ATX: J.05.A.F.01 Zidovudine
A synthetic nucleoside analog. Inside the cell, zidovudine is sequentially phosphorylated to the active metabolite, zidovudine-5′-triphosphate. Zidovudine triphosphate inhibits HIV reverse transcriptase by interrupting DNA synthesis of the virus after inclusion in the nucleotide chain. Zidovudine triphosphate weakly inhibits cellular DNA polymerases alpha and gamma.
In combination with other antiviral drugs it increases the number of CD4+ cells.
Pharmacokinetics when taken orally are dose-independent over a dose range from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
Absorption is rapid; ingestion with fatty foods reduces the extent and rate of absorption. Bioavailability in adults is 54-74%. Time of maximum concentration achievement in blood (ТСmах) after oral intake – 0.5-1.5 hours. Volume of distribution is 1.0-2.2 l/kg.
The binding to plasma proteins is less than 38%.
It penetrates into most tissues and body fluids. It is found in cerebrospinal fluid at concentrations of 15-64% of that in plasma. It is metabolized in the liver. The main metabolite of zidovudine is glucuronide, the area under the curve “concentration-time” (AUC) of which is 3 times greater than the AUC of zidovudine. The average half-life (T1/2) from cells is 3.3 h; from blood serum in adults is about 1 h (0.8-1.2 h). After oral administration 14% of zidovudine and 74% of its metabolite are detected in urine.
Patients with impaired renal function
In patients with severe renal impairment the maximum concentration of zidovudine in plasma is increased by 50% compared to that in patients without renal impairment. Systemic exposure of the drug (defined as the area under the “concentration-time” curve) is increased by 100%; the elimination half-life does not change significantly. In renal failure there is a significant cumulation of the main metabolite of zidovudine – glucuronide, with no signs of toxic effects. Hemodialysis and peritoneal dialysis have no effect on zidovudine elimination, while excretion of glucuronide is increased.
Patients with impaired hepatic function
In hepatic insufficiency there may be cumulation of zidovudine due to decreased glucuronidation, which requires adjustment of the drug dose.
Patients in the elderly
The pharmacokinetics of zidovudine have not been studied in patients older than 65 years.
Pharmacokinetics in children
In children over 5-6 months of age, pharmacokinetic parameters are similar to those in adults.
The pharmacokinetics in pregnant women are similar to those in non-pregnant women.
The plasma concentration of zidovudine in children at birth is the same as in their mothers at delivery.
Treatment of HIV-infection caused by HIV-1 (as part of combined antiretroviral therapy).
Prevention of perinatal HIV transmission from infected mother to child, as zidovudine reduces the risk of intrauterine infection of the fetus.
1 tablet contains:
The active ingredient:
Zidovudine 300 mg
Each film-coated tablet contains:
Core: sodium carboxymethyl starch (primogel) – 5.0 mg, pregelatinized starch -15.0 mg, colloidal silicon dioxide (aerosil grade A-300) – 1.2 mg, magnesium stearate – 1.8 mg, microcrystalline cellulose – 258.0 mg.
Water-soluble film coating: Ready-made water-soluble film coating – 9.0 mg. (Shell composition: hydroxypropyl methylcellulose (hypromellose) – 25.0%, copolyvidone – 22.5%, polyethylene glycol 6000 (Macrogol 6000) – 9.5%, glyceryl caprylocaprate – 3.0%, polydextrose – 15.0%, titanium dioxide – 25.0%).
How to take, the dosage
Ingestion, regardless of meals.
In adults, the drug is prescribed in a dose of 600 mg per day in several doses. In children with body weight over 30 kg – 300 mg 2 times a day or 200 mg 3 times a day. If the body surface area is considered, 160 or 240 mg/m2 3 or 2 times daily, respectively (daily dose 480 mg/m2).
In case of hemoglobin decrease to 75-90 g/l and/or neutrophil count decrease to 0.75-1.0 x 107l it may be necessary to decrease the dose of the drug or cancel therapy with zidovudine until hematopoiesis recovery. If anemia occurs, withdrawal of the drug does not always reduce the need for blood transfusions. For more rapid recovery of bone marrow function, epoetin alfa may be administered in the recommended doses.
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 these patients special caution should be exercised when using zidovudine and appropriate monitoring before and during treatment with the drug.
In severe renal failure, the recommended daily dose is 300 to 400 mg. Further dose adjustment may be required depending on the peripheral blood response and clinical effect. Hemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination, but accelerate excretion of its metabolite – glucuronide. For patients with terminal renal failure who are on hemodialysis or peritoneal dialysis, the recommended dose of zidovudine is 100 mg every 6-8 hours.
In patients with hepatic failure, there may be cumulation of zidovudine due to decreased glucuronidation, which may require adjustment of the drug dose. 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.
Preventing mother-to-fetus transmission of HIV
There are 2 prevention regimens that are effective:
1. Pregnant women, starting at 14 weeks of pregnancy, are advised to administer zidovudine orally until delivery at a dose of 500 mg per day (100 mg five times a day).
2. pregnant women from 36 weeks of pregnancy are recommended to prescribe zidovudine orally in a dose of 600 mg daily (300 mg twice a day) until delivery and then in a dose of 300 mg every 3 hours until delivery.
Zidovudine is used as part of combined 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 the maximum blood concentration (28%) for zidovudine when administered together with lamivudine, however, the overall exposure (AUC) is not affected. Zidovudine has no effect on the pharmacokinetics of lamivudine.
Phenytoin: zidovudine reduces the blood concentration of phenytoin, which requires monitoring the blood concentration of phenytoin when administered simultaneously with zidovudine.
Probenicide: decreases glucuronidation and increases the mean half-life and AUC of zidovudine. Renal excretion of glucuronide and zidovudine itself is reduced in the presence of probenicid.
Atovachone: zidovudine does not affect the pharmacokinetic parameters of atovachone. Atovachone slows down glucuronidation of zidovudine (AUC of zidovudine at equilibrium increases by 33%, maximum glucuronide concentrations decrease by 19%). A change in the safety profile of zidovudine administered at doses of 500 or 600 mg daily is unlikely when used concomitantly with atovaquone for three weeks.
If longer concomitant use of these drugs is necessary, close monitoring of the patient’s clinical condition is recommended.
Clarithromycin: reduces absorption of zidovudine. A break of at least 2 hours between doses of the drugs.
Valproic acid, fluconazole, methadone: decrease the clearance of zidovudine, which increases its systemic exposure.
Ribavirin: the nucleoside analogue ribavirin is an antagonist of zidovudine. Simultaneous use of zidovudine and ribavirin should be avoided.
Rifampicin: The combination of zidovudine with rifampicin results in a 48%±34% decrease in the AUC for zidovudine; however, the clinical significance of this change is unknown.
Stavudine: zidovudine can inhibit intracellular phosphorylation of stavudine.
Stavudine should not be used concomitantly with zidovudine.
Other: medications such as paracetamol, acetylsalicylic acid, codeine, methadone, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone, isoprinosine can impair zidovudine metabolism through competitive inhibition of glucuronidation or direct inhibition of microsomal metabolism in the liver. The possibility of using these drugs in combination with zidovudine, especially for long-term therapy, should be approached with caution. The combination of zidovudine, especially for emergency therapy, with potentially nephrotoxic and myelotoxic drugs (e.g., pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin) increases the risk of adverse reactions to zidovudine. Renal function and blood parameters should be monitored and the dose of drugs should be reduced if necessary.
Patients should be informed of the dangers of concomitant use of zidovudine with over-the-counter medications and that use of zidovudine does not prevent the risk of HIV transmission to others through sexual contact or blood transfusion. Therefore, patients should take appropriate precautions.
Emergency prophylaxis for probable HIV infection
In accordance with international recommendations, if infection is probable through the blood of an HIV-infected person (e.g., through an injection needle), a combination therapy of zidovudine and lamivudine should be administered promptly (within 1 to 2 hours of infection). If there is a high risk of infection, a drug from the protease inhibitor group should be included in the antiretroviral therapy regimen. Prophylactic treatment is recommended for four weeks. Despite rapid initiation of antiretroviral treatment, the possibility of seroconversion cannot be excluded.
Symptoms that are mistaken for adverse reactions to zidovudine may be a manifestation of the underlying disease or a reaction to other HIV medications. The relationship between the symptoms that develop and the effects of zidovudine is often very difficult to establish, especially when the clinical picture of HIV infection is more advanced. In such cases it is possible to reduce the dose of the drug or cancel it.
Zidovudine does not cure HIV infection, and patients remain at risk of developing the unfolding of the disease with suppression of immunity and the occurrence of opportunistic infections and malignant neoplasms. In HIV infection, zidovudine reduces the risk of opportunistic infections, but does not reduce the risk of lymphoma.
Adverse reactions from the hematopoietic organs
Anemia (usually observed after 6 weeks from the beginning of therapy with zidovudine, but sometimes it can occur earlier), neutropenia (usually occurs after 4 weeks from the beginning of therapy with zidovudine, but sometimes it occurs earlier), leukopenia may occur in patients with developed clinical picture of HIV infection receiving zidovudine, especially in high doses (1200-1500 mg/day), with decreased bone marrow reserve before the start of therapy. Blood tests should be monitored at least once every 2 weeks during the first 3 months of therapy, and monthly thereafter in patients with a clear clinical picture of HIV infection. In the early stage of HIV infection (when medullary hematopoiesis is still normal) adverse blood reactions are rare, therefore blood tests are performed less frequently – depending on the general condition of the patient once every 1-3 months.
In case of hemoglobin decrease up to 75-90 g/l and/or neutrophil count decreasing to 0.75-1.0 x 109/l the daily dose of the drug shall be decreased or zidovudine shall be stopped for 2-4 weeks until the blood parameters are restored. The blood count usually normalizes after 2 weeks, after which zidovudine at a reduced dose may be prescribed again. If anemia occurs, withdrawal of the drug does not always reduce the need for blood transfusions.
Radiation therapy increases the myelosuppressive effect of zidovudine.
Lactic acidosis and marked hepatomegaly with steatosis
These complications can be fatal with both zidovudine monotherapy and when zidovudine is used as part of combination antiretroviral therapy.
The risk of these complications is higher in female patients. Signs of these complications may include general weakness, sudden unexplained weight loss, anorexia, digestive symptoms (nausea, vomiting, abdominal pain), respiratory symptoms (rapid breathing or dyspnea). In case of clinical or laboratory signs of lactic acidosis or toxic liver damage zidovudine should be discontinued.
Distribution of subcutaneous fatty tissue
In some patients, combination antiretroviral therapy may be accompanied by redistribution/accumulation of subcutaneous fatty tissue, including decreased facial and limb fat, increased visceral fat, breast fat, and fatty deposits around the back of the neck and back (“buffalo hump”), and elevated serum lipid and blood glucose concentrations.
While one or more of the above adverse reactions associated with the common syndrome often referred to as lipodystrophy can be caused by all drugs in the protease inhibitor and nucleoside reverse transcriptase inhibitor classes, accumulating evidence suggests that there are differences between individual members of these drug classes in their ability to cause these adverse reactions.
In addition, lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, older age, and duration of antiretroviral therapy play an important, possibly potentiating, role in the development of this complication. The long-term effects of these adverse reactions are currently unknown. The clinical evaluation of patients should include examination for signs of adipose tissue redistribution. Serum lipid and glucose concentrations should also be monitored. Lipid metabolism disorders should be corrected according to clinical indications.
It should be taken into account that the development of symptoms of myopathy (myalgia, weakness, increased creatine phosphokinase activity) in HIV-infected patients may be associated with the underlying disease. When using zidovudine at doses of 500 mg or 600 mg per day, myopathy associated with taking the drug is rarely observed. In the case of development of myopathy caused by taking zidovudine, the drug should be discontinued.
Immune reconstitution syndrome
In HIV-infected patients with severe immunodeficiency during initiation of antiretroviral therapy, inflammation may worsen with asymptomatic or sluggish opportunistic infection, which may cause serious deterioration or exacerbation of symptoms. Usually such reactions have been observed in the first weeks or months after the start of antiretroviral therapy. The most significant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infection, and pneumocystis pneumonia. Any symptoms of inflammation should be identified immediately and treatment started promptly. Autoimmune diseases (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) were observed against the background of immune recovery, but the timing of the primary manifestations varied, and the disease could occur many months after the start of therapy and have an atypical course.
Patients co-infected with HIV and hepatitis C virus (HCV)
In vitro studies have shown that ribavirin can reduce phosphorylation of pyrimidine nucleoside analogs, including zidovudine. Although no clear evidence of pharmacokinetic and pharmacodynamic interaction between ribavirin and zidovudine in patients with co-infection (HIV-1/HCV) has been found. An exacerbation of ribavirin-induced anemia has been reported in HIV-infected patients receiving concomitant therapy with zidovudine. The mechanism of this effect is currently unknown. Therefore, concomitant use of ribavirin and zidovudine is not recommended. The antiretroviral therapy regimen should be changed to an alternative regimen that does not contain zidovudine, especially if there is a history of anemia associated with taking zidovudine.
Cases of hepatic failure (sometimes fatal) have been reported in patients infected with HIV-1 with concomitant hepatitis C receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. If zidovudine and interferon alfa with or without ribavirin are used concomitantly, patients should be closely monitored for signs of toxicity, particularly liver failure, neutropenia, and anemia. If clinical signs of toxicity increase, especially hepatic failure (> 6 points on the Child-Pugh scale), doses should be reduced or interferon alfa, ribavirin or both should be withdrawn. In case of development of myelosuppression, discontinuation or withdrawal of therapy with zidovudine should be considered.
Effect on the ability to drive motor vehicles:
During treatment, caution should be exercised when driving motor vehicles and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions. If such adverse events as dizziness, somnolence, lethargy and seizures occur, the following activities should be avoided.
High sensitivity to zidovudine or any other drug component; neutropenia/leukopenia (neutrophil count below 0.75 x 109/l); anemia (hemoglobin below 75 g/l); simultaneous use with stavudine, doxorubicin, other drugs that reduce the antiviral activity of zidovudine; childhood age (body weight less than 30 kg).
Inhibition of medullary hematopoiesis, cyanocobalamin or folic acid deficiency, liver failure, older age, obesity, hepatomegaly, hepatitis or any liver disease risk factors, neutropenia/leukopenia (neutrophil count 0.75-1.0 x 109/L); anemia (hemoglobin 75-90 g/L).
The adverse reactions that occur when treated with zidovudine are the same in children and adults.
The following gradations are used to estimate the incidence of adverse reactions: very common (>1/10), common (>1/100, < 1/10), infrequent (>1/1000, < 1/100), rare (>1/10000, < 1/1000), very rare (< 1/10000).
Hematopoietic organs: often – anemia (which may require hemotransfusions), neutropenia, leukopenia, infrequent – thrombocytopenia, pancytopenia with bone marrow hypoplasia, rare – red cell aplasia, very rare – aplastic anemia.
Gastro-intestinal tract: very often – nausea, often – vomiting, upper abdominal pain, diarrhea, rarely – flatulence, rarely – dyspepsia, distortion of taste, pigmentation of the oral mucosa, pancreatitis, anorexia.
Hepatobiliary system: often – hyperbilirubinemia, increased activity of “liver” enzymes, rarely – marked hepatomegaly with steatosis.
Nervous system: very common – headache, common – dizziness, rare – paresthesia, insomnia, somnolence, decreased mental performance, seizures, anxiety, depression.
Respiratory system: infrequent – shortness of breath, rare – cough.
Cardiovascular system: cardiomyopathy.
Urinary system disorders: rarely – frequent urination.
Endocrine system and metabolism: frequently – hyperlactatemia, rarely – lactate acidosis, gynecomastia.
Musculoskeletal system: often – myalgia, rarely – myopathy.
Skin disorders: infrequent – skin rash, itching, rarely – pigmentation of nails and skin, increased sweating, urticaria.
Others: often – malaise, infrequently – fever, asthenia, generalized pain syndrome, rarely – flu-like syndrome, chills, chest pain, redistribution/accumulation of subcutaneous fat.
Some adverse reactions occurring when using zidovudine to prevent mother-to-fetus transmission of HIV.
Pregnant women tolerate zidovudine in recommended doses well. In children there is a decrease in hemoglobin, which, however, does not require hemotransfusions. Anemia disappears 6 weeks after completion of therapy with zidovudine.
Symptoms: fatigue, headache, vomiting, disorders of hematological parameters.
Treatment: symptomatic. Hemodialysis and peritoneal dialysis are not effective in removing zidovudine from the body, but accelerate excretion of its metabolite – glucuronide.
Zidovudine passes through the placenta. The drug can be used during pregnancy earlier than 14 weeks only if the potential benefit to the mother exceeds the possible risk to the fetus. Use of zidovudine after 14 weeks of pregnancy with its subsequent use in newborns leads to a decrease in the frequency of HIV transmission from mother to fetus. Long-term effects of zidovudine in children who received it in the intrauterine or neonatal periods are not known. The possibility of carcinogenic effects cannot be completely excluded.
If zidovudine is used during lactation, breastfeeding should be stopped.
2 years. Do not use after the expiry date printed on the package.
|Conditions of storage|
Store in the original package of the manufacturer at the temperature not more than 25 °С. Keep out of reach of children.
Pharmasintez JSC, Russia
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