Formerly called azidothymidine, it is a pyrimidine nucleoside analog active against HIV-1.
The chemical name for zidovudine is 3’azido-3′-deoxythymidine.
This medication is used with other HIV medications to help control the infection. It helps decrease the amount of HIV in your body so that your immune system can work better.
It improves immune function, partially reverses HIV-induced neurological dysfunction, and improves some other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of the bone marrow, resulting in anemia and leukopenia.
This reduces your chance of getting HIV complications (such as new infections and cancer) and improves your quality of life. Zidovudine belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs).
Zidovudine is used in pregnant women to prevent the passing the HIV to the unborn baby. This drug is also used in newborns of HIV-infected mothers to prevent infections in newborns.
Zidovudine is an odorless white to beige crystalline solid with a molecular weight of 267.24 and a solubility of 20.1 mg per ml in water at 25 ° C. The molecular formula is C10H13N5O4.
A dideoxynucleoside compound in which an azido group has replaced the 3′-hydroxy group in the sugar moiety. This modification prevents the formation of phosphodiester bonds necessary to complete nucleic acid chains.
Zidovudine capsules are for oral administration. Each capsule contains 100 mg of zidovudine and the inactive ingredients cornstarch, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.
100mg empty hard gelatin capsule, printed with edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soy lecithin, and titanium dioxide.
Zidovudine syrup is for oral administration; it is colorless to pale yellow with a strawberry flavor.
Each ml of zidovudine syrup contains 10 mg of zidovudine and the inactive ingredients, 0.2% sodium benzoate (added as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide can be added to adjust the pH.
Zidovudine injection is a sterile solution for IV infusion only. Each ml contains 10 mg of zidovudine in water for injections. You may have added hydrochloric acid and sodium hydroxide to adjust the pH to about 5.5.
Zidovudine injection does not contain preservatives. Zidovudine injection vial stoppers contain dry natural rubber latex.
This compound belongs to the class of organic compounds known as pyrimidine 2 ‘, 3’-dideoxyribonucleosides. These compounds consist of a pyrimidine attached to a ribose that lacks a hydroxyl group at positions 2 and 3.
Zidovudine is a potent nucleoside reverse transcriptase inhibitor with activity against human immunodeficiency virus type 1 (HIV-1). Zidovudine is phosphorylated into active metabolites that compete for incorporation into viral DNA.
They inhibit the HIV reverse transcriptase enzyme and act as a chain terminator for DNA synthesis.
The lack of a 3′-OH group in the incorporated nucleoside analog prevents the formation of the 5 ‘to 3’ phosphodiester bond essential for DNA strand elongation, and thus the growth of the viral DNA is terminated.
It can cause headaches, nausea, vomiting, trouble sleeping, or loss of appetite. As your immune system strengthens, it can begin to fight the infections you already had, possibly causing the symptoms of the disease to return.
These reactions can occur at any time (shortly after starting HIV treatment or many months later). Seek medical attention immediately if you have any severe symptoms, including:
Unexplained weight loss, severe tiredness, muscle aches/weakness that won’t go away, severe or won’t go away headaches, joint pain.
Also, numbness/tingling in the hands/feet/arms/legs, vision changes, signs of infection such as fever, chills, swollen lymph nodes, trouble breathing, cough, or skin sores that do not heal.
Also, signs of an overactive thyroid (such as irritability, nervousness, heat intolerance, fast/pounding/irregular heartbeat, bulging eyes, and an unusual growth in the neck/thyroid known as goiter).
Body fat loss (such as in the face, arms, legs, and buttocks) can occur while taking this medicine. This effect can be permanent. Tell your doctor immediately if you notice any change in body fat.
Mechanism of action
Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP).
It inhibits the reverse transcriptase (RT) activity of HIV-1 by terminating the DNA strand after incorporating the nucleotide analog.
It competes with the natural substrate deoxyguanosine triphosphate (dGTP) and is incorporated into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ.
After oral administration, rapid and almost complete absorption from the gastrointestinal tract; however, due to first-pass metabolism, the systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52-75%).
The bioavailability in neonates up to 14 days is approximately 89% and decreases to about 61% and 65% in newborns older than 14 days and children three months to 12 years, respectively.
Administration with a high-fat meal may decrease the rate and degree of absorption.
It is metabolized by glucuronide conjugation to the significant inactive metabolite, 3′-azido-3′-deoxy-5′-O-beta-D-glucopyranuronosylthymidine (GZDV).
UDP-Glucuronosyltransferase-2B7 is the primary isoform UDP-glycosyltransferase (UGT) responsible for glucuronidation.
Compared to zidovudine, the area of glucopyranuronosylthymidine under the curve is approximately three times greater. Cytochrome P450 isozymes are responsible for reducing the azido moiety to form 3′-amino-3′-deoxythymidine (AMT).
As in adult patients, the main route of elimination was by metabolism to glucopyranuronosyl-thymidine. After intravenous administration, approximately 29% of the dose was excreted in the urine unchanged, and about 45% of the amount was excreted as glucopyranuronosyl-thymidine.
Symptoms of an overdose include fatigue, headache, nausea, and vomiting. LD50 is 3084 mg / kg (orally in mice).
Dosage and administration
Oral dose for adults treating HIV-1 infection
The recommended oral dose of zidovudine is 300 mg twice daily with other antiretroviral agents. The recommended intravenous (IV) dose is 1 mg per kg infused at a constant rate for 1 hour every 4 hours.
Patients should receive zidovudine injection only until oral therapy can be administered.
Zidovudine injection must be diluted before administration. The calculated dose should be removed from the 20 ml vial and added to a 5% dextrose injection solution to achieve a concentration of no more than 4 mg per ml.
After dilution, the solution is physically and chemically stable for 24 hours at room temperature and 48 hours when refrigerated at 2 ° C to 8 ° C (36 ° F to 46 ° F).
As an additional precaution, the diluted solution should be administered within 8 hours if stored at 25 ° C (77 ° F) or 24 hours if refrigerated at 2 ° C to 8 ° C to minimize possible delivery of a solution. Microbiologically contaminated.
Parenteral medicinal products should be visually inspected for particulate matter and discoloration before administration whenever the solution and container permit, and discarded if either is observed.
Rapid infusion or bolus injection should be avoided. Zidovudine injection should not be administered intramuscularly.
Oral dose for pediatrics (4 weeks to under 18 years) in treatment of HIV-1 infection
Healthcare professionals should pay particular attention to accurate zidovudine dosage calculation, drug order transcript, dispensing information, and dosing instructions to minimize the risk of drug dosing errors.
Prescribers should calculate the appropriate dose of zidovudine for each child based on body weight (kg) and should not exceed the recommended amount for adults.
Before prescribing zidovudine capsules, children’s ability to swallow the tablets should be evaluated. If a child cannot reliably swallow a zidovudine capsule, the zidovudine syrup formulation should be prescribed.
The recommended oral dose in pediatric patients from 4 weeks to under 18 years of age and weighing 4 kg or more. Zidovudine syrup should be used to provide accurate dosing when capsules are not appropriate.
Alternatively, the zidovudine dosage can be based on each child’s body surface area (BSA).
The recommended oral dose of zidovudine is 480 mg per m2 per day in divided doses (240 mg per m2 twice a day or 160 mg per m2 three times a day).
In some cases, the dose calculated in mg per kg will not be the same as that calculated by body surface area.
Prevention of maternal-fetal transmission of HIV-1
The recommended dosage regimen for administration to pregnant women (over 14 weeks of pregnancy) and their newborns is:
- 100 mg orally five times a day until the onset of labor.
During labor and delivery, intravenous zidovudine should be administered at 2 mg per kg (total body weight) for 1 hour, followed by a continuous intravenous infusion of 1 mg per kg per hour (total body weight) until the umbilical cord is clamped.
Begin neonatal dosing within 12 hours of birth and continue until six weeks of age. Neonates who cannot receive the oral dose may receive zidovudine intravenously.
Patients with severe anemia and neutropenia
Significant anemia (hemoglobin less than 7.5 g per dL or reduction more important than 25% from baseline) and significant neutropenia (granulocyte count less than 750 cells per mm3 or squeeze more potent than 50% from baseline) may require a dose interruption until marrow recovery is observed.
In patients who develop significant anemia, interrupting the dose does not necessarily eliminate the need for transfusion.
If bone marrow recovery occurs after dose interruption, dose resumption may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematological indices, such as serum erythropoietin level and tolerance of the patient.
Patients with kidney failure
In patients on hemodialysis or peritoneal dialysis or with Cockcroft-Gault creatinine clearance (CrCl) of less than 15 ml per minute, the recommended oral dose is 100 mg every 6 to 8 hours.
The intravenous dosage regimen equivalent to oral administration of 100 mg every 6 to 8 hours is approximately 1 mg per kg every 6 to 8 hours.
Patients with liver failure
There are insufficient data to recommend dose adjustment of zidovudine in patients with hepatic impairment or liver cirrhosis. Frequent monitoring of hematologic toxicities is recommended.
Concomitant use of zidovudine with stavudine should be avoided as an antagonistic relationship demonstrated in vitro.
Nucleoside analogs that affect DNA replication
Some nucleoside analogs that affect DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided.
Concomitant zidovudine with doxorubicin should be avoided as an antagonistic relationship has been demonstrated in vitro.
Hematologic / Bone Marrow Suppressive / Cytotoxic Agents
Concomitant administration of ganciclovir, interferon alfa, ribavirin, and other cytotoxic agents or bone marrow suppressants may increase the hematological toxicity of zidovudine.
Hematologic toxicity/bone marrow suppression
Zidovudine should be cautioned in patients with bone marrow involvement, evidenced by a granulocyte count of fewer than 1,000 cells per mm3 or hemoglobin below 9.5 g per dL.
Hematologic toxicities appear to be related to the bone marrow reserve before treatment and the dose and duration of therapy.
In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most significant adverse events observed.
In patients experiencing hematologic toxicity, a reduction in hemoglobin can occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks.
There have been reports of pancytopenia associated with using zidovudine, which was reversible in most cases after discontinuation of the drug.
However, significant anemia, which in many cases requires dose adjustment, discontinuation of zidovudine, and blood transfusions, has occurred during treatment with zidovudine alone or in combination with other antiretrovirals.
Blood counts are frequently recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease treated with zidovudine.
Periodic blood counts are recommended for people infected with HIV-1 and patients with asymptomatic or early HIV-1 disease. If anemia or neutropenia develops, dose interruption may be necessary.
Allergic reaction to latex
Zidovudine injection vial stoppers contain dry natural rubber (a derivative of latex) that can cause allergic reactions in people sensitive to latex.
Myopathy and myositis with pathological changes, similar to those produced by HIV-1 disease, have been associated with long-term use of zidovudine.
Lactic acidosis and severe hepatomegaly with steatosis
These cases (including fatal cases) have been reported using nucleoside analogs, including zidovudine.
Most of these cases have been in women. Female sex and obesity may be risk factors for developing lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogs.
The zidovudine procedure should be discontinued in all patients who develop clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, including hepatomegaly and steatosis, even in the absence of marked transaminase elevations.
Use with interferon and ribavirin-based regimens in HIV-1 / HCV coinfected patients.
In vitro studies have shown that ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs, such as zidovudine.
Although no pharmacokinetic or pharmacodynamic interactions (such as loss of virologic suppression of HIV-1 / HCV) were observed when ribavirin was co-administered with zidovudine in HIV-1 / HCV coinfected subjects.
An exacerbation of ribavirin anemia has been reported when zidovudine is part of the HIV regimen.
Concomitant administration of ribavirin and zidovudine is not recommended. Consideration should be given to replacing zidovudine in the established combination of HIV-1 / HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
Hepatic decompensation (some fatal) has occurred in HIV-1 / HCV coinfected patients receiving combination antiretroviral therapy for HIV-1 and interferon-alpha with or without ribavirin.
Patients receiving interferon-alpha with or without ribavirin and zidovudine should be closely monitored for treatment-related toxicities, especially liver decompensation, neutropenia, and anemia.
Discontinuation of zidovudine should be considered medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicity, including liver decompensation, is observed (e.g., Child-Pugh score greater than 6).
Zidovudine treatment has been associated with subcutaneous fat loss. The incidence and severity of lipoatrophy are related to cumulative exposure.
This fat loss, which is most evident on the face, limbs, and buttocks, maybe only be partially reversible, and improvement may take months or years after switching to a regimen that does not contain zidovudine.
Patients should be regularly evaluated for signs of lipoatrophy during treatment with zidovudine and other zidovudine-containing products. If feasible, therapy should be switched to an alternative regimen if suspected lipoatrophy.
Pregnancy and breastfeeding
Pregnant women may need to take this medicine five times a day. Newborns usually receive the liquid form every 6 hours for six weeks after birth to prevent infection.
Take this medicine 2 hours before or after taking clarithromycin. Clarithromycin can prevent your body from fully absorbing zidovudine.
You must continue to take this medicine (and other HIV medicines) exactly as prescribed by your doctor. Do not skip any doses.
Please do not take more or less of this medication than prescribed or stop taking it (or other HIV medications), even for a short time, unless your doctor tells you to.
Skipping or changing your dose without your doctor’s approval can increase the virus, make the infection more difficult to treat (resistant), or worsen side effects.
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breastfeed babies to avoid the risk of postnatal transmission of HIV-1 infection.
Lamivudine is present in human milk; there is no information on the effects of lamivudine or zidovudine on the breastfed infant or the effects of drugs on milk production; due to its potential to:
- HIV-1 transmission (in HIV-negative babies).
- Develop viral resistance (in HIV-positive babies).
- Severe adverse reactions in a breastfed infant.
Instruct mothers not to breastfeed if they are receiving therapy.
The Food and Drug Administration classifies medications based on their safety during pregnancy. Five categories: A, B, C, D, and X, are used to classify the possible risks to the fetus when taking a drug during pregnancy.
This medicine belongs to category C. In animal studies, pets were given this medicine, and some babies were born with problems.
Well-controlled studies in humans have not been performed. Therefore, this drug can be used if the potential benefits to the mother outweigh the potential risks to the fetus.
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: it can be acceptable. Either animal studies show no risk, but human studies are not available, or animal studies showed minor risks, and human studies were done and showed no risk.
C: Use with caution if the benefits outweigh the risks. Animal studies show risk, human studies are not available, or no animal or human studies were conducted.
D – Use in life-threatening emergencies when no safer drug is available—positive evidence of human fetal risk.
X: do not use in pregnancy. The risks involved outweigh the potential benefits. There are safer alternatives.