg/m2 twice daily (maximum dose 200 mg 2 times a day) Rash, hepatotoxicity, hyperbilirubinemia<6 недельНарушения со стороны ЖКТ: в особенности диареяPACTG 353, 356 PENTA 7RTV Норвир®350-450 мг/м2 2 раза в сутки у новорожденных в возрасте <4 недель (в рамках исследования)Гипербилирубинемия, Нарушения со стороны ЖКТ, в особенности тошнотаPACTG 345, 354LPV/r Калетра®300/75 мг/м2 2 раза в сутки у новорожденных в возрасте <6 недельНарушения со стороны ЖКТ, в особенности диареяPACTG P 1030 IMPAACTG P1060 (P)ACTG - (Pediatric) AIDS Clinical Trials Group исследования в области СПИДа (у детей). HIV-NAT - HIV-Netherlands Australia Thailand R- Объединение медицинских учреждений, проводящих клинические Сотрудничество по проведению исследова-
research in the field of HIV infection in the Netherlands, Australia and Thailand. Note: With the exception of zidovudine for use in term neonates, other drugs at the indicated doses have been used only in studies. Where possible, drugs that are not approved for use in neonates should only be used in clinical trials. and other abnormalities in newborns whose mothers took antiretrovirals during pregnancy: Antiretroviral Pregnancy Registry, Research Park, 1011 Ashes Drive, Wilmington NC 28405
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Dosage form
Oral solution 10 mg/ml, 200 ml
Compound
5 ml of solution contain
active substance - zidovudine 50 mg,
excipients: hydrogenated glucose syrup, glycerin, anhydrous citric acid1, sodium benzoate, sodium saccharin, strawberry flavor, white sugar flavor, purified water.
1 - instead of anhydrous citric acid, citric acid monohydrate can be used
Description
Clear, pale yellow solution with a characteristic strawberry odour.
Pharmacotherapeutic group
Antiviral drugs for systemic use. Nucleosides are reverse transcriptase inhibitors. Zidovudine.
ATX code J05AF01
Pharmacological properties
Pharmacokinetics
Pharmacokinetics in adults
Suction
Zidovudine is well absorbed from the intestine. Bioavailability is 60-70%. The average equilibrium maximum Css max and Css min after ingestion of a solution of zidovudine 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.
Distribution
After 2-4 hours after oral administration in adults, the average ratio of the concentration of zidovudine in the cerebrospinal fluid and in the blood plasma is 0.5, and in children after 0.5-4 hours this figure is 0.52-0.85. Zidovudine crosses the placenta and is determined in the amniotic fluid and in the blood of the fetus. Zidovudine has also been found in semen and breast milk. The binding of the drug to plasma proteins is 34-38%, respectively, competitive binding with other drugs by the mechanism of substitution is not expected.
Metabolism
5"-glucuronide is the main metabolite of zidovudine, is determined both in plasma and in the urine and accounts for approximately 50-80% of the dose of the drug, which is excreted through the kidneys.
breeding
The mean half-life, 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 that of creatinine, indicating its predominant elimination by tubular secretion.
Pharmacokinetics in children
Suction
In children over the age of 5-6 months, pharmacokinetic parameters are similar to those in adults.
Zidovudine is well absorbed from the intestine, bioavailability is 60-74% with an average value of 65%.
After ingestion of a solution of zidovudine at a dose of 120 mg / m2 of body surface and 180 mg / m2, the Css max level is 1.19 μg / ml (4.45 μM) and 2.06 μg / ml (7.7 μM), respectively.
Doses of 180 mg/m2 4 times a day in children had the same systemic effect (24 h AUC 40.0 h*µm or 10.7 h*µg/mL) as dosing of 200 mg 6 times a day. day for adults (40.7 h * μm or 10.9 h * μg / ml).
Distribution
When administered intravenously, the mean terminal plasma half-life was 1.5 hours and the total clearance was 30.9 ml/min/kg.
In children, the mean CSF/plasma concentration ratio of zidovudine ranges from 0.52 to 0.85 0.5-4 hours after oral dosing (for oral treatment) and is 0.87 one hour after intravenous infusion ( with intravenous treatment). During continuous intravenous infusion, the mean steady-state CSF/plasma concentration ratio was 0.24.
Metabolism
The main metabolite is 5"-glucuronide. After an intravenous dose, 29% of the dose was found in the urine unchanged, and 45% was excreted as glucuronide.
breeding
The renal clearance of zidovudine is much greater than that of creatinine, indicating significant elimination by tubular secretion. In newborns under the age of 14 days of life, a decrease in zidovudine glucuronidation is observed, followed by an increase in its bioavailability, a decrease in clearance, and a prolongation of the half-life. In children older than 14 days of age, the pharmacokinetics of zidovudine are similar to those in adults.
Pregnancy
The pharmacokinetic properties of zidovudine were studied in a study in which 8 women who were in the 3rd trimester of pregnancy took part. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetic properties of zidovudine were similar to non-pregnant women. Similar to the passive passage of the drug through the placenta, plasma levels of zidovudine in the blood plasma of children at birth were equal to the levels in the plasma of mothers at birth.
No pharmacokinetic studies have been conducted in patients over 65 years of age.
Impaired kidney function
In patients with severe renal insufficiency, the maximum plasma concentration of zidovudine is increased by 50% compared with its concentration in patients without impaired renal function. Hemodialysis and peritoneal dialysis do not affect the elimination of zidovudine, while the excretion of glucuronide increases.
Impaired liver function
Pharmacokinetic data in patients with hepatic impairment are limited.
Pharmacodynamics
Retrovir is an antiviral drug highly active against retroviruses, including the human immunodeficiency virus (HIV).
Further phosphorylation of zidovudine monophosphate to zidovudine di- and triphosphate (TF) is catalyzed by cellular thymidine kinase and nonspecific kinases, respectively.
The subsequent phosphorylation of zidovudine monophosphate to a diphosphate and then to a triphosphate derivative is catalyzed by cellular thymidine kinase and nonspecific kinases, respectively.
Zidovudine triphosphate (TF) acts as an inhibitor and substrate for viral reverse transcriptase. The formation of viral 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 α-polymerase. Retrovir does not antagonize other antiviral drugs (lamivudine, didanosine, interferon-alpha, abacavir).
Indications for use
Treatment of HIV infection as part of combination antiretroviral therapy in children and adults
Reducing the rate of transplacental transmission of HIV from HIV-positive pregnant women to the fetus
Dosage and administration
Treatment with Retrovir should be carried out by a physician experienced in the management of HIV-infected patients.
Adults and adolescents weighing over 30 kg
2 schemes of prevention are effective.
1. Pregnant women, starting from 14 weeks of pregnancy, it is recommended to prescribe the drug Retrovir inside before the onset of labor at a dose of 500 mg / day (100 mg 5 times a day). During childbirth, Retrovir is administered intravenously at a dose of 2 mg/kg of body weight for 1 hour, then it is necessary to continue intravenous infusion at a dose of 1 mg/kg/hour until the umbilical cord is clamped. Newborns are prescribed Retrovir orally as a solution in the first 12 hours after birth up to 6 weeks at the rate of 2 mg / kg every 6 hours.
Given the need to administer small volumes of solution, care should be taken when calculating doses intended for administration to newborns. An appropriate size dosing syringe must be used to accurately determine the dose. If neonates cannot receive Retrovir by mouth, they should be given Retrovir as a 30-minute intravenous infusion at a dose of 1.5 mg/kg body weight every 6 hours.
Instructions for use
Use the dosing syringe included in the package for more accurate dosing.
1. Open the vial and put the cap aside
2. Attach the plastic adapter to the neck of the bottle, holding the bottle firmly
3. Firmly insert the dosing syringe into the adapter
4. Turn the bottle upside down
5. Pull back on the plunger of the syringe and draw up the first part of your recommended dose
6. Turn the vial over and remove the syringe from the adapter
7. Enter the entire amount of the drug into the oral cavity directly from the syringe towards the inner surface of the cheek, slowly moving the syringe plunger to its base. This manipulation will allow you to swallow the solution without causing difficulty in swallowing. Do not press the plunger too hard and do not inject the drug too quickly towards the back of the throat, as this can lead to a cough reflex.
8. Repeat steps 3 - 7 until the entire recommended dose has been taken
9. Do not leave the syringe in the vial. Remove the adapter and syringe from the vial and rinse thoroughly with clean water. Make sure the syringe and adapter are dry before using them again.
10. Carefully close the vial with a cap
kidney failure
In severe renal insufficiency (creatinine clearance<10 мл/мин) рекомендуемая доза препарата составляет 300-400 мг в сутки. В зависимости от реакции со стороны периферической крови и клинического эффекта, может потребоваться дальнейшая корректировка дозы. Гемодиализ и перитонеальный диализ не влияют на элиминацию зидовудина, в то же время выведение глюкуронида усиливается. Для пациентов с терминальной стадией почечной недостаточности, находящихся на гемодиализе или перитонеальном диализе, рекомендуемая доза препарата Ретровир составляет 100 мг каждые 6-8 часов.
Liver failure
Data obtained in patients with cirrhosis of the liver suggest a possible accumulation of zidovudine due to a decrease in glucuronidation, which may require dose adjustment of the drug, but due to limited data, there are no specific recommendations for this category of patients. If it is not possible to control the level of zidovudine in plasma, then the doctor should pay special attention to clinical signs of intolerance to the drug, such as the development of adverse reactions from the hematopoietic organs (anemia, leukopenia, neutropenia) and, if necessary, adjust the dose and / or increase the interval between doses. in each specific case.
Adverse reactions from the hematopoietic organs
A change in dosage or discontinuation of the drug Retrovir may be required in patients whose hemoglobin content decreases (up to 7.5-9.0 g / dL (4.65-5.59 mmol / L)) or the number of neutrophils drops to a clinically significant level (up to 0.75-1.0 x 109 / l). Other possible causes of anemia or neutropenia must be excluded. Dose reduction or interruption of therapy with Retrovir should be considered in the absence of alternative treatments.
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, special care must be taken when prescribing the drug Retrovir and appropriate monitoring should be carried out before and during treatment with the drug.
Side effects
The side effect profile is similar in adults and children.
Very often (>1/10), often (>1/100,<1/10), нечасто (>1/1,000, <1/100), редко (>1/10,000, <1/1,000), очень редко (<1/10,000).
Often
Headache
Nausea
Anemia (may require blood transfusions), neutropenia and leukopenia; these conditions develop with the use of high doses of the drug Retrovir (1200-1500 mg / day) and in patients with severe HIV infection (especially in patients with reduced bone marrow reserve before treatment), mainly with a decrease in the number of CD4 cells below 100/mm3 ; in these cases, it may be necessary to reduce the dose of the drug Retrovir or cancel it; the incidence of neuropenia increases in patients who have experienced a decrease in the number of neutrophils, hemoglobin and vitamin B12 in serum at the beginning of treatment.
Dizziness, general malaise
Vomiting, abdominal pain, diarrhea
Increased levels of bilirubin and liver enzymes
Myalgia
Thrombocytopenia and pancytopenia (with bone marrow hypoplasia)
Flatulence
Skin rash, pruritus
Myopathies
Fever, generalized pain syndrome, asthenia
Aplasia of the red germ
Lactic acidosis in the absence of hypoxemia
Anorexia
Insomnia, paresthesia, drowsiness, reduced speed of thinking,
convulsions
cardiomyopathy
Pigmentation of the oral mucosa, taste disturbance, dyspepsia, pancreatitis
Severe hepatomegaly with steatosis
Pigmentation of nails and skin, hives and increased sweating
Frequent urination
Gynecomastia
Chills, chest pain, flu-like symptoms
Anxiety, depression
Rarely
aplastic anemia
After several weeks of therapy, the incidence of nausea and other
the most common adverse reactions to Retrovir are reduced.
Adverse reactions that occur when using the drug Retrovir to prevent the transmission of HIV infection from mother to fetus
There is a tendency to develop mild to moderate anemia, which should be controlled before delivery, in the treatment of women with Retrovir.
In children, a decrease in hemoglobin content was observed, which, however, does not require blood transfusions. Anemia disappears within 6 weeks after completion of therapy with Retrovir. The long-term effects of the use of the drug Retrovir during pregnancy on the fetus and in newborns are unknown.
When taking zidovudine, cases of lactic acidosis, usually associated with hepatomegaly and fatty degeneration of the liver, have been reported (see "Special Instructions").
Patients taking Retrovir should be monitored for signs of lipoatrophy.
Treatment with zidovudine has been associated with loss of subcutaneous adipose tissue, which is most pronounced in the face, limbs, and buttocks. If the development of lipoatrophy is detected, treatment with Retrovir should be discontinued (see "Special Instructions").
During antiretroviral therapy, body weight may increase and blood lipid and glucose levels may increase (see "Special Instructions").
In HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur during the initiation of antiretroviral therapy (ART), which can cause serious clinical conditions or exacerbation of symptoms (see "Special Instructions").
Cases of osteonecrosis have been reported, especially in patients with advanced HIV disease and/or on long-term combination antiretroviral therapy. The incidence of osteonecrosis is unknown (see "Special Instructions").
It is possible to develop anemia with the simultaneous administration of zidovudine with ribavirin, and therefore this combination is not recommended for such patients.
Reporting suspected side effects
The provision of data on suspected adverse drug reactions is very important to enable continuous monitoring of the risk/benefit ratio of the medicinal product. Health care professionals should be provided with information about any suspected adverse reactions through the contacts listed at the end of the instructions, as well as through the national information collection system.
Contraindications
Hypersensitivity to zidovudine or any other component of the drug
Neutropenia (neutrophil count less than 0.75 x 109/l)
Decreased hemoglobin (less than 7.5 g/dL or 4.65 mmol/L)
Children under 3 months of age and body weight less than 4 kg
lactation period
Newborns with hyperbilirubinemia requiring treatment other than phototherapy or with transaminase levels greater than five times the upper limit.
Caution: liver failure
Drug Interactions
Rifampicin: Combination with rifampicin results in a 48% ± 34% reduction in AUC for zidovudine. Simultaneous administration with rifampicin should be avoided, as this may lead to partial or complete loss of the effectiveness of the drug Retrovir.
Stavudine: Zidovudine in combination with stavudine has antagonistic activity in vitro. The simultaneous use of stavudine and zidovudine should be avoided.
Probenecid: Probenecid increases the AUC of zidovudine by 106% (range 100 to 170%). Patients receiving both drugs should be carefully monitored for the development of hematological toxicity.
Lamivudine: There is a moderate increase in Cmax (28%) for zidovudine when administered together with lamivudine, however, the total exposure (AUC) is not affected. Zidovudine does not affect the pharmacokinetics of lamivudine.
Phenytoin: reduces the concentration of phenytoin in the blood (there was a single case of an increase in the concentration of phenytoin), which requires monitoring the level of phenytoin in the blood while prescribing it with the drug Retrovir.
Atovaquone: Zidovudine does not alter the pharmacokinetics of atovaquone. However, pharmacokinetic data show that atovaquone reduces the rate of metabolism of zidovudine to its 5-glucuronide metabolite (AUC increased by 33% when target zidovudine concentrations were reached, peak plasma glucuronide concentration decreased by 19%). When using zidovudine at a dose of 500 or 600 mg /day It is unlikely that three weeks of simultaneous treatment with atovaquone for the treatment of acute pneumocystis pneumonia can lead to an increase in the frequency of adverse reactions associated with elevated plasma concentrations of zidovudine.Increased caution should be exercised against the background of long-term therapy with atovaquone.
With the introduction of valproic acid, fluconazole or methadone, simultaneously with zidovudine, an increase in AUC and a corresponding decrease in its clearance were observed.
When zidovudine is administered concomitantly with valproic acid, fluconazole, or methadone, patients should be carefully monitored for potential zidovudine toxicity, as only limited data are available and the clinical significance of these results is unclear.
Exacerbation of anemia due to the use of ribavirin was observed against the background of combined treatment with the drug Retrovir as part of ART in the treatment of HIV; the exact mechanism of interaction has not been elucidated. Co-administration of ribavirin and Retrovir is not recommended, and consideration should be given to replacing zidovudine as part of the ART regimen. This is especially important in patients with a history of anemia while on zidovudine treatment.
Clarithromycin: Clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by taking zidovudine and clarithromycin separately at least two hours apart.
Others: Drugs such as aspirin, 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 hepatic microsomal metabolism. The possibility of using these drugs in combination with the drug Retrovir, especially for long-term therapy, should be approached with caution.
special instructions
Effective viral suppression with antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission, but a residual risk cannot be ruled out. Precautions to prevent infection are taken in accordance with national guidelines.
Retrovir does not cure HIV infection and patients taking Retrovir or taking any other antiretroviral therapy remain at risk of developing opportunistic infections and other complications of HIV infection.
Adverse reactions from the blood
Anemia (usually observed after 6 weeks from the start of the use of the drug Retrovir, but sometimes it can develop earlier); neutropenia (usually develops 4 weeks after the start of treatment with Retrovir, but sometimes occurs earlier); leukopenia (usually on the background of neutropenia) can occur in patients with a developed clinical picture of HIV infection receiving Retrovir, especially at high doses (1200 mg - 1500 mg / day), and who have reduced bone marrow hematopoiesis before treatment.
Blood counts should be carefully monitored.
While taking the drug Retrovir in patients with a developed 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. 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 0.75x109 / l -1.0x109 / l, the daily dose of Retrovir should be reduced until the blood counts are restored, or Retrovir is canceled for 2-4 weeks before the restoration of blood counts. Usually, the blood picture returns to normal after 2 weeks, after which the drug Retrovir at a reduced dosage can be re-appointed. Patients with severe anemia, despite reducing the dose of the drug Retrovir, need a blood transfusion.
lactic acidosis
Lactic acidosis, usually associated with hepatomegaly and fatty liver, has been reported with antiretroviral nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) of lactic acidosis may include digestive symptoms (nausea, vomiting, and abdominal pain), general weakness, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (in including tachypnea).
Lactic acidosis has a high mortality rate and may be associated with pancreatitis, liver failure, or kidney failure.
Lactic acidosis usually occurs after several months of treatment.
Treatment with nucleoside analogs should be discontinued in the event of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly rising aminotransferase levels.
Caution should be exercised when administering nucleoside analogs to a patient (particularly obese women) with hepatomegaly, hepatitis, or other known risk factors associated with liver disease and fatty liver (including certain drugs and alcohol). Patients co-infected with hepatitis C and treated with alpha-interferon and ribavirin are at particular risk.
High-risk patients should be closely monitored.
Mitochondrial dysfunction after intrauterine exposure to nucleoside and nucleotide analogs.
Nucleoside and nucleotide analogues can affect mitochondrial function to varying degrees, most pronounced with stavudine, didanosine, and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogs; these cases predominantly involved treatment regimens that included zidovudine. The main reported adverse reactions were hematological disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). Often these reactions are transient. A small number of late-onset neurological disorders (hypertension, convulsions, abnormal behavior) have been reported. Whether neurological disorders are transient or permanent is currently unknown. The possibility of these events should be considered in every infant exposed in utero to nucleoside and nucleotide analogs who has severe clinical signs of unknown etiology, in particular neurological disorders. These results do not affect current national recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Lipodystrophy
Treatment with zidovudine has been associated with loss of subcutaneous fat, which in turn has been associated with mitochondrial toxicity. The incidence and severity of lipoatrophy is associated with a cumulative effect. This fat loss, which is most prominent in the face, limbs, and buttocks, may not be reversible by switching to a free regimen of zidovudine. Patients should be regularly checked for signs of lipoatrophy during therapy with zidovudine and zidovudine-containing drugs (Combivir and Trizivir®). If lipoatrophy is suspected, alternative treatment should be considered.
Body weight and metabolic parameters
When conducting antiretroviral therapy, an increase in body weight and the concentration of lipids and glucose in the blood is possible. Such changes may be partly related to the treatment of the disease and lifestyle. So for lipids in some cases there is evidence of an effect of therapy, while for weight gain there is no strong evidence of an association with any particular treatment. To control the concentration of lipids and glucose in the blood, refer to the guidelines for the treatment of HIV. Lipid abnormalities should be corrected as is customary in clinical practice.
Patients with impaired liver function
The clearance of zidovudine in patients with mild hepatic impairment without cirrhosis is similar to the creatinine clearance observed in healthy subjects, so dose adjustment of zidovudine is not required. For patients with moderate to severe liver disease, it is not possible to provide specific dosage recommendations due to the inhomogeneous effects of zidovudine. Therefore, the administration of zidovudine in this group of patients is not recommended.
Patients with chronic hepatitis B or hepatitis C treated with combination antiretroviral therapy are at increased risk for serious and potentially fatal hepatic adverse events. In case of concomitant antiviral treatment for hepatitis B or hepatitis C, please also refer to the relevant information on these medicines.
Patients with pre-existing hepatic impairment, including chronic active hepatitis, are more likely to experience abnormal liver function tests during combination antiretroviral therapy and should be monitored according to standard practice. If signs of progressive liver disease are found in such patients, the possibility of discontinuing or canceling treatment should be considered.
Immune Reconstitution Inflammatory Syndrome In severely immunocompromised HIV-infected patients, an inflammatory response to asymptomatic or residual opportunistic infections may occur during initiation of antiretroviral therapy (ART), which may cause serious clinical conditions or exacerbation of symptoms. Typically, these reactions occurred within the first few weeks or months after starting ART. Typical examples of such conditions are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (P. carinii). Any inflammatory symptoms should be assessed without delay and treatment initiated if necessary. Autoimmune diseases (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have been observed in association with immune reactivation, but the time of onset varied and the disease could appear many months after the start of therapy.
Patients should be warned about the need to be careful while taking medications on their own. Retrovir is not recommended for use in patients with rare congenital problems of fructose intolerance.
osteonecrosis
Although the etiology is thought to be multifactorial (including corticosteroid use, alcohol consumption, severe immune suppression, high body mass index), cases of osteonecrosis have been reported, especially in patients with advanced HIV disease and/or on long-term combination antiretroviral therapy. Patients should see a doctor if they experience joint aches and pains, joint stiffness, and difficulty moving.
Patients with concomitant viral hepatitis C
It is possible to develop anemia with the simultaneous administration of zidovudine with ribavirin and alpha-interferon, and therefore this combination is not recommended for such patients.
Pregnancy and lactation
Fertility
Zidovudine did not impair reproductive function in male and female rats given oral doses up to 450 mg/kg/day. There is no data on the effect of Retrovir on female reproductive function in humans. With the introduction of Retrovir to men, there was no change in the number, structure or motility of spermatozoa.
Pregnancy
In general, the decision to use antiretrovirals to treat HIV infection in pregnant women, and therefore to reduce the risk of vertical transmission of HIV to the newborn, should take into account data from animal studies as well as clinical experience in pregnant women.
In particular, the use of zidovudine by pregnant women followed by neonatal treatment has reduced mother-to-child transmission of HIV. A large body of data from pregnant women taking lamivudine and zidovudine has shown no risk of fetal defects (more than 3,000 first trimester results for each drug, of which over 3,000 results include both lamivudine and zidovudine). Based on the data mentioned, a malformative risk in humans is unlikely.
When conducting studies of zidovudine in animals, toxic effects of zidovudine on reproductive function were observed.
The active substances that make up the drug Retrovir may have an inhibitory effect on cell DNA replication. In animal studies, one case of intrauterine carcinogenic effects of zidovudine was identified. The clinical significance of these indicators is not established. In humans, penetration of zidovudine through the placental barrier has been observed.
Mitochondrial dysfunction
Nucleoside and nucleotide analogs have demonstrated in vitro and in vivo the ability to induce mitochondrial disorders of varying degrees of damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed to nucleoside analogues in utero and/or postpartum.
Lactation
After administration of a single dose of 200 mg zidovudine to HIV-infected women, mean zidovudine concentrations in breast milk and serum were similar.
Prevention of HIV transmission from mother to fetus
The use of the drug Retrovir after 14 weeks of pregnancy, followed by its appointment in newborns, leads to a decrease in the frequency of transmission of HIV from mother to fetus. A slight and transient increase in fetal serum lactic acid levels has been identified, which may be caused by mitochondrial dysfunction. The clinical significance of this fact is unknown. There is also evidence of the occurrence of developmental delays, the development of seizures and other neurological disorders in very rare cases in children whose mothers took the drug Retrovir, however, a direct relationship between taking the drug and these pathologies has not been identified. The data obtained do not affect the recommendations for the use of the drug Retrovir to prevent the vertical transmission of HIV infection. Long-term effects of the use of the drug Retrovir in children who received it in utero or neonatal periods are unknown. It is impossible to completely exclude the possibility of a carcinogenic effect, about which pregnant women must be informed.
Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms
The effect of the drug Retrovir on the ability to drive a car and other mechanisms has not been studied. However, adverse effects on these abilities are unlikely. However, when deciding on the ability to drive a car and other mechanisms, one should keep in mind the patient's condition and the possibility of developing adverse reactions (dizziness, drowsiness, lethargy, convulsions) while taking the drug Retrovir.
Overdose
Symptoms: There were no specific symptoms or signs of overdose with Retrovir, with the exception of established adverse reactions: fatigue, headache, vomiting, and rare changes in blood counts.
A 16-fold increase in plasma levels of zidovudine compared to therapeutic concentrations was recorded, which was not accompanied by any clinical, biochemical or hematological consequences.
Treatment: observation of the patient for the development of signs of intoxication and symptomatic supportive therapy. Hemodialysis and peritoneal dialysis are not highly effective in removing zidovudine from the body, but increase the excretion of its glucuronide metabolite.
Release form and packaging
Oral solution 10 mg/ml, 200 ml.
200 ml of the drug is placed in a glass bottle of yellow glass.
1 bottle, together with a dosing syringe of 1, 5 or 10 ml, an adapter and instructions for medical use in the state and Russian languages, is placed in a cardboard box.
Registration certificate holder
ViiV Healthcare ULC, Canada
(8455 Route Transcanadienne, Montreal, Quebec, Canada, H4S 1Z1)
Active ingredient: 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.
Clear, light yellow solution with a characteristic strawberry odor.
Pharmacotherapeutic group: antiviral [HIV] agent.
ATX code: J05AF01.
Pharmacodynamics
Zidovudine is an antiviral thymidine analog highly active against retroviruses, including the human immunodeficiency virus (HIV).
Zidovudine undergoes phosphorylation in both infected and intact cells with the formation of monophosphate by 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 human cellular DNA polymerase α-polymerase.
Zidovudine acts additively or synergistically with a large number of antiretroviral drugs such as lamivudine, didanosine, and interferon-alpha to inhibit 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 the 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 out of 6 mutations. Mutations do not cause cross-resistance to other nucleosides, which allows the use of other reverse transcriptase inhibitors for the treatment of HIV infection.
Two types of mutations lead to the development of multiple drug resistance. In one case, mutations occur at positions 62, 75, 77, 116 and 151 of HIV reverse transcriptase, and in the second case, we are talking about T69S mutation with the insertion of 6 pairs of nitrogenous bases 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.
Decreased sensitivity to zidovudine in vitro in HIV isolates has been observed with long-term treatment of HIV infection with zidovudine.
At present, the relationship between sensitivity to in vitro zidovudine 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 acquiring resistance to lamivudine. Clinical studies have demonstrated that the use of zidovudine in combination with lamivudine delays the emergence of zidovudine-resistant viral strains in patients who have not previously received antiretroviral therapy.
Suction
Zidovudine is well absorbed after oral administration, bioavailability is 60-70%. Mean steady state maximum (Css rnax) and minimum (Cssmin) plasma concentrations when taking zidovudine 5 mg/kg 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, amounting to 34-38%. Zidovudine passes into the cerebrospinal fluid, placenta, amniotic fluid, fetal blood, semen and breast milk.
Metabolism
The zidovudine 5'-glucuronide is the major end metabolite of zidovudine and is found in both plasma and urine and accounts for approximately 50-80% of the dose excreted by the kidneys.
breeding
The renal clearance of zidovudine is much greater than that of creatinine, indicating its predominant elimination by tubular secretion. .
Special patient groups
In children over the age of 5-6 months, 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 concentration was 4.45 µmol (1.19 µg/mL) and 7.7 µmol (2.06 µg/mL), respectively.
Pharmacokinetic data suggest that zidovudine glucuronidation in neonates and infants is reduced, resulting in increased bioavailability. Decreased clearance and a longer half-life are recorded in infants under 14 days of age, then pharmacokinetic parameters become similar to those in adults.
Elderly patients
The pharmacokinetics of zidovudine in patients over 65 years of age has not been studied.
In patients with severe renal insufficiency, the maximum plasma concentration of zidovudine is increased by 50% compared with that in patients without impaired renal function. The systemic exposure of zidovudine AUC (defined as the area under the concentration-time curve) is increased by 100%; the half-life does not change significantly. In case of impaired renal function, a significant accumulation of the main metabolite 5 "- zidovudine glucuronide is observed, but no signs of toxic effects are detected. Hemodialysis and peritoneal dialysis do not affect the excretion of zidovudine, while the excretion of 5"-zidovudine glucuronide increases.
In liver failure, zidovudine accumulation may occur due to a decrease in glucuronidation, which requires dose adjustment of the drug.
Pregnancy
Pharmacokinetic parameters of zidovudine in pregnant women do not change; there are no signs of cumulation of zidovudine.
Treatment of HIV infection, as part of combination therapy.
Treatment of HIV infection in pregnant women to reduce the rate 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 should only be used before 14 weeks of gestation 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, followed by its appointment in newborns, leads to a decrease in the frequency of vertical transmission of HIV. Long-term effects of the use of Retrovir in children who received it in utero 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 ongoing therapy.
Lactation
Women should not breastfeed while taking Retrovir.
Influence on childbearing function
There is no data on the effect of Retrovir on the reproductive function of women. In men, taking Retrovir does not affect the composition of sperm, 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, has been used in clinical trials. The 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 efficacy of doses in the range below 720 mg/m2/day (about 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 kidney function and possible changes in peripheral blood parameters, in such patients, special care must be taken when prescribing Retrovir and appropriate monitoring should be carried out before and during treatment with Retrovir.
Patients with impaired renal function
In severe renal impairment, the recommended dose of Retrovir is 300-400 mg per day. Depending on the reaction from the peripheral blood and the clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis do not significantly affect the excretion of zidovudine, but accelerate the elimination of zidovudine 5'-glucuronide.
For patients with end-stage renal disease on hemodialysis or peritoneal dialysis, the recommended dose of Retrovir is 100 mg every 6 to 8 hours.
Patients with impaired liver function
Data obtained in patients with cirrhosis of the liver indicate that in patients with hepatic insufficiency, zidovudine may accumulate due to a decrease in glucuronidation, and therefore, dose adjustment may be required. If monitoring of plasma concentrations of zidovudine 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 dosing regimen - dose reduction or withdrawal of Retrovir may be required in patients with adverse reactions from the hematopoietic system, in case 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 HIV transmission from mother to fetus
The following 2 prophylaxis regimens for pregnant women have been shown to be effective:
Pregnant women, starting from 14 weeks of pregnancy, it is 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, it is recommended to prescribe Retrovir at a dose of 600 mg / day (300 mg twice a day) orally until the onset of labor. Then every 3 hours, 300 mg of Retrovir orally from the onset of labor until delivery
Newborns are shown the appointment of Retrovir at a dose of 2 mg / kg of 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 a solution of Retrovir by mouth should be given Retrovir intravenously.
Adverse reactions that occur during treatment with Retrovir are the same in children and adults.
On the part of the hematopoiesis and lymphatic system: often - anemia (which may require blood transfusions), neutropenia and leukopenia. The incidence of neutropenia increases in patients who have experienced a decrease in the number of neutrophils, hemoglobin and vitamin B12 in 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 side of 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 side of 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 side of the liver, biliary tract and pancreas: often - an increase in the level of bilirubin and the activity of liver enzymes; rarely - liver dysfunction, such as severe hepatomegaly with steatosis; pancreatitis.
From the skin and its appendages: sometimes - rash, pruritus; 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 at recommended doses. In children, there is a decrease in hemoglobin, which, however, does not require blood transfusions. Anemia disappears 6 weeks after completion of therapy with Retrovir.
Symptoms
There may be a feeling of fatigue, headache, vomiting; very rarely - changes in blood counts. There is one report of an overdose of an unknown amount of zidovudine, when the concentration of zidovudine in the blood exceeded 16 times the usual therapeutic concentration, however, there were no clinical, biochemical or hematological symptoms. At the maximum dose of 7.5 mg/kg body weight by infusion 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 therapy. Hemodialysis and peritoneal dialysis are not highly effective for removing zidovudine from the body, but increase the excretion of its metabolite, 5'-zidovudine glucuronide.
Zidovudine is predominantly excreted as an inactive metabolite, which is a glucuronide conjugate formed in the liver. Drugs that have a similar route of elimination have the potential to inhibit the metabolism of zidovudine.
Atovaquone: Zidovudine does not affect the pharmacokinetic parameters of atovaquone. Atovaquone slows down the transformation of zidovudine into a glucuronide derivative (azidovudine AUC at steady state increases by 33% and peak glucuronide concentrations decrease by 19%). The safety profile of zidovudine at doses of zidovudine 500 or 600 mg/day is unlikely to change when co-administered with atovaquone for three weeks. If more prolonged 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 does not affect the pharmacokinetics of lamivudine.
Phenytoin: with the 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 intracellular phosphorylation of stavudine. Therefore, it is not recommended to co-administer stavudine 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 hepatic microsomal metabolism. 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 therapy, with potentially nephrotoxic and myelotoxic drugs (eg, pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of adverse reactions to Retrovir. It is necessary to monitor kidney function and blood count; if necessary, reduce the dose of drugs.
Because some patients may develop opportunistic infections despite therapy with Retrovir, prophylactic antimicrobial therapy should be considered. Such prophylaxis includes cotrimoxazole, pentamidine B aerosol, pyrimethamine AND acyclovir. Limited data obtained during clinical trials did not reveal a significant increase in the risk of adverse reactions when using Retrovir together with these drugs.
Treatment with Retrovir should be carried out by a physician experienced in the treatment of HIV-infected patients.
Patients should be informed of the dangers of concomitant 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 security 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 fluids), it is urgent to 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. Preventive treatment is recommended for 4 weeks. Despite rapid initiation of antiretroviral treatment, seroconversion cannot be ruled out.
Symptoms that are mistaken for adverse reactions of therapy with Retrovir may be a manifestation of the underlying disease or a reaction to taking other drugs used to treat HIV infection. The relationship between the developed symptoms and the action of Retrovir is often very difficult to establish, especially with a detailed clinical picture of HIV infection. In such cases, it is possible to reduce the dose of the drug or cancel it.
Retrovir does not cure HIV infection, and patients remain at risk of developing a full picture of the disease with immune suppression and the occurrence of opportunistic infections and malignancies. In AIDS, Retrovir reduces the risk of developing opportunistic infections, but does not reduce the risk of developing lymphomas.
Undesirable reactions from the hematopoietic system
Anemia (usually observed after 6 weeks from the start of treatment with Retrovir, but sometimes may develop earlier), neutropenia (usually occurs after 4 weeks from the start of treatment with Retrovir, but sometimes occurs earlier), leukopenia may occur in patients with a developed clinical picture of HIV infection receiving Retrovir, especially at high doses (eg, 1200 mg-1500 mg/day in clinical trials), and those with reduced bone marrow hematopoiesis prior to 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 the bone marrow hematopoiesis is still within the normal range), adverse 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 the blood counts are restored; or Retrovir is canceled for 2-4 weeks until the restoration of blood counts. Usually, the blood picture returns to normal after 2 weeks, after which Retrovir in a reduced dose can be re-appointed. Despite the dose reduction of Retrovir, with severe anemia, blood transfusions may be required.
Lactic acidosis and severe hepatomegaly with steatosis
These complications can be fatal both with Retrovir monotherapy and with the use of Retrovir as part of multicomponent therapy. Clinical signs of these complications may include weakness, anorexia, sudden weight loss, gastrointestinal symptoms, and respiratory symptoms (dyspnea 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 evidence of lactic acidosis or hepatotoxicity (which may include hepatomegaly with steatosis even in the absence of transaminase elevations).
Redistribution of subcutaneous fat
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, an increase in serum lipids and blood sugar were noted as in the complex, and alone 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 referred to as lipodystrophy. However, data show 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.
The clinical examination should include a 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 according to clinical indications.
In HIV-infected patients with severe immunodeficiency at the time of initiation of antiretroviral therapy (APT), an exacerbation of the inflammatory process against the background of an asymptomatic or residual opportunistic infection is possible, which can cause a serious worsening of the condition or worsening of symptoms. Usually such reactions were described in the first weeks or months of the beginning of 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 treated when needed.
Co-infection with HIV and viral hepatitis C
An 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.
EFFECT ON ABILITY TO DRIVE/ OTHER MECHANISMS
The effect of Retrovir on the ability to drive a car / use machines has not been studied. However, an adverse effect on these abilities is unlikely based on the pharmacokinetics of the drug. However, when deciding whether to drive a car / mechanisms, 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 with a plastic cap
opening control device. One bottle, together with a plastic dosing syringe, an adapter and instructions for use, is placed in a cardboard box.
At a temperature not higher than 30 °C. Keep out of the reach of children.
Do not use after the expiry date stated on the packaging.
By prescription.
Self-medication can be harmful to your health. It is necessary to consult a doctor and 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 activity of the liver 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 sensory organs: macular edema, amblyopia, photophobia, vertigo, hearing loss.
From the respiratory system: shortness of breath, cough, rhinitis, sinusitis.
From the side of 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 syndrome of various localization, chills, development of a secondary infection, redistribution of adipose tissue.
www.vidal.ru
Retrovir for infusions - official instructions for use
REGISTRATION NUMBER: P No. 014790/01.
Trade name of the drug: Retrovir
International non-proprietary name:
zidovudine.Dosage form:
solution for infusionDescription: transparent or slightly opalescent, colorless or light yellow solution, practically free from mechanical impurities.
Notes:
- 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 highly active in vitro against retroviruses, including human immunodeficiency virus (HIV).
The process of phosphorylation of zidovudine is carried out in both infected and uninfected cells of the human body with the formation of 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 about 100 times stronger than for the a-polymerase of human cellular DNA. Zidovudine acts additively or synergistically with a large number of antiretroviral drugs such as lamivudine, didanosine, and interferon-alpha to inhibit 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 analogs as a result of combined mutations at codons 41 and 215 or through the accumulation of at least 4 of 6 mutations. These thymidine analog resistance mutations (MPATs) do not cause cross-resistance to any other nucleoside reverse transcriptase inhibitors (NRTIs), allowing other NRTIs to be used 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 the HIV reverse transcriptase, in the second case, we are talking about T69S mutations with the insertion of 6 pairs of nitrogenous bases 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.
Decreased sensitivity to zidovudine has been observed with long-term treatment of HIV infection with this drug. At present, the relationship between sensitivity to in vitro zidovudine 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 Plasma protein binding of zidovudine 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 determined in the amniotic fluid and in the blood of the fetus. Zidovudine is also found in semen and breast milk.
The metabolism of zidovudine 5'-glucuronide is the main metabolite of zidovudine, is determined both in plasma and in the urine and is approximately 50-80% of the dose of the drug, which is excreted by the kidneys.
3'amino-3'-deoxythymidine (AMT) is a metabolite of zidovudine, which is formed when the drug is administered intravenously.
Elimination The renal clearance of zidovudine is much greater than that of creatinine, indicating significant elimination of zidovudine by tubular secretion.
Special patient groups
Children In children over the age of 5-6 months, 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 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 dose of the drug is excreted through the kidneys unchanged, 45% of the dose is in the form of glucuronide.
Patients with impaired renal function In patients with severe renal insufficiency, the maximum plasma concentration of zidovudine is increased by 50% compared with that in patients without impaired renal function. The systemic exposure of zidovudine (defined as the area under the concentration-time pharmacokinetic curve, AUC) is increased by 100%; the half-life of the drug does not change significantly. In case of impaired renal function, a significant cumulation of the main metabolite of zidovudine, glucuronide, is observed, however, signs of toxic action are not 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 liver failure, zidovudine accumulation may occur due to a decrease in glucuronidation, which requires dose adjustment.
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 with the parameters in non-pregnant women, there are no signs of cumulation of zidovudine.
The plasma concentration of zidovudine in children at birth is the same as that of their mothers during childbirth.
Indications
- Severe manifestations of HIV infection in patients with AIDS when oral administration of Retrovir is not possible.
- HIV infection in pregnant women from the 14th week of gestation and their newborns to reduce the incidence of vertical transmission of HIV.
Contraindications
- Hypersensitivity to zidovudine or any other component of the drug;
- Neutropenia (neutrophil count less than 0.75 x 10 9 / l);
- Decreased hemoglobin content (less than 75 g/l or 4.65 mmol/l).
Use during pregnancy and lactation
Fertility There are no data on the effect of Retrovir on female fertility. In men, taking Retrovir does not affect the composition of sperm, morphology and sperm motility.
Pregnancy Zidovudine crosses the placenta. Before the 14th week of gestation, Retrovir can only be used if the potential benefit to the mother outweighs the risk to the fetus.
There are reports of slight, transient increases in serum lactate concentrations, which may be due to mitochondrial dysfunction in neonates and infants exposed to intrauterine or perinatal exposure to nucleoside reverse transcriptase inhibitors. The clinical significance of a transient increase in serum lactate concentration is unknown. There are very rare reports of developmental delay, seizures, and other neurological disorders such as muscle spasticity. However, a causal 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 mother-to-fetal transmission of HIV The use of Retrovir after 14 weeks of gestation followed by its administration to newborns leads to a decrease in the frequency of transmission of HIV from mother to fetus (infection rate with placebo - 23% compared with the frequency with zidovudine - 8%).
The long-term effects of the use of Retrovir in children who received it in utero 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 to formulate clear recommendations on the dosing regimen of the drug, with oppression of bone marrow hematopoiesis, vitamin B12 and folic acid deficiency, liver failure.
Dosing and Administration Retrovir, solution for infusion, should be administered diluted by slow intravenous infusion over one hour.
The drug must NOT be administered intramuscularly.
The drug Retrovir, solution for infusion, should be used only until patients can 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 5°C to 25°C.
Since there is no antimicrobial preservative in the preparation Retrovir, solution for infusion, 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. /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 malignancy 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, which is 240–320 mg/m2 per day for 3–4 injections, is comparable to the recommended dose of 360 mg/m2 to 480 mg/m2 per day for 3–4 oral administrations. However, at present there are no data on the effectiveness of the use of Retrovir solution for intravenous administration at such low doses.
Children under the age of 3 months Caution is advised when prescribing the infusion dosage form to patients under the age of 3 months, as limited data do not allow the formulation of clear recommendations on the dosing regimen of the drug.
Prevention of mother-to-fetal transmission of HIV infection Two dosing regimens of Retrovir have been proven effective:
1. Pregnant women, starting from a period of 14 weeks, it is 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 childbirth and delivery, it is necessary to use the drug Retrovir, solution for infusion, intravenously at a dose of 2 mg / kg for an hour, followed by a continuous intravenous infusion at a dose of 1 mg / kg / h until the umbilical cord is clamped.
Neonates should then be given Retrovir oral solution at a dose of 2 mg/kg every 6 hours starting no later than 12 hours after birth until 6 weeks of age. Children who are unable to take oral forms should receive the drug Retrovir, solution for infusion, intravenously at a dose of 1.5 mg/kg of 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 moment of onset of labor until delivery.
Patients with impaired renal function In severe 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 by mouth for patients in this group. Depending on the reaction from the peripheral blood and the clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis do not significantly affect the elimination of zidovudine, but accelerate the elimination of the glucuronide metabolite.
For patients with end-stage renal disease on hemodialysis or peritoneal dialysis, the recommended dose of Retrovir is 100 mg every 6 to 8 hours.
Patients with impaired liver function Data obtained in patients with cirrhosis of the liver indicate that in patients with hepatic insufficiency, zidovudine may accumulate due to reduced glucuronidation, and therefore dose adjustment may be required. If monitoring of plasma concentrations of zidovudine is not possible, then 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 injections of the drug.
Dose adjustment for adverse reactions from the hematopoietic system Adequate correction of the dosing regimen - dose reduction or withdrawal of Retrovir may be required in patients in the event of adverse reactions from the hematopoietic system, in the event of a decrease in hemoglobin levels 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 the age of 65 years has not been studied. However, given the age-related decline in kidney function and possible changes in peripheral blood parameters, in such patients, special care must be taken when prescribing Retrovir and appropriate monitoring should be carried out before and during treatment with Retrovir.
Side effects Undesirable reactions that occur during treatment with Retrovir are the same in children and adults.
To assess the frequency of occurrence of adverse reactions, the following gradations were used: very often (> 1/10), often (> 1/100, 1/1000, 1/10000, On the part of the hematopoietic system: often - anemia (which may require blood transfusions), neutropenia and leukopenia have developed with high doses of Retrovir (eg, 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 in the number of CD4 lymphocytes below 100 cells / mm3.In these cases, it may be necessary to reduce the dose of Retrovir or cancel it.The incidence of neutropenia increases in patients who have experienced a decrease in the number of neutrophils, hemoglobin and vitamin B12 in 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 side of 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 side of 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 side of the liver and pancreas: often - an increase in the level of bilirubin and the activity of liver enzymes; rarely - severe hepatomegaly with steatosis; pancreatitis.
On the part of the skin and its appendages: sometimes - skin rash (except for urticaria), pruritus; 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 a solution of Retrovir for intravenous administration over 2 weeks up to 12 weeks. The most common adverse 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 at recommended doses. In children, there is a decrease in hemoglobin, which, however, does not require blood transfusions. Anemia disappears after 6 weeks, after completion of therapy with Retrovir.
Overdose
Symptoms Feeling tired, headache, vomiting; very rarely - changes in blood counts. There is one report of an overdose of an unknown amount of zidovudine, when the concentration of zidovudine in the blood exceeded 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 by infusion 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 increase the excretion of its glucuronide metabolite.
Interaction with other medicinal products and other forms of interaction Zidovudine is mainly excreted as an inactive metabolite, which is a glucuronide conjugate formed in the liver. Drugs that have a similar route of elimination have the potential to inhibit the metabolism of zidovudine.
Zidovudine is used in combination antiretroviral therapy 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 simultaneously with lamivudine, however, the total exposure (AUC) does not change. Zidovudine does not affect the pharmacokinetics of lamivudine.
Phenytoin: with the 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.
Atovachone: Zidovudine does not affect the pharmacokinetic parameters of atovachone. Atovachone slows down the transformation of zidovudine into a glucuronide derivative (azidovudine AUC at steady state increases by 33% and maximum glucuronide concentrations decrease by 19%). It is unlikely that the safety profile of zidovudine will change at doses of zidovudine 500 or 600 mg/day when co-administered with atovachone for three weeks. If more prolonged combined use of these drugs is necessary, careful monitoring of the patient's clinical condition is recommended.
Clarithromycin: Decreases the absorption of zidovudine. The interval between dosing should be at least 2 hours.
Ribavirin: The nucleoside analog ribavirin is a zidovudine antagonist and combinations should be avoided.
Rifampicin: The combination of Retrovir with rifampicin results in a 48% ± 34% reduction in AUC for zidovudine, but the clinical significance of this change is not known.
Stavudine: Zidovudine may inhibit intracellular phosphorylation of stavudine.
Valproic acid, fluconazole, 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 zidovudine metabolism by competitive inhibition of glucuronidation or direct suppression of hepatic microsomal metabolism. 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 therapy, with potentially nephrotoxic and myelotoxic drugs (eg, pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of adverse reactions to Retrovir. It is necessary to monitor kidney function and blood count; if necessary, reduce the dose of drugs.
Cautions Treatment with Retrovir should be carried out by a physician experienced in the management of HIV-infected patients.
Patients should be informed about the dangers of concomitant 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 security 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 fluids), it is urgent 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. Preventive treatment is recommended for 4 weeks. Despite rapid initiation of antiretroviral treatment, seroconversion cannot be ruled out.
Symptoms that are mistaken for adverse reactions to Retrovir may be a manifestation of the underlying disease or a reaction to taking other drugs used to treat HIV infection. The relationship between the developed symptoms and the action of Retrovir is often very difficult to establish, especially with a detailed clinical picture of HIV infection. In such cases, it is possible to reduce the dose of the drug or cancel it.
Retrovir does not cure HIV infection and patients remain at risk of developing a full-blown disease pattern with immune suppression and the occurrence of opportunistic infections and malignancies. In 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 ongoing therapy.
Use in children under the age of 3 months limited data do not allow the formulation of clear recommendations on the dosing regimen of the drug.
Adverse reactions from the hematopoietic system Anemia (usually observed after 6 weeks from the start of the use of Retrovir, but sometimes may develop earlier), neutropenia (usually develops after 4 weeks from the start of treatment with Retrovir, but sometimes occurs earlier), leukopenia (usually secondary due to neutropenia ) may occur in patients with advanced clinical picture of HIV infection receiving Retrovir, especially in high doses (1200 mg-1500 mg/day), and with reduced bone marrow hematopoiesis prior to 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 the bone marrow hematopoiesis is still within the normal range), adverse reactions from the blood develop rarely, 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 the blood counts are restored; or Retrovir is canceled for 2-4 weeks until the restoration of blood counts. Usually, the blood picture returns to normal after 2 weeks, after which Retrovir in a reduced dose can be re-appointed. Despite the dose reduction of Retrovir, with severe anemia, blood transfusions may be required.
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, sudden weight loss, gastrointestinal symptoms, and respiratory symptoms (dyspnea and tachypnea). Warning about the risk of such conditions should be made with each appointment of zidovudine, 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 evidence of lactic acidosis or liver toxicity.
Redistribution of subcutaneous fat Redistribution/accumulation of subcutaneous fat, including general obesity, increased fat layer in the back of the neck (“buffalo hump”), loss of fat layer on the periphery, on the face, gynecomastia, increased serum lipids and blood glucose were noted both in combination and separately in some patients receiving combined antiretroviral therapy.
Although until now it was believed that all drugs from the class of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were associated with one or more specific adverse events associated with a common syndrome often referred to as lipodystrophy, new data demonstrate that there is a difference in the risk of developing this syndrome between specific representatives of therapeutic classes.
In addition, lipodystrophy syndrome has a multifactorial etiology; for example, factors such as stage of HIV infection, advanced age of the patient, and duration of antiretroviral therapy play an important, possibly potentiating, role.
The long-term consequences of these events are currently unknown.
The clinical examination should include a 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 according to clinical indications.
immune reconstitution syndrome
In HIV-infected patients with severe immunodeficiency at the time of initiation of antiretroviral therapy (APT), an exacerbation of the inflammatory process against the background of an asymptomatic or indolent opportunistic infection is possible, which can cause a serious worsening of the condition or worsening of symptoms. Usually such reactions were described in the first weeks or months of the beginning of 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 treated when needed.
Radiation therapy enhances the myelosuppressive effect of zidovudine.
Influence on the ability to drive a car / mechanisms The effect of Retrovir on the ability to drive a car / mechanisms has not been studied. However, an adverse effect on these abilities is unlikely based on the pharmacokinetics of the drug. However, when deciding whether to drive a car / mechanisms, one 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; reduction in the frequency of transplacental transmission of HIV from mother to fetus.
solution for infusions 200 mg/20 ml; bottle (bottle) 20 ml, box (box) 5;
The average T1 / 2, the average total clearance and volume of distribution are 1.1 h, 27.1 ml / min / kg and 1.6 l / kg, respectively. The renal clearance of zidovudine is much greater than that of creatinine, indicating its predominant elimination by tubular secretion. Zidovudine 5"-glucuronide is the main metabolite, is determined both in plasma and in urine, and makes up approximately 50-80% of the dose of the drug, which is excreted through the kidneys. When the drug is administered intravenously, the metabolite 3" amino-3 "-deoxytidimine is formed. children over the age of 5-6 months, pharmacokinetic parameters are similar to those in adults.When taken orally, it is well absorbed from the intestine, bioavailability is 60-74% (mean - 65%).After ingestion of a solution of Retrovir at a dose of 120 mg / m2 of surface body and 180 mg / m2, the level of the average equilibrium maximum concentration is 4.45 and 7.7 μM (or 1.19 and 2.06 μg / ml).After an IV infusion at a dose of 80 mg / m2, 120 mg / m2 and 160 mg / m2, it is 1.46, 2.26 and 2.96 μg / ml, respectively. The average T1 / 2 and total clearance are 1.5 h and 30.9 ml / min / kg, respectively. The main metabolite is 5 - a glucuronide. After intravenous administration, 29% of the dose of the drug 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, a decrease in clearance and a prolongation of T1 / 2. After 2-4 hours after oral administration in adults, no glucuronidation of zidovudine with a subsequent increase in its average ratio of zidovudine concentration in the cerebrospinal fluid and in plasma is 0.5, and in children after 0.5-4 hours - 0.52-0.85 . In pregnant women, there are no signs of accumulation of zidovudine, and its pharmacokinetics are similar to those in non-pregnant women. Zidovudine passes through the placenta and is determined in the amniotic fluid and in the blood of the fetus. 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). The binding of the drug to plasma proteins is 34-38%. In patients with severe renal insufficiency, Cmax of zidovudine in plasma is increased by 50% compared with its concentration in patients without impaired renal function. The systemic exposure of the drug (defined as the area under the concentration-time curve) is increased by 100%; T1 / 2 is significantly impaired. In renal failure, there is a significant accumulation of the main glucuronide metabolite, but no signs of toxic effects are observed. Hemo- and peritoneal dialysis do not affect the elimination of zidovudine, while the excretion of glucuronide increases.
With liver failure, zidovudine accumulation may occur due to a decrease in glucuronidation (requires dose adjustment).
Earlier than 14 weeks of pregnancy, the use is possible only if the expected effect of therapy outweighs the potential risk to the fetus. At the time of treatment should stop breastfeeding.
Hypersensitivity to the components of the drug, neutropenia (the number of neutrophils is less than 0.75 109 / l); decrease in 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 side of 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-
Instructions for medical use
medicinal product
Retrovir ®
Tradename
Retrovir ®
International non-proprietary name
Zidovudine
Dosage form
Oral solution 10 mg/ml, 200 ml
Compound
5 ml of solution contain
active substance- zidovudine 50 mg,
Excipients: hydrogenated glucose syrup, glycerin, anhydrous citric acid 1, sodium benzoate, sodium saccharin, strawberry flavor, white sugar flavor, purified water.
1 - instead of anhydrous citric acid, citric acid monohydrate can be used
Description
Clear, pale yellow solution with a characteristic strawberry odour.
Farmacotherapeutic group
Antiviral drugs for systemic use. Nucleosides are reverse transcriptase inhibitors. Zidovudine.
ATX code J05AF01
Pharmacological properties
Pharmacokinetics
Pharmacokinetics in adults
Suction
Zidovudine is well absorbed from the intestine. Bioavailability is 60-70%. The average equilibrium maximum C ss max and C ss min after ingestion of a solution of zidovudine 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.
Zidovudine is phosphorylated in virus-affected and non-viral cells to monophosphate (MP) derivatives by cellular thymidine kinase.
Distribution
After 2-4 hours after oral administration in adults, the average ratio of the concentration of zidovudine in the cerebrospinal fluid and in the blood plasma is 0.5, and in children after 0.5-4 hours this figure is 0.52-0.85. Zidovudine crosses the placenta and is determined in the amniotic fluid and in the blood of the fetus. Zidovudine has also been found in semen and breast milk. The binding of the drug to plasma proteins is 34-38%, respectively, competitive binding with other drugs by the mechanism of substitution is not expected.
Metabolism
5"-glucuronide is the main metabolite of zidovudine, is determined both in plasma and in the urine and accounts for approximately 50-80% of the dose of the drug, which is excreted through the kidneys.
breeding
The mean half-life, 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 that of creatinine, indicating its predominant elimination by tubular secretion.
Pharmacokinetics in children
In children over the age of 5-6 months, pharmacokinetic parameters are similar to those in adults.
Zidovudine is well absorbed from the intestine, bioavailability is 60-74% with an average value of 65%.
After ingestion of a solution of zidovudine at a dose of 120 mg / m 2 of body surface and 180 mg / m 2, the Css max level is 1.19 μg / ml (4.45 μM) and 2.06 μg / ml (7.7 μM), respectively.
The main metabolite is 5 "-glucuronide. The renal clearance of zidovudine is much higher than the clearance of creatinine, which indicates its significant excretion by tubular secretion. In newborns under the age of 14 days of life, a decrease in zidovudine glucuronization is observed, followed by an increase in its bioavailability, a decrease in clearance and a prolongation of the period half-life In children older than 14 days of life, the pharmacokinetics of zidovudine are similar to those in adults.
Elderly
No pharmacokinetic studies have been conducted in patients over 65 years of age.
Impaired kidney function
In patients with severe renal insufficiency, the maximum plasma concentration of zidovudine is increased by 50% compared with its concentration in patients without impaired renal function. The systemic exposure of the drug (defined as the area under the concentration-time curve) is increased by 100%, the half-life of the drug does not change significantly. In renal failure, a significant accumulation of the main glucuronide metabolite is observed, but no signs of toxic action are detected. Hemodialysis and peritoneal dialysis do not affect the elimination of zidovudine, while the excretion of glucuronide increases.
Impaired liver function
In hepatic insufficiency, zidovudine accumulation may occur due to a decrease in its glucuronidation, which may require dose adjustment of the drug, but due to limited data, there are no specific recommendations for this category of patients.
Pregnant women
There are data on the pharmacokinetics of zidovudine in women in the last trimester of pregnancy. With the progression of pregnancy, no accumulation effect of zidovudine was observed. The pharmacokinetics of zidovudine were identical to those in non-pregnant women. Due to the passive mechanism of passage of zidovudine through the placenta, its concentration in fetal plasma was identical to that in maternal plasma.
Pharmacodynamics
Retrovir ® - an antiviral drug highly active against retroviruses, including the human immunodeficiency virus (HIV).
Further phosphorylation of zidovudine monophosphate to zidovudine di- and triphosphate (TF) is catalyzed by cellular thymidine kinase and nonspecific kinases, respectively.
Zidovudine triphosphate (TF) acts as an inhibitor and substrate for viral reverse transcriptase. The formation of viral 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 α-polymerase. Retrovir ® does not antagonize other antiviral drugs (lamivudine, didanosine, interferon-alpha, abacavir).
Post-exposure prophylaxis of HIV
International guidelines for the prevention of HIV transmission following accidental exposure to HIV-infected blood, such as a needle stick, recommend starting combination therapy with zidovudine and lamivudine (Epivir™) within 1 to 2 hours of exposure. In case of a higher risk of infection, protease inhibitors should be included in the treatment regimen. It is recommended to continue antiretroviral prophylaxis for four weeks. Controlled clinical studies to support these recommendations are limited. Seroconversion may occur despite appropriate antiretroviral treatment.
Indications for use
Treatment of HIV infection as part of combination antiretroviral therapy in children and adults
Reducing the rate of transplacental transmission of HIV from HIV-positive pregnant women to the fetus
Dosage and administration
Treatment with Retrovir ® should be performed by a physician experienced in the management of HIV-infected patients.
Adults and adolescents weighing over 30 kg
Children weighing 9 kg to 30 kg
Children weighing 4 kg to 9 kg
Prevention of mother-to-child transmission of HIV fetus
2 schemes of prevention are effective.
1. Pregnant women, starting from 14 weeks of pregnancy, it is recommended to prescribe the drug Retrovir ® inside before the onset of labor at a dose of 500 mg / day (100 mg 5 times a day). During childbirth, the drug Retrovir ® is administered intravenously at a dose of 2 mg/kg of body weight for 1 hour, then it is necessary to continue the intravenous infusion at a dose of 1 mg/kg/hour until the clamp is applied to the umbilical cord. Newborns are prescribed Retrovir® orally as a solution in the first 12 hours after birth up to 6 weeks at a rate of 2 mg / kg every 6 hours.
An appropriate size dosing syringe must be used to accurately determine the dose. If newborns cannot receive Retrovir ® inside, they need to prescribe Retrovir ® as a 30-minute intravenous infusion at a dose of 1.5 mg/kg of body weight every 6 hours.
Instructions for use
Use the dosing syringe included in the package for more accurate dosing.
- Open the vial and put the cap aside
- Attach the plastic adapter to the neck of the vial, holding the vial firmly.
- Firmly insert the dosing syringe into the adapter
- Flip the vial
- Pull back the plunger of the syringe and draw up the first part of your recommended dose
- Invert the vial and remove the syringe from the adapter
- Enter the entire amount of the drug into the oral cavity directly from the syringe towards the inner surface of the cheek, slowly moving the syringe plunger to its base. This manipulation will allow you to swallow the solution without causing difficulty in swallowing. Do not press the plunger too hard and do not inject the drug too quickly towards the back of the throat, as this can lead to a cough reflex.
- Repeat steps 3-7 until the entire recommended dose has been taken
- Do not leave the syringe in the vial. Remove the adapter and syringe from the vial and rinse thoroughly with clean water. Make sure the syringe and adapter are dry before using them again.
- Close the bottle carefully
kidney failure
In severe renal failure, the recommended dose of the drug is 300-400 mg per day. Depending on the reaction from the peripheral blood and the clinical effect, further dose adjustment may be required. Hemodialysis and peritoneal dialysis do not affect the elimination of zidovudine, while the excretion of glucuronide increases. For patients with end-stage renal disease who are on hemodialysis or peritoneal dialysis, the recommended dose of Retrovir is ® is 100 mg every 6-8 hours.
Liver failure
Data obtained in patients with cirrhosis of the liver suggest a possible accumulation of zidovudine due to a decrease in glucuronidation, which may require dose adjustment of the drug, but due to limited data, there are no specific recommendations for this category of patients. If control of plasma levels of zidovudine is not possible, then 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.
Adverse reactions from the hematopoietic organs
Change in dosing or discontinuation of the drug Retrovir ® may be required in patients with adverse reactions from the hematopoietic organs, in which the hemoglobin content decreases to 7.5-9.0 g / dl (4.65-5.59 mmol / l) or the number of neutrophils decreases to 0.75-1.0 x 10 9 / 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, special care must be taken when prescribing Retrovir. ® and to carry out appropriate monitoring before and during treatment with the drug.
Side effects
The side effect profile is similar in adults and children.
Very often (>1/10), often (>1/100,<1/10), нечасто (>1/1,000, <1/100), редко (>1/10,000, <1/1,000), очень редко (<1/10,000).
Often
Headache
Nausea
Often
Anemia (may require blood transfusions), neuropenia and leukopenia; these conditions develop with the use of high doses of Retrovir ® (1200-1500 mg / day) and in patients with severe HIV infection (especially in patients with reduced bone marrow reserve before treatment), mainly with a decrease in the number of CD 4 cells below 100 / mm 3; in these cases, it may be necessary to reduce the dose of Retrovir ® or its cancellation; the incidence of neuropenia increases in patients who have experienced a decrease in the number of neutrophils, hemoglobin and vitamin B 12 in serum at the beginning of treatment
Hyperlactatemia
Dizziness, malaise
Vomiting, abdominal pain, diarrhea
Increased levels of bilirubin and liver enzymes
Myalgia
Infrequently
Thrombocytopenia and pancytopenia (with bone marrow hypoplasia)
Flatulence
Skin rash, pruritus
Myopathies
Fever, pain syndrome, asthenia
Rarely
Aplasia of the red germ
lactic acidosis
Anorexia
Redistribution/accumulation of body fat (has a multifactorial etiology, in particular, the use of combination therapy with antiretroviral drugs)
Insomnia, paresthesia, drowsiness, reduced speed of thinking,
convulsions
cardiomyopathy
Pigmentation of the oral mucosa, taste disturbance, dyspepsia,
pancreatitis
Severe hepatomegaly with steatosis
Pigmentation of nails and skin, hives and increased sweating
Frequent urination
Gynecomastia
Chills, chest pain, flu-like symptoms
Anxiety, depression
Rarely
aplastic anemia
After several weeks of therapy, the incidence of nausea and other
most common adverse reactions to Retrovir ® decreases.
Adverse reactions that occur when using Retrovir ® to prevent transmission of HIV infection from mother tofetus
In children, a decrease in hemoglobin content was observed, which, however, did not
requires blood transfusions. Anemia disappears within 6 weeks after completion of therapy with Retrovir ® . Long-term consequences of the use of the drug Retrovir ® in utero and in neonates are unknown.
Contraindications
Hypersensitivity to zidovudine or any other component of the drug
Neutropenia (neutrophil count less than 0.75 x 10 9 / l)
Decreased hemoglobin (less than 7.5 g/dL or 4.65 mmol/L)
Children under 3 months of age and body weight less than 4 kg
lactation period
Caution: liver failure
Drug Interactions
Since zidovudine is eliminated predominantly via hepatic metabolism as an inactive metabolite, drugs with a similar mechanism of action (glucuronidation) may potentially inhibit the metabolism of Retrovir.
The list of interactions listed below should not be considered exhaustive, however, they are typical for drugs that require careful use together with zidovudine.
Atovaquone: zidovudine does not interfere with the pharmacokinetics of atovaquone. However, pharmacokinetic data show that atovaquone reduces the rate of metabolism of zidovudine to its 5-glucuronide metabolite (AUC increased by 33% when target zidovudine concentrations were reached, peak plasma glucuronide concentration decreased by 19%). When using zidovudine at a dose of 500 or 600 mg /day It is unlikely that three weeks of simultaneous treatment with atovaquone for the treatment of acute pneumocystis pneumonia can lead to an increase in the frequency of adverse reactions associated with elevated plasma concentrations of zidovudine.Increased caution should be exercised against the background of long-term therapy with atovaquone.
Clarithromycin: clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by taking zidovudine and clarithromycin separately at least two hours apart.
Lamivudine: there is a moderate increase in Cmax (28%) for zidovudine when administered together with lamivudine, however, the total exposure (AUC) is not disturbed. Zidovudine does not affect the pharmacokinetics of lamivudine.
Phenytoin: reduces the concentration of phenytoin in the blood (there was a single case of an increase in the concentration of phenytoin), which requires monitoring the level of phenytoin in the blood while prescribing it with Retrovir ® .
Probenicid: reduces glucuronidation and increases the mean half-life and AUC of zidovudine. Renal excretion of glucuronide and zidovudine itself is reduced in the presence of probenecid.
Rifampicin: combination with rifampicin results in a decrease in AUC for
zidovudine by 48% ± 34%, however, the clinical significance of this change is unknown.
Stavudin: zidovudine may inhibit intracellular phosphorylation
Stavudin, and therefore the combined use of drugs is not recommended.
Other: drugs such as aspirin, codeine, methadone, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, isoprinosine can interfere with the metabolism of zidovudine by competitive inhibition of glucuronidation or direct suppression of hepatic microsomal metabolism. To the possibility of using these drugs in combination with Retrovir ® , especially for long-term therapy, should be approached with caution.
Retrovir combination ® , especially in the treatment of acute conditions, with potentially nephrotoxic and myelotoxic drugs (eg, pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of adverse reactions to Retrovir ® . It is necessary to monitor kidney function and blood counts and reduce the dose of drugs, if necessary.
Treatment of opportunistic infections with co-trimoxazole, aerosol pentamidine, pyrimethamine and acyclovir is not associated with a significant risk of an increase in the incidence of adverse reactions to Retrovir ® .
resistance
The development of resistance to thymidine analogues (zidovudine is one of them) occurs as a result of the gradual appearance of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of the HIV reverse transcriptase. Viruses acquire phenotypic resistance to thymidine analogs as a result of a combination of mutations at codons 41 and 215 or the accumulation of at least 4 of 6 mutations. Mutations do not cause cross-resistance to other nucleosides, which allows the use of other reverse transcriptase inhibitors for the treatment of HIV infection.
Two types of mutations lead to the development of multiple drug resistance.
In one case, mutations occur at codons 62, 75, 77,116 and 151 of the HIV reverse transcriptase, and 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. Decreased sensitivity to zidovudine has been observed with long-term treatment of HIV infection with Retrovir ® . Available data indicate that in the early stages of HIV infection, the frequency and degree of desensitization in vitro significantly less than in the later stages of the disease.
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 with other nucleoside reverse transcriptase inhibitors and drugs from other groups (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).
special instructions
Patients should be informed about the dangers of the simultaneous use of the drug Retrovir. ® with other drugs without notifying the attending physician and that the use of the drug Retrovir ® does not prevent HIV transmission through sexual contact or through contaminated blood. Appropriate security measures are required.
Retrovir ® does not cure HIV infection, and patients remain at risk of developing an extensive immune-suppressed disease pattern, including opportunistic infections and malignancies. The drug has been shown to reduce the risk of developing opportunistic infections, however, data on the occurrence of neoplasms, including lymphomas, are limited. Available data from patients treated in advanced HIV infection show that the risk of developing lymphoma is similar to that of untreated patients. In patients with early stage HIV disease who are on long-term therapy, the risk of developing lymphoma is unknown.
According to international recommendations, in case of accidental infection through HIV-infected blood, it is urgent to prescribe a 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. Preventive treatment is recommended for 4 weeks. Despite prompt initiation of antiretroviral treatment, seroconversion can still occur.
Symptoms that are mistaken for adverse reactions to Retrovir ® , may be a manifestation of the underlying disease or a reaction to taking other drugs used to treat HIV infection. The relationship between the developed symptoms and the action of Retrovir® is often very difficult to establish, especially with a developed clinical picture of HIV infection. In such cases, it is possible to reduce the dose of the drug or cancel it.
Adverse reactions from the blood
Anemia (usually observed after 6 weeks from the start of the use of the drug Retrovir ® , but sometimes it can develop earlier); neutropenia (usually develops 4 weeks after the start of treatment with Retrovir ® , but sometimes occurs earlier); leukopenia may occur in patients with an advanced clinical picture of HIV infection receiving Retrovir ® , especially at high doses (1200 mg - 1500 mg / day), and those 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 the bone marrow hematopoiesis is still within the normal range), adverse reactions from the blood develop rarely, 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 0.75x10 9 /l -1.0x10 9 /l, daily dose of Retrovir ® should be reduced until blood counts are restored, or Retrovir ® canceled for 2-4 weeks until the restoration of blood counts. Usually the blood picture returns to normal after 2 weeks, after which the drug Retrovir ® at a reduced dosage may be re-appointed. Patients with severe anemia despite dose reduction of Retrovir ® need a blood transfusion.
Lactic acidosis and severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with fatty liver, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues both alone and in combination with Retrovir. ® . The risk of developing these complications increases in women. Retrovir ® should be discontinued in all cases of clinical (general weakness, anorexia, sudden and unexplained weight loss, gastrointestinal symptoms, dyspnea, tachypnea) or laboratory signs of lactic acidosis with or without hepatitis (which may include hepatomegaly and steatosis even in the absence of an increase in marker levels -transaminases).
Patients with known risk factors for liver failure should use Retrovir. ® carefully.
Redistribution of body fat
Redistribution/accumulation of body fat, including central obesity, dorsocervical type obesity (buffalo hump), peripheral deposits, including facial area, gynecomastia, and elevated lipid and blood glucose levels, have been observed separately or together in some patients receiving combination antiretroviral therapy.
Since all drugs from the group of protease inhibitors and reverse nucleoside transcriptase inhibitors are associated with the occurrence of one or more of the above side effects, combined in the general syndrome of lipodystrophy, the data indicate differences in the risk of developing lipodystrophy between individual groups of patients of the respective therapeutic classes.
In addition, lipodystrophy syndrome has a multifactorial nature: the stage of HIV disease, older age and duration of antiretroviral therapy, which together can play a synergistic role.
The long-term consequences of these events are currently unknown.
The clinical examination should include a physical evaluation for signs of fat redistribution. The issue of determining the levels of serum lipids and blood glucose should be resolved. Lipid disorders require an appropriate clinical approach.
Inflammatory immune reconstitution syndrome
In HIV-infected patients with severe immunodeficiency at the start of antiretroviral therapy (ART), an inflammatory response to asymptomatic or residual opportunistic infections may cause worsening of clinical symptoms of comorbidities. Usually, cytomegalovirus rhinitis, generalized and/or focal mycobacterial infections, and pneumocystis pneumonia were observed during the first few weeks or months after starting ART. It is necessary to timely identify any symptoms of inflammation and, if necessary, prescribe appropriate anti-inflammatory therapy. Autoimmune disorders (polymyositis, Julian-Barr syndrome, diffuse toxic goiter) have been reported in the immune reconstitution inflammatory syndrome, however, the time of onset of the disease is quite variable - up to several months from the start of therapy and may be accompanied by atypical symptoms.
Patients co-infected with hepatitis C virus
Exacerbation of anemia due to the use of ribavirin was observed against the background of combined treatment with Retrovir ® as part of ART for HIV treatment; the exact mechanism of interaction has not been elucidated. Co-administration of ribavirin and Retrovir ® is not recommended, and consideration should be given to replacing zidovudine as part of the ART regimen. This is especially important in patients with a history of anemia while on zidovudine treatment.
Pregnancy and lactation
Fertility
No data on the effect of the drug Retrovir ® on the reproductive function of women. In men, taking the drug Retrovir ® does not affect the composition of sperm, morphology and sperm motility.
Pregnancy
Zidovudine droops through the placenta. Drug Retrovir ® can be used before 14 weeks of pregnancy only if the potential benefit to the mother outweighs the possible risk to the fetus.
Pregnant women considering the use of the drug Retrovir ® during pregnancy to prevent the transmission of HIV infection to the fetus, should be informed about the risk of infection of the fetus, despite ongoing therapy.
Prevention of HIV transmission from mother to fetus
The use of the drug Retrovir ® after 14 weeks of pregnancy, followed by its appointment in newborns leads to a decrease in the frequency of transmission of HIV from mother to fetus. A slight and transient increase in fetal serum lactic acid levels has been identified, which may be caused by mitochondrial dysfunction. The clinical significance of this fact is unknown. There is also evidence of the occurrence of developmental delay, the development of seizures and other neurological disorders in very rare cases in children whose mothers took the drug Retrovir. ® however, no direct relationship between the drug intake and these pathologies was found. The data obtained do not affect the recommendations for the use of the drug Retrovir ® to prevent vertical transmission of HIV infection. Long-term effects of the use of the drug Retrovir ® in children who received it in utero or neonatal periods are unknown. It is impossible to completely exclude the possibility of a carcinogenic effect, about which pregnant women must be informed.
Lactation
Breastfeeding is not recommended for women with HIV infection to avoid transmission of the virus, but when other feeding is not possible, official recommendations should be followed when considering breastfeeding by women on antiretroviral therapy.
It should be borne in mind that when prescribing the drug Retrovir ® at a dose of 200 mg, the concentration of zidovudine in breast milk is identical to that in plasma serum. When taking zidovudine at a dose of 300 mg twice a day, the ratio of zidovudine concentrations in plasma and breast milk was 0.4 - 3.2. The mean serum zidovudine concentration was 24 ng/mL. Since intracellular levels of zidovudine triphosphate (the active metabolite of zidovudine) have not been determined in nursing infants, the clinical significance of serum concentrations of these substances is unknown.
Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms
Influence of the drug Retrovir ® the ability to drive a car and other mechanisms has not been studied. However, adverse effects on these abilities are unlikely. However, when deciding whether to drive a car and other mechanisms, one should keep in mind the patient's condition and the possibility of developing adverse reactions (dizziness, drowsiness, lethargy, convulsions) while taking the drug Retrovir ® .
Overdose
Symptoms: specific symptoms or signs of overdose with Retrovir ® It was not revealed, except for the established adverse reactions: fatigue, headache, vomiting and rare changes in blood counts.
A 16-fold increase in plasma levels of zidovudine compared to therapeutic concentrations was recorded, which was not accompanied by any clinical, biochemical or hematological consequences.
Treatment: observation of the patient for the development of signs of intoxication and symptomatic supportive therapy. Hemodialysis and peritoneal dialysis are not highly effective in removing zidovudine from the body, but increase the excretion of its glucuronide metabolite.
Release form and packaging
Oral solution 10 mg/ml, 200 ml.
200 ml of the drug is placed in a glass bottle of yellow glass.
1 bottle, together with a dosing syringe of 1, 5 or 10 ml, an adapter and instructions for medical use in the state and Russian languages, is placed in a cardboard box.
Storage conditions
Store at a temperature not exceeding 30 0 С.
Keep out of the reach of children!
Shelf life
Do not use after the expiration date
Terms of dispensing from pharmacies
On prescription
Manufacturer
GlaxoSmithKline Inc., Canada
Packer
GlaxoSmithKline Inc., Canada
(7333 Mississauga Road North, Mississauga, Ontario, Canada, L5N 6L4)
Owner registration certificates
ViiV Healthcare ULC, Canada
(8455 Route Transcanadienne, Montreal, Quebec, Canada, H4S 1Z1)
Retrovir is a registered trademark of the group of companiesViiV healthcare
Address of the organization accepting claims from consumers on the quality of products (goods) on the territory of the Republic of Kazakhstan
Representative office of GlaxoSmithKline Export Ltd in Kazakhstan
050059, Almaty, Furmanov street, 273
Phone number: +7 701 9908566, +7 727 258 28 92, +7 727 259 09 96
Fax number: + 7 727 258 28 90
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