AHFS Class:

• HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors 8:18.08.20

Generic Name(s):

• Zidovudine

Zidovudine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).1

Treatment of HIV Infection

Oral and IV zidovudine are used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients >4 weeks of age.1,231

Although the drug was used more commonly in the past, zidovudine is currently not recommended for clinical use to treat HIV-1 infection in most adults and adolescents due to its high risk for serious toxicities.200 In pediatric patients, zidovudine is a preferred component of a dual-nucleoside reverse transcriptase inhibitor (NRTI) backbone in infants ≤1 month of age and an alternative component of a dual-NRTI backbone in pediatric patients ≥1 month of age.201 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202 Consult guidelines for the most current information on recommended regimens.200,201

Clinical Experience

Monotherapy

Although monotherapy and 2-drug regimens that include only NRTIs are no longer recommended for the treatment of HIV infection,200 early studies evaluating safety and efficacy of zidovudine for initial antiretroviral therapy in antiretroviral-naïve HIV-infected adults used zidovudine monotherapy or 2-drug regimens of zidovudine and didanosine, lamivudine, or zalcitabine (no longer commercially available in the US).1,231,485,487,489,490,497

Efficacy of zidovudine as monotherapy was demonstrated in several early clinical trials, including BW 002, ACTG 016, and ACTG 019.1,61,153,231,537 Compared to placebo, zidovudine was more effective in reducing the risk of HIV-1 disease progression; however, ACTG 016 and ACTG 019 did not find a survival benefit associated with zidovudine monotherapy.1,231 Later trials found that the clinical efficacy of monotherapy with zidovudine was time limited.1,231

Combination Therapy

Efficacy and safety of combination therapy with zidovudine were established in the ACTG Study 320, a multicenter, double-blind, placebo-controlled trial.1,292 231 A total of 1156 treatment-naïve adult patients were given zidovudine as part of a 2-drug or 3-drug regimen.292 The primary endpoint (development of an AIDS-defining event or death) was lower with the 3-drug regimen versus a 2-drug regimen (6.1 versus 10.9%, respectively).1,231

Pediatric Patients

ACTG 300 was a multicenter, randomized, double-blind trial comparing zidovudine plus lamivudine to didanosine monotherapy.1,231,538 A total of 471 treatment-naïve pediatric patients (median age 2.7 years; mean baseline CD4⁺ cell count 868 cells/mm³; mean baseline HIV-1 RNA level 5.0 log₁₀ copies/mL) were enrolled.1,231 Disease progression occurred in 6.4% of patients who received zidovudine plus lamivudine versus 15.7% who received didanosine monotherapy.1,231 The risk of death was also lower in the combination therapy group compared with the didanosine monotherapy group (0.8 versus 4.7%, respectively). 1,231

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Zidovudine, an NRTI, was commonly used as part of a dual-NRTI “backbone” of a fully suppressive antiretroviral regimen.200 In the 2023 HHS adult and adolescent HIV treatment guideline, zidovudine is no longer recommended for use in clinical practice due to its high risk for serious toxicities.200

In the 2023 HHS pediatric HIV treatment guideline, zidovudine is included in various antiretroviral regimens.201 Zidovudine plus lamivudine or emtricitabine is recommended as a preferred dual-NRTI backbone combination for children from birth to 1 month of age.201 Zidovudine plus lamivudine or emtricitabine, or plus abacavir is recommended as an alternative dual-NRTI backbone combination with other drugs for infants and children ≥1 month to <6 years, and for children and adolescents ≥6 years who are not sexually mature.201

Prevention of Perinatal HIV Transmission

Oral and IV zidovudine are used for prevention of maternal-fetal HIV-1 transmission, including maternal antepartum and intrapartum therapy and post-partum therapy of an HIV-1 exposed neonate.1,231 Guidelines generally recommend zidovudine as a preferred or non-preferred alternative treatment option for these indications; consult guidelines for the most current information on recommended regimens.202

Clinical Experience

Efficacy of zidovudine for the prevention of maternal-infant transmission of HIV-1 was demonstrated in ACTG 076, a placebo-controlled, double-blind, randomized trial.1,231,458 A total of 477 primarily treatment-naïve pregnant women infected with HIV-1 (median CD4⁺ cell count of 560 cells/mm³) were randomized to treatment with zidovudine or placebo; treatment was initiated orally between 14 to 34 weeks gestation (median duration 11 weeks), administered IV during labor and delivery, and administered to the newborn orally for 6 weeks following delivery.458 Based on evaluation of 363 infants, the risk of HIV-1 infection was 7.8% in the group that received zidovudine compared with 24.9% in the placebo group, for a relative risk reduction of 68.7%. 1,231

Clinical Perspective

In the 2023 HHS perinatal HIV treatment guideline, zidovudine/lamivudine is included as a non-preferred alternative dual-NRTI backbone component for antiretroviral-naïve patients during pregnancy.202 Zidovudine is also listed as a non-preferred alternative dual-NRTI backbone component for pregnant patients who are restarting antiretroviral therapy, if a current regimen is not well-tolerated or fully suppressive, or prior to pregnancy.202 Additionally, intrapartum IV zidovudine is recommended for pregnant patients with HIV-1 RNA levels >1000 copies/mL, unknown HIV-1 RNA levels, adherence concerns, those who are not receiving ART, and those who are diagnosed with HIV while in labor.202 For newborns at low-risk for perinatal HIV acquisition, a 2 to 6 week zidovudine regimen is recommended, with duration of treatment dependent on maternal HIV-1 and antiretroviral treatment status and infant age at birth.202 For newborns at high-risk for perinatal HIV acquisition, zidovudine is recommended as part of a 3-drug regimen, with either lamivudine plus nevirapine or lamivudine plus raltegravir for 2 to 6 weeks; zidovudine should be given for a total of 6 weeks.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Oral zidovudine is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals.199

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine), or zidovudine and emtricitabine.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Zidovudine is used in conjunction with other antiretrovirals as a part of preferred and alternative regimens for adult and adolescent patients with renal dysfunction, as a part of an alternative regimen for children aged 2 to 12 years, and as part of preferred and alternative regimens for children 4 weeks to <2 years of age for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) after sexual, injection drug use, or other nonoccupational exposures in individuals.198

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).198 In adults and adolescents 13 years of age or older with impaired renal function (creatinine clearance 59 mL/minute or less), CDC recommends a regimen of either raltegravir or dolutegravir used in conjunction with zidovudine and lamivudine.

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

General

Patient Monitoring

• Frequently monitor complete blood counts (CBC) to detect severe anemia and neutropenia, particularly in patients with advanced human immunodeficiency virus (HIV)-1 infection receiving zidovudine.1,231 Periodically monitor CBC in asymptomatic or early HIV-1 infection.1,231
• Frequently monitor for hematologic toxicities in patients with hepatic impairment or liver cirrhosis.1,231
• Closely monitor for treatment toxicities such a hepatic decompensation, neutropenia, and anemia in patients coinfected with HIV and hepatitis C who receive concomitant zidovudine and interferon alfa with or without ribavirin.1,231

Reconstitution and Administration

Zidovudine is administered orally1,231 or by intermittent or continuous IV infusion.1 Do not administer zidovudine by rapid IV infusion or injection and do not give IM.1

When used for the treatment of HIV infection, administer zidovudine by intermittent IV infusion only until oral therapy can be substituted.1

Store commercially available zidovudine capsules and oral solution at 15-25°C.1 Store zidovudine film-coated tablets at 20-25°C.231 Store commercially available zidovudine for injection concentrate for IV infusion at 15-25°C and protect from light.1 Following dilution in 5% dextrose injection, solutions containing 4 mg or less of zidovudine per mL are physically and chemically stable for 24 hours at room temperature or 48 hours when refrigerated at 2-8°C.1 However, because zidovudine for injection concentrate for IV infusion contains no preservatives, the manufacturer recommends that diluted solutions of the concentrate be administered within 8 hours if stored at 25°C or within 24 hours if refrigerated at 2-8°C to minimize the potential administration of a microbiologically contaminated solution.1

Oral Administration

Administer zidovudine capsules, tablets, or oral solution without regard to meals.1,231

Administer zidovudine oral solution to children who cannot reliably swallow an intact capsule or tablet.1,231

IV Administration

Commercially available zidovudine concentrate for IV infusion containing 10 mg of the drug per mL must be diluted prior to administration.1 Withdraw the appropriate dose of zidovudine from the vial and dilute in 5% dextrose injection to provide a solution containing no more than 4 mg of the drug per mL.1

Rate of Administration

In adults, administer intermittent IV infusions of zidovudine over 60 minutes.1

In neonates, administer intermittent IV infusions of zidovudine over 30 minutes.1

When used for intrapartum IV prophylaxis in pregnant HIV-infected women, administer an initial zidovudine dose by IV infusion over 60 minutes followed by continuous IV infusion at a rate of 1 mg/kg per hour.1

Fixed Combinations Containing Zidovudine

For treatment of HIV infection, zidovudine is commercially available in fixed-combination tablets containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir^®, generic)227 and fixed-combination tablets containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir^®, generic).229 See the full prescribing information for dosage of each of these combination products.227,229

Dosage

Pediatric Dosage

Dosage of zidovudine in pediatric patients usually is based on body weight or, alternatively, body surface area.1,231 To avoid medication errors, use extra care in calculating the dose, transcribing the medication order, dispensing the prescription, and providing dosage instructions.1,231 Use a graduated oral syringe with 0.1 mL measurement increments to ensure accurate dosing of zidovudine oral solution in neonates.1 Zidovudine dosage in pediatric patients should not exceed adult dosage.1,231

Treatment of HIV Infection in Infants and Children

For recommended weight-based dosage of oral zidovudine for the treatment of HIV-1 infection in infants and children 4 weeks of age or older weighing at least 4 kg, see Table 1.

Alternatively, if body surface area is used to calculate dosage of oral zidovudine for the treatment of HIV-1 infection in pediatric patients 4 weeks of age or older, the manufacturer recommends 240 mg/m² twice daily or 160 mg/m² 3 times daily.1,231

Prevention of Perinatal HIV Transmission

For prevention of perinatal HIV transmission in HIV-exposed neonates, zidovudine can be used alone for prophylaxis in neonates at low risk of perinatal HIV acquisition, but is used in conjunction with other antiretrovirals for prophylaxis or empiric HIV therapy† in neonates at higher risk of perinatal HIV acquisition.202

When used for prophylaxis of perinatal HIV transmission in premature neonates (gestational age less than 30 weeks), experts recommend an oral zidovudine dosage of 2 mg/kg twice daily or an IV dosage of 1.5 mg/kg twice daily initiated as soon as possible after birth (within 6 hours).202 At 4 weeks of age, dosage should be increased to 3 mg/kg orally twice daily or 2.3 mg/kg IV twice daily.202 If HIV infection is confirmed in the infant, at 8 weeks of age, dosage should be increased to 12 mg/kg orally twice daily or 9 mg/kg IV twice daily.202

When used for prophylaxis of perinatal HIV transmission in premature neonates (gestational age of 30 weeks to less than 35 weeks), experts recommend an oral zidovudine dosage of 2 mg/kg twice daily or an IV dosage of 1.5 mg/kg twice daily initiated as soon as possible after birth (within 6 hours).202 At 2 weeks of age, dosage should be increased to 3 mg/kg orally twice daily or 2.3 mg/kg IV twice daily.202 If HIV infection is confirmed in the infant, at 6 weeks of age, dosage should be increased to 12 mg/kg orally twice daily or 9 mg/kg IV twice daily.202

When used for prophylaxis of perinatal HIV transmission in full-term neonates (gestational age 35 weeks or more), experts recommend an oral zidovudine dosage of 4 mg/kg twice daily or an IV dosage of 3 mg/kg twice daily, initiated as soon as possible after birth (within 6 hours).202 If HIV infection is confirmed in the infant, at 4 weeks of age, dosage should be increased to 12 mg/kg twice daily orally or 9 mg/kg IV twice daily.202 Alternatively, when a simplified weight-based dosage of zidovudine oral solution containing 10 mg/mL is used in full-term neonates (gestational age 35 weeks or more), experts recommend that those weighing 2 to less than 3 kg receive 10 mg (1 mL) twice daily, those weighing 3 to less than 4 kg receive 15 mg (1.5 mL) twice daily, and those weighing 4 to less than 5 kg receive 20 mg (2 mL) twice daily.202

When full-term neonates (gestational age ≥37 weeks) meet criteria for low risk of HIV acquisition (i.e., infants born to mothers who received ≥10 weeks of antiretroviral therapy during pregnancy with sustained viral suppression near delivery, did not have acute HIV infection during pregnancy, and no concerns related to maternal adherence to the treatment regimen), a 2-week zidovudine prophylaxis regimen may be used alone.202

The manufacturer recommends that HIV-exposed neonates receive oral zidovudine in a dosage of 2 mg/kg every 6 hours, initiated within 12 hours of birth and continued through 6 weeks of age for prevention of perinatal HIV transmission.1,231 The manufacturer states that neonates unable to receive oral therapy should receive IV zidovudine in a dosage of 1.5 mg/kg every 6 hours (given by IV infusion over 30 minutes) initiated within 12 hours of birth and continued through 6 weeks of age.1,231

When empiric HIV therapy† is used for prevention of perinatal HIV transmission in neonates at highest risk of HIV acquisition, a 3-drug regimen of zidovudine, lamivudine, and nevirapine, or zidovudine, lamivudine, and raltegravir is recommended and should be initiated as soon as possible after birth (within 6 hours).202 Zidovudine dosage recommended for empiric HIV therapy† in neonates for prevention of perinatal HIV transmission is identical to that recommended for prophylaxis.202 Optimal duration of empiric HIV therapy in HIV-exposed neonates at highest risk of HIV acquisition is unknown.202 The lamivudine and nevirapine or lamivudine and raltegravir components of the 3-drug regimens may be administered for 2-6 weeks; recommended duration is dependent on HIV nucleic acid tests (NAT), maternal viral load at delivery, and additional risk factors for HIV transmission.202 If either regimen duration is shorter than 6 weeks, experts recommend continuing zidovudine alone for a total prophylaxis regimen length of 6 weeks in high-risk patients.202

Clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding selection of antiretrovirals, including dosage considerations, for prevention of perinatal HIV transmission.202

Adult Dosage

Treatment of HIV Infection

The recommended oral dosage of zidovudine for the treatment of HIV-1 infection in adults is 300 mg twice daily in combination with other antiretroviral agents.1,231

The recommended IV dosage of zidovudine for the treatment of HIV-1 infection in adults is 1 mg/kg every 4 hours.1

Prevention of Perinatal HIV Transmission

When the intrapartum IV zidovudine prophylaxis regimen is indicated for prevention of perinatal HIV transmission in pregnant HIV-infected women based on plasma HIV-1 RNA levels near the time of delivery, the IV prophylaxis regimen should be initiated at the start of labor (or 3 hours before scheduled cesarean delivery),1,202,231 regardless of the woman's current antiretroviral treatment regimen.202

If the intrapartum IV zidovudine prophylaxis regimen is indicated in pregnant HIV-infected women, an initial zidovudine dose of 2 mg/kg should be given by IV infusion over 60 minutes followed by 1 mg/kg per hour for 2 hours (at least 3 hours total) given by continuous IV infusion.1,202,231 If an urgent, unscheduled cesarean delivery is indicated, some experts recommend administering the 2 mg/kg loading dose, then proceeding to delivery.202 Intrapartum IV zidovudine is indicated in pregnant HIV-infected women, regardless of the the antepartum antiretroviral regimen;202 if the peripartum antiretroviral regimen must be temporarily stopped for less than 24 hours, stop and restart all drugs simultaneously to minimize the development of resistance.202

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the recommended dosage of oral zidovudine is 300 mg twice daily.199 Zidovudine usually is used with lamivudine or emtricitabine in conjunction with a recommended HIV integrase strand transferase inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI).199

When lamivudine/zidovudine is used as the dual NRTI option in PEP† regimens, adults should receive 1 tablet (150 mg of lamivudine and 300 mg of zidovudine) twice daily in conjunction with a recommended INSTI, NNRTI, or PI.199

PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals with impaired renal function (creatinine clearance 59 mL/minute or less), oral zidovudine in conjunction with lamivudine and either raltegravir or dolutegravir is a preferred regimen.198 Zidovudine dosage should be adjusted based on the degree of renal impairment.198

The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days.198 If it has been more than 72 hours since the exposure, nPEP may not be recommended.198

Dosage Modification for Toxicity

Dosage interruption of zidovudine may be required in patients that develop significant anemia (hemoglobin levels of less than 7.5 g/dL or a reduction of over 25% from baseline) and/or neutropenia (granulocyte count less than 750 cells/mm³or a reduction of over 50% from baseline) until bone marrow recovery is evident.1,231 In patients who develop significant anemia, dosage interruption does not necessarily eliminate the need for blood transfusions.1,231

If marrow recovery occurs following dosage interruption, reinitiation of zidovudine therapy may be appropriate using adjunctive measures (e.g., epoetin alfa), depending on hematologic indices such as serum erythropoetin level and patient tolerance.1,231

Special Populations

Hepatic Impairment

Data are insufficient to recommend zidovudine dosage adjustments for patients with impaired hepatic function or liver cirrhosis.1,231 However, because plasma concentrations of zidovudine appear to be increased in patients with hepatic impairment and may increase the risk of adverse hematologic effects, frequent monitoring for hematologic toxicities is advised.1,231

Renal Impairment

Zidovudine dosage should be reduced in patients with severe renal impairment (i.e., creatinine clearance less than 15 mL/minute).1,231 Adults maintained on hemodialysis or peritoneal dialysis or with creatinine clearance less than 15 mL/minute should receive an oral zidovudine dosage of 100 mg every 6-8 hours1,231 or an IV dosage of 1 mg/kg every 6-8 hours for treatment of HIV infection.1

Geriatric Patients

The manufacturer provides no specific dosage recommendations in geriatric patients.1,231 The manufacturer states that in general, the dosage of zidovudine should be selected with caution in geriatric patients because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1,231

Contraindications

• History of potentially life-threatening hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to the drug or any ingredient in the formulation.1,231

Warnings/Precautions

Warnings

Hematologic Toxicity

A boxed warning regarding the risk of hematologic toxicity is included in the prescribing information for zidovudine.1,231 Zidovudine therapy has been associated with hematologic toxicity, including neutropenia and/or severe anemia, especially in patients with advanced human immunodeficiency virus (HIV) disease.1,231 Zidovudine should be used with caution in patients who have bone marrow compromise evidenced by a granulocyte count less than 1000 cells/mm³ or hemoglobin concentrations less than 9.5 g/dL.1,231 Hematologic toxicity is related to bone marrow reserve at baseline, and to dosage and duration of therapy with zidovudine.1,231

A decrease in hemoglobin concentration may occur as early as 2-4 weeks after initiation of zidovudine therapy.1,231 Neutropenia occurs most commonly after 6-8 weeks of therapy.1,231 Pancytopenia has also been reported, which is usually reversible after discontinuation of zidovudine.1,231

Frequent monitoring of blood cell counts (CBCs) and indices of anemia (e.g., hemoglobin, mean corpuscular volume) are recommended during treatment with zidovudine to detect severe anemia and neutropenia, particularly in those with advanced HIV disease.1,231 Periodic monitoring of the CBC is recommended in patients with early or asymptomatic HIV infection.1,231

Dose interruption of zidovudine, and potential transfusion, may be required in patients that develop significant anemia (hemoglobin levels of less than 7.5 g/dL or a reduction of over 25% from baseline) or neutropenia (granulocyte count less than 750 cells/mm³ or reduction of over 50% from baseline) until bone marrow recovery is evident.1,231 In patients who develop significant anemia, dosage interruption does not necessarily eliminate the need for blood transfusions.1,231 If marrow recovery occurs following dosage interruption, reinitiation of zidovudine therapy may be appropriate using adjunctive measures (e.g., epoetin alfa), depending on hematologic indices such as serum erythropoetin level and patient tolerance.1,231

Musculoskeletal Effects

A boxed warning regarding the risk of musculoskeletal effects is included in the prescribing information for zidovudine.1,231 Myopathy and myositis with pathologic changes, similar to that produced by HIV infection, have been associated with prolonged use of zidovudine.1,231

Lactic Acidosis and Severe Hepatomegaly with Steatosis

A boxed warning regarding the risk of lactic acidosis and severe hepatomegaly with steatosis is included in the prescribing information for zidovudine.1,231 Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported in patients receiving nucleoside analogs, including zidovudine.1,231 Most reported cases have involved female patients;1,231 obesity also may be a risk factor.1,231

Suspend treatment with zidovudine if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of markedly increased serum aminotransferase concentrations).1,231

Other Warnings and Precautions

Allergic Reaction to Latex

The vial stoppers of zidovudine concentrate for IV infusion contain dry natural rubber, which may cause allergic reactions in latex-sensitive individuals.1

Use with Interferon- and Ribavirin-Based Regimens in HIV-1/Hepatitis C Virus (HCV) Coinfected Patients

Exacerbation of anemia has been reported in patients coinfected with HIV and HCV receiving zidovudine, interferon alfa, and ribavirin concomitantly.1,231 Hepatic decompensation, sometimes fatal, has also been reported in HIV-infected patients coinfected with HCV who received antiretroviral therapy concomitantly with interferon alfa with or without ribavirin.1,231 Closely monitor for signs of toxicity (e.g., hepatic decompensation, neutropenia, anemia) in patients receiving concomitant zidovudine and interferon alfa with or without ribavirin.1,231

Concomitant use of ribavirin and zidovudine is not recommended.1,231 Consider replacing zidovudine in established HIV-1/HCV regimens, particularly in those patients with a known history of anemia caused by zidovudine.1,231

Discontinue zidovudine as medically necessary.1,231 Also consider dosage reduction or discontinuation of interferon alfa, ribavirin, or both agents, if worsening toxicity, including hepatic decompensation (e.g., Child Pugh score of over 6) occurs.1,231

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); this may necessitate further evaluation and treatment.1,231

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution;1,231 however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1,231

Lipodystrophy

Zidovudine treatment has been associated with lipoatrophy (loss of subcutaneous fat); the incidence and severity of this effect are related to cumulative exposure to the drug.1,231 Fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to an antiretroviral regimen that does not contain zidovudine.1,231 Patients receiving zidovudine should be regularly assessed for signs of lipoatrophy.1,231 If fat loss is suspected, therapy should be switched to an alternative antiretroviral regimen if feasible.1,231

Specific Populations

Pregnancy

Zidovudine crosses the human placenta and concentrations in neonatal plasma at birth were equivalent to maternal plasma concentrations.1,231 In neonates and infants exposed to zidovudine in utero, cases of mild and transient serum lactate elevations, possibly due to mitochondrial dysfunction, have been reported; the clinical significance of these elevations is unknown.1,231 There have also been few reports of seizures, developmental delays, and other neurological disorders; however, a causal relationship of zidovudine exposure in utero or during the peri-partum phase with these events has not been established.1,231

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including zidovudine, the Antiretroviral Pregnancy Registry was established.1,231 Clinicians are encouraged to contact the registry at 800-258-4263 or [Web] to enroll such women.1,231

Data from the Antiretroviral Pregnancy Registry show no difference in the overall risk of birth defects for zidovudine compared with the background rate for birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1,231 Registry data include over 13,000 prospective reports of zidovudine exposures during pregnancy resulting in live births, including over 4000 first trimester exposures to the drug.1,231

Lactation

Zidovudine is distributed into human milk.1,231 The effects of zidovudine on milk production, or on the breast-fed infant are not known.1,231

Because of the risk of transmission of HIV to an uninfected infant through breast milk, the US Centers for Disease Control and Prevention (CDC) recommend that HIV-infected women not breast-feed infants.1,231

Pediatric Use

Pharmacokinetics of zidovudine in pediatric patients older than 3 months of age are similar to those reported in adults.1,231 Zidovudine pharmacokinetics in neonates 2 weeks of age and younger are substantially different from neonates over 2 weeks of age1,231

Geriatric Use

While clinical experience to date has not revealed age-related differences in response to zidovudine, clinical studies evaluating zidovudine have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1,231

Zidovudine should be used with caution in geriatric patients because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1,231

Hepatic Impairment

Zidovudine is primarily eliminated via hepatic metabolism.1,231 Because plasma concentrations of zidovudine appear to be increased in patients with hepatic impairment and may increase the risk of adverse hematologic effects, frequent monitoring for hematologic toxicities is advised.1,231

Renal Impairment

Unchanged zidovudine and its glucuronide metabolite primarily undergo renal excretion.1,231 In patients with severe renal impairment (creatinine clearance less than 15 mL/minute), zidovudine exposure based on AUC and the elimination half-life are increased in comparison to normal renal function.1,231 The elimination half-life of zidovudine in severe renal impairment averages approximately 1.4 hours.1,231

Common Adverse Effects

Adverse reactions occurring in 15% or more of adult patients receiving zidovudine for HIV-1 in clinical trials include headache, malaise, nausea, vomiting, and anorexia.1,231 In pediatric patients receiving zidovudine for HIV-1 in clinical trials, fever and cough were the most commonly reported adverse reactions, occurring in 15% or more of patients.1,231 In neonates who received zidovudine for the prevention of maternal-fetal transmission of HIV-1, the most common adverse reaction was anemia (incidence of 15% or greater).1,231

Adverse systemic effects reported with IV zidovudine are similar to those reported with oral zidovudine.1,231 However, long-term IV zidovudine therapy (i.e., longer than 2-4 weeks) has not been evaluated in adults and may enhance adverse hematologic effects.1,231

The following drug interactions are based on studies using single-entity zidovudine.1,231 When a fixed combination containing zidovudine is used, interactions associated with each drug in the fixed combination should be considered.227,229

Atovaquone

Concomitant use of zidovudine (200 mg every 8 hours) and atovaquone (750 mg every 12 hours with food) in 14 human immunodeficiency virus (HIV)-infected adults increased the AUC of zidovudine by about 31% (range 23-78% increase), and did not affect the pharmacokinetics of atovaquone.1,231

Routine zidovudine dosage adjustments are not warranted in patients receiving zidovudine concomitantly with atovaquone.1,231

Clarithromycin

Concomitant use of clarithromycin (500 mg twice daily) and zidovudine (100 mg every 4 hours for 7 days) decreased the AUC of zidovudine by 12% (range 34% decrease to 14% increase).1,231

Routine zidovudine dosage adjustments are not warranted in patients receiving zidovudine and clarithromycin concomitantly.1,231

Doxorubicin

Because there is in vitro evidence that doxorubicin antagonizes the antiretroviral activity of zidovudine,1,231 concomitant use of doxorubicin and zidovudine should be avoided.1,231

Fluconazole

Concomitant use of zidovudine (200 mg every 8 hours) and fluconazole (400 mg daily) increased the AUC of zidovudine by 74% (range 54-98% increase).1,231

The manufacturer of zidovudine states that routine zidovudine dosage adjustments are not warranted in patients receiving concomitant fluconazole.1,231

HIV Protease Inhibitors

Concomitant use of zidovudine (single 200-mg dose) and nelfinavir (750 mg every 8 hours for 7-10 days) resulted in a 35% decrease in the AUC of zidovudine (range 28-41% decrease); concentrations of nelfinavir were not affected by concomitant zidovudine.1,231

Routine zidovudine dosage adjustments are not warranted in patients receiving zidovudine and nelfinavir concomitantly.1,231

Concomitant use of oral zidovudine (200 mg every 8 hours) and oral ritonavir (300 mg every 6 hours) for 4 days decreased the AUC of zidovudine by 25% (range 15-34% decrease), but did not affect the pharmacokinetics of ritonavir.1,231

Dosage adjustments are not necessary in patients receiving zidovudine and ritonavir concomitantly.1,231

Ganciclovir

Concomitant use of zidovudine and ganciclovir may increase the hematologic toxicity of zidovudine.1,231

Interferon Alfa

Concomitant use of interferon alfa and zidovudine can increase the risk of hematologic (e.g., neutropenia, thrombocytopenia) and hepatic toxicity.1,231 Potentially fatal hepatic decompensation has been reported in HIV-infected patients coinfected with hepatitis C virus (HCV) who received antiretroviral therapy concomitantly with interferon alfa with or without ribavirin.1,231 Patients receiving zidovudine with interferon alfa with or without ribavirin should be closely monitored for toxicities, especially hepatic decompensation, neutropenia, and anemia.1,231 Consider discontinuation of zidovudine as medically appropriate.1,231 If worsening toxicities (e.g., hepatic decompensation with Child-Pugh scores greater than 6) occur, consider immediate discontinuation or dosage reduction of interferon alfa and/or ribavirin.1,231

Lamivudine

Concomitant use of lamuvidine (300 mg every 12 hours) and oral zidovudine (single 200-mg dose) resulted in a 13% increase in the AUC of zidovudine (range 2-27% increase), but did not affect concentrations of lamivudine.1,231

The manufacturer of zidovudine states that routine zidovudine dosage adjustments are not warranted in patients receiving concomitant lamivudine.1,231

Methadone

Concomitant use of methadone (30-90 mg daily) and oral zidovudine (200 mg every 4 hours) resulted in an 43% increase in the AUC of zidovudine (range 16-64% increase), but did not affect the pharmacokinetics of methadone.1,231

The manufacturer of zidovudine states that routine zidovudine dosage adjustments are not warranted in patients receiving concomitant methadone.1,231

Myelosuppressive Agents

Drugs that are cytotoxic or myelosuppressive (e.g., ganciclovir, interferon alfa, ribavirin) may increase the risk of hematologic toxicity of zidovudine.1,231

Phenytoin

Decreased plasma phenytoin concentrations have been reported in some patients receiving concomitant zidovudine and, in at least one patient, an increased phenytoin concentration was reported.1,231

In one study in adults with HIV infection receiving oral zidovudine therapy (200 mg every 4 hours), administration of a single 300-mg dose of phenytoin resulted in a 30% decrease in clearance of zidovudine; pharmacokinetics of phenytoin were not affected.1,231

Probenecid

Concomitant use of probenecid (500 mg every 6 hours for 2 days) and zidovudine (2 mg/kg every 8 hours for 3 days) increased the AUC of zidovudine by 106% (range 100-170% increase).1,231

The manufacturer of zidovudine states that routine zidovudine dosage adjustments are not warranted if probenecid and zidovudine are used concomitantly.1,231

Rifampin

Concomitant use of zidovudine (200 mg every 8 hours) and rifampin (600 mg once daily) for 14 days resulted in a 47% decrease in zidovudine AUC (range 41-53% decrease).1,231

The manufacturer of zidovudine states that routine dosage adjustments are not necessary if rifampin and zidovudine are used concomitantly.1,231

Ribavirin

The manufacturers of zidovudine state that the concomitant use of zidovudine and ribavirin is not recommended and should be avoided.1,231 If zidovudine and ribavirin are used concomitantly, closely monitor for virologic response and toxicities such as hepatic decompensation, neutropenia, and anemia.1,231

In vitro, ribavirin antagonizes the antiviral activity of zidovudine against HIV.1,231 This antagonism appears to result from the inhibition of zidovudine phosphorylation.1,231 Despite this antagonism, no evidence of pharmacokinetic or pharmacodynamic (e.g., loss of virologic suppression of HIV or HCV) interactions were observed when ribavirin and zidovudine were given concomitantly to HIV-1 and HCV-coinfected patients, although exacerbation of anemia from ribavirin has been reported when zidovudine is used concomitantly.1,231

Valproic Acid

Concomitant use of valproic acid (250 or 500 mg every 8 hours) and oral zidovudine (100 mg every 8 hours) for 4 days in 6 HIV-infected adults resulted in an 80% increase in the AUC of zidovudine.1,231 The effect of concomitant zidovudine on the pharmacokinetics of valproic acid was not evaluated.1,231 Severe anemia has been reported following initiation of valproic acid therapy (500 mg twice daily) in an HIV-infected adult who was receiving an antiretroviral regimen that contained zidovudine, lamivudine, and abacavir; the patient had stable hematologic status at the time valproic acid was started.509

The manufacturer of zidovudine states that routine zidovudine dosage adjustments are not warranted in patients receiving zidovudine and valproic acid concomitantly.1,231

Description

Zidovudine is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).1 Following conversion to a pharmacologically active metabolite, zidovudine inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1,2,4,5,7,16,18,25,29,30,46,66,79,260 Like other HIV NRTIs, the antiviral activity of zidovudine appears to depend on intracellular conversion of the drug to a triphosphate metabolite.1,2,4,5,7,16,18,25,29,30,46,47,260 Zidovudine 5'-triphosphate and not unchanged zidovudine appears to be the pharmacologically active form of the drug.1,2,30

Zidovudine has a limited spectrum of antiviral activity.1,231 Following intracellular conversion to a pharmacologically active metabolite, the drug is active in vitro against HIV type 1.1,231 The antiretroviral activity of zidovudine has been evaluated in vitro in cell culture systems, including monocytes and human blood lymphocytes.1,231

HIV type 1 strains with reduced susceptibility or resistance to zidovudine have been selected in vitro in cell culture and also have emerged during therapy with the drug.1,231 Genotypic analyses of isolates selected in cell culture and recovered from zidovudine-treated patients showed thymidine analog mutations (TAMs) in the HIV-1 reverse transcriptase that include M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N/Q.1,231 The degree of zidovudine resistance appears to depend on the number and combination of these mutations.1,231 Cross-resistance has been reported among the HIV NRTIs.1,231 TAM substitutions in HIV-1 reverse transcriptase selected by zidovudine can confer cross-resistance to abacavir, didanosine, and tenofovir.1,231

Following IV infusion of zidovudine, dose-independent pharmacokinetics are observed over the dosage range of 1-5 mg/kg.1,231 Zidovudine is rapidly absorbed from the GI tract, with peak serum concentrations generally occurring within 0.5-1.5 hours after an oral dose of the drug.1,231 In fasting adults, mean oral bioavailability of zidovudine is 64%.1,231 In pediatric patients, mean oral bioavailability is 61% in infants 14 days to 3 months of age and 65% in pediatric patients 3 months to 12 years of age.1,231 Bioavailability is greater in neonates 14 days old or younger and is reported to be 89%.1,231 Systemic exposure of zidovudine following administration of zidovudine tablets or oral solution is equivalent to that following administration of the capsules.1,231 In children 3 months to 12 years of age, zidovudine appears to have dose-dependent increases in plasma concentrations after administration of an oral solution over the dosage range of 90-240 mg/m² every 6 hours.1,231 Zidovudine is distributed into CSF following oral or IV administration.1,231 The drug is less than 38% bound to plasma proteins.1,231 Zidovudine primarily undergoes elimination via hepatic metabolism.1,231 Following oral administration of zidovudine, 14% of the total dose is excreted in urine as unchanged zidovudine and 74% as the major metabolite, 3'-azido-3'-deoxy-5'- O -β- D -glucopyranuronosylthymidine (GZDV).1,231 Following IV administration, 18% of the total dose is excreted in the urine as unchanged zidovudine, and 60% as GZDV.1,231 The plasma half-life of zidovudine in adults averages approximately 0.5-3 hours following oral or IV administration.1,231 The plasma half-life of zidovudine in neonates and infants averages approximately 3.1 hours in neonates up to 14 days of age, 1.9 hours in infants 14 days to 3 months of age, and 1.5 hours in pediatric patients 3 months to 12 years of age.1,231 Zidovudine clearance is decreased and plasma concentrations are increased in patients with hepatic impairment.1,231 Hemodialysis and peritoneal dialysis appear to have a negligible effect on removal of zidovudine,1,231 but may enhance elimination of GZDV.1,231 Results of a limited single-dose study indicate that sex does not affect the pharmacokinetics of zidovudine.1,231

Advice to Patients

• Inform patients that neutropenia and/or anemia are the major toxicities reported with zidovudine and that the frequency and severity are greater in patients with more advanced HIV disease and in those who initiate therapy later in the course of their infection.1,231 Importance of CBC monitoring, especially in patients with advanced symptomatic HIV disease.1,231 Advise patients that if hematologic toxicity develops, transfusions or discontinuance of the drug may be required.1,231
• Inform patients that potentially life-threatening hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) have been reported in patients receiving zidovudine. Importance of immediately contacting a clinician if rash develops since this may be a sign of a more serious reaction.1,231
• Advise latex-sensitive patients that vial stoppers of zidovudine concentrate for IV infusion contain dry natural rubber (a latex derivative), which may cause allergic reactions in individuals sensitive to latex.1
• Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine.1,231
• Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogs and other antiretrovirals.1,231 Importance of discontinuing zidovudine and notifying a clinician if symptoms suggestive of lactic acidosis or pronounced hepatotoxicity develop.1,231
• Inform HIV-infected patients coinfected with HCV that hepatic decompensation (sometimes fatal) has been reported when antiretrovirals were used for treatment of HIV infection in patients receiving interferon alfa with or without ribavirin.1,231
• Inform patients that myopathy and myositis with pathologic changes have been reported in individuals who received long-term zidovudine therapy.1,231
• Advise patients to immediately contact a clinician if they have any signs or symptoms of infection since inflammation from previous infections may occur soon after antiretroviral therapy is initiated.1,231
• Inform patients that loss of subcutaneous fat may occur in patients receiving zidovudine and that they will be regularly assessed for this effect during therapy.1,231
• Advise caregivers to use an appropriate-sized oral syringe with 0.1 mL graduations in neonates to ensure the accurate dosing of zidovudine oral solution.1
• Instruct patients that if they miss a dose of zidovudine, to take it as soon as they remember.1,231 Advise patients not to double their next dose or take more than the prescribed dose.1,231
• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription (e.g., ganciclovir, interferon alfa, ribavirin) and OTC drugs and dietary or herbal products, and any concomitant illnesses.1,231
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Inform pregnant women considering the use of zidovudine during pregnancy for prevention of HIV transmission to their infants that transmission may still occur in some cases despite therapy.1,231 Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to zidovudine during pregnancy.1,231 Advise HIV-infected women not to breast-feed because HIV can be passed to the baby in the breast milk.1,231
• Inform patients of other important precautionary information.1,231

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. ViiV Healthcare. Retrovir^® (zidovudine) capsules, oral solution, and injection for IV use prescribing information. Research Triangle Park, NC; 2023 June.

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