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Zidovudine

Pronunciation

Class: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: 3′-Azido-3′-deoxythymidine
CAS Number: 30516-87-1
Brands: Combivir, Retrovir, Trizivir

Warning(s)

  • Hematologic Toxicity
  • Hematologic toxicity reported, particularly in patients with advanced HIV-1 disease.1 227 229 231 (See Hematologic Effects under Cautions.)

  • Myopathy
  • Symptomatic myopathy reported with prolonged use.1 227 229 231 (See Musculoskeletal Effects under Cautions.)

  • Lactic Acidosis and Severe Hepatomegaly
  • Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported rarely in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs) alone or in conjunction with other antiretrovirals.1 227 229 231 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  • Fixed Combinations
  • If using Combivir or Trizivir, consider that severe, acute exacerbations of HBV have been reported following discontinuance of lamivudine in patients coinfected with HBV and HIV.227 229 Monitor hepatic function closely;227 229 initiate HBV treatment if appropriate.227 229

  • If using Trizivir, consider that abacavir has been associated with serious and sometimes fatal hypersensitivity reactions.229 Because individuals with human leukocyte antigen (HLA)-B*5701 allele are at high risk for abacavir hypersensitivity reactions,229 screening for HLA-B*5701 allele recommended prior to initiation of Trizivir.229 Discontinue Trizivir as soon as a hypersensitivity reaction is suspected.229 Regardless of patient’s HLA-B*5701 status, permanently discontinue if hypersensitivity cannot be ruled out.229

Introduction

Antiretroviral; nucleoside reverse transcriptase inhibitor (NRTI).1 4 12 16 18 200 231 260 296

Uses for Zidovudine

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.1 200 201 231

Used with another NRTI (dual NRTIs) in conjunction with a nonnucleoside reverse transcriptase inhibitor (NNRTI) or HIV protease inhibitor (PI) in NNRTI- or PI-based regimens.200 201 Also used with another NRTI (dual NRTIs) in conjunction with an HIV integrase inhibitor or HIV entry inhibitor.200

For initial treatment in HIV-infected adults and adolescents, some experts state that zidovudine and either emtricitabine or lamivudine is an acceptable (not preferred or alternative) dual NRTI option.200 Zidovudine and lamivudine remains the preferred dual NRTI option in antiretroviral-naive pregnant women.200

When PI- or NNRTI-based regimens are used for initial treatment in HIV-infected children, some experts state that zidovudine and either lamivudine or emtricitabine is a preferred dual NRTI option; zidovudine and abacavir (use only in those ≥3 months of age who test negative for HLA-B*5701 allele) or zidovudine and didanosine are alternative dual NRTI options.201

Dual NRTI option of zidovudine and stavudine not recommended at any time because of antagonistic antiretroviral effects.200 201

Fixed-combination preparation containing zidovudine and lamivudine (Combivir) used when dual NRTI option of zidovudine and lamivudine is indicated in conjunction with other antiretrovirals.200 227

Fixed-combination preparation containing abacavir, lamivudine, and zidovudine (Trizivir) used for triple NRTI regimen;200 229 used alone or in conjunction with other antiretrovirals.229 Consider that Trizivir is intended only for regimens that require all 3 drugs and that data are limited regarding use of the fixed combination in patients with higher viral loads (>100,000 copies/mL) at baseline.229

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Triple NRTI regimen of abacavir, lamivudine, and zidovudine not generally recommended because of inferior virologic efficacy;200 201 consider use only in special circumstances when other regimens cannot be used (e.g., because of concerns regarding drug interactions or adherence).200 201

Prevention of Perinatal HIV Transmission

Prevention of maternal-fetal transmission of HIV.1 202 231

Multiple-drug antiretroviral therapy should be discussed with and offered to all HIV-infected pregnant women in the US, regardless of plasma HIV-1 RNA level or CD4+ T-cell count.202 Multiple-drug antiretroviral regimens (≥3 drugs) are considered the standard of care in the US for HIV treatment during pregnancy and for prevention of perinatal HIV transmission; such regimens are recommended even in pregnant women who do not require an antiretroviral regimen for their own health (e.g., those with undetectable or low HIV-1 RNA levels).202

Zidovudine used alone during pregnancy for prevention of perinatal HIV transmission is not optimal, but may be an option in some HIV-infected pregnant women not currently receiving antiretroviral therapy who have plasma HIV-1 RNA levels <1000 copies/mL and wish to minimize fetal exposure to antiretrovirals.202

In addition, to decrease risk of perinatal HIV transmission, certain pregnant HIV-infected women in the US should receive intrapartum IV zidovudine prophylaxis initiated at onset of labor and continued until delivery (unless contraindicated) and all neonates born to HIV-infected women should receive oral or IV zidovudine prophylaxis initiated as soon as possible after birth (within 6–12 hours) and continued through 6 weeks of age.202

Intrapartum IV zidovudine regimen indicated during labor in all HIV-infected women with HIV-1 RNA levels ≥400 copies/mL (or with unknown HIV-1 RNA levels) near delivery, regardless of current antiretroviral regimen or mode of delivery.202 IV zidovudine regimen no longer required during labor in those with HIV-1 RNA levels <400 copies/mL near delivery.202

In situations when an HIV-infected woman received no antiretrovirals prior to and/or during labor, some experts recommend that a multiple-drug regimen be used for neonatal prophylaxis (e.g., 2-drug regimen that includes 3 neonatal nevirapine doses given during first week of life in addition to the usual 6-week neonatal zidovudine regimen).202 Decisions regarding use of multiple-drug neonatal prophylaxis regimens in this situation and other situations associated with increased risk of perinatal HIV transmission (e.g., HIV-infected woman with high viral load or known antiretroviral-resistant HIV at time of delivery) should be made in consultation with a pediatric HIV specialist.202

Clinicians can consult National Perinatal HIV Hotline at 888-448-8765 for information regarding antiretroviral treatment of pregnant HIV-infected women and their infants and prevention of perinatal HIV transmission.202 Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries.202

Postexposure Prophylaxis of HIV

Postexposure prophylaxis of HIV infection in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.96 97 98 149 194 199 337 338 339 340 341 342 343 344 418 465 531 Used in conjunction with other antiretrovirals.199

Postexposure prophylaxis of HIV infection in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

Zidovudine Dosage and Administration

Administration

Administer orally or by intermittent or continuous IV infusion.1 231 Do not administer by rapid or bolus IV injection, IM injection, or sub-Q injection.231

Oral Administration

Administer single-entity preparations (Retrovir, generic) or fixed-combination preparations (Combivir, Trizivir) orally without regard to meals.1 227 229

To reduce risk of esophageal irritation and ulceration, administer zidovudine capsules while patient is in an upright position and with adequate amounts of fluid (e.g., at least 120 mL of water).184

For children, zidovudine oral solution can be used.1 Alternatively, children who can reliably swallow an intact tablet or capsule may receive zidovudine tablets or capsules.1

Combivir: Because dosages of the drugs in this fixed combination (lamivudine, zidovudine) cannot be adjusted individually, do not use in children or adolescents weighing <30 kg, patients with impaired renal function (i.e., Clcr <50 mL/minute), patients with impaired hepatic function, patients who experience dose-limiting adverse effects, or others requiring dosage adjustment.227

Trizivir: Because dosages of the drugs in this fixed combination (abacavir, lamivudine, zidovudine) cannot be adjusted individually, do not use in pediatric patients, adolescents weighing <40 kg, patients with impaired renal function (i.e., Clcr <50 mL/minute), patients with impaired hepatic function, or others requiring dosage adjustment.229

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Oral zidovudine should replace parenteral zidovudine as soon as feasible.231

Dilution

Zidovudine concentrate for IV infusion containing 10 mg/mL must be diluted prior to administration.231 Withdraw appropriate dose from the vial and dilute in 5% dextrose injection to provide a solution containing ≤4 mg/mL.231

Rate of Administration

Intermittent IV infusions should be infused over 60 minutes.231

In neonates, intermittent IV infusions should be infused over 30 minutes.231

Dosage

IV dosage of 1 mg/kg every 4 hours is equivalent to oral dosage of 100 mg every 4 hours.231

Dosage of Combivir and Trizivir expressed as number of tablets.227 229

Pediatric Patients

Treatment of HIV Infection

Dosage in children is based on weight or, alternatively, body surface area (BSA).1 To avoid medication errors, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.1

Oral

Premature neonates: 2 mg/kg every 12 hours; increase frequency of administration to every 8 hours at 2 weeks of age in neonates with ≥30 weeks gestation at birth or at 4 weeks of age in those with <30 weeks gestation at birth.201

Neonates and infants <6 weeks of age: 2 mg/kg every 6 hours.201

Table 1. Oral Zidovudine Dosage in Pediatric Patients ≥4 Weeks of Age Who Weigh ≥4 kg 1

Body Weight (kg)

Dosage Regimen

4 to <9

12 mg/kg twice daily or 8 mg/kg 3 times daily

9 to <30

9 mg/kg twice daily or 6 mg/kg 3 times daily

≥30

300 mg twice daily or 200 mg 3 times daily

Alternatively, if dosage for pediatric patients ≥4 weeks of age is based on BSA: 240 mg/m2 twice daily or 160 mg/m2 3 times daily.1

Combivir (children or adolescents weighing ≥30 kg): 1 tablet twice daily.201 227

Trizivir (adolescents weighing ≥40 kg): 1 tablet twice daily.201 229

IV

Premature neonates: 1.5 mg/kg every 12 hours; the frequency of administration may be increased to every 8 hours at 2 weeks of age in neonates with ≥30 weeks gestation at birth or at 4 weeks of age in those with <30 weeks gestation at birth.201

Neonates and infants <6 weeks of age: 1.5 mg/kg every 6 hours.201

Prevention of Perinatal HIV Transmission
Neonates born to HIV-infected Women
Oral

Premature neonates <30 weeks of gestation: Initiate prophylaxis with 2 mg/kg every 12 hours as soon as possible after birth (within 6–12 hours); increase dosage to 3 mg/kg every 12 hours after 4 weeks of age and continue through 6 weeks of age.202

Premature neonates ≥30 weeks to <35 weeks of gestation: Experts recommend 2 mg/kg every 12 hours initiated as soon as possible after birth (within 6–12 hours); increase dosage to 3 mg/kg every 12 hours at 15 days of age and continue through 6 weeks of age.202

Neonates ≥35 weeks of gestation: Experts recommend 4 mg/kg twice daily initiated as soon as possible after birth (within 6–12 hours) and continued through 6 weeks of age.202

Neonates: Manufacturer recommends 2 mg/kg every 6 hours initiated within 12 hours of birth and continued through 6 weeks of age.1 231

Used in conjunction with intrapartum IV zidovudine prophylaxis regimen in the HIV-infected mother.202

Consultation with pediatric HIV specialist recommended if making decisions regarding use of multiple-drug neonatal prophylaxis regimens that include other antiretrovirals in addition to zidovudine.202 (See Prevention of Perinatal HIV Transmission under Uses.)

IV

Premature neonates <30 weeks of gestation: Initiate prophylaxis with 1.5 mg/kg every 12 hours as soon as possible after birth (within 6–12 hours); increase dosage to 2.3 mg/kg every 12 hours after 4 weeks of age and continue through 6 weeks of age.202

Premature neonates ≥30 weeks to <35 weeks of gestation: Experts recommend 1.5 mg/kg every 12 hours initiated as soon as possible after birth (within 6–12 hours); increase dosage to 2.3 mg/kg every 12 hours at 15 days of age and continue through 6 weeks of age.202

Neonates ≥35 weeks of gestation: 3 mg/kg every 12 hours as soon as possible after birth (within 6–12 hours) and continue through 6 weeks of age.1 202 231

Used in conjunction with intrapartum IV zidovudine prophylaxis regimen in the HIV-infected mother.201

Consultation with pediatric HIV specialist recommended if making decisions regarding use of multiple-drug neonatal prophylaxis regimens that include other antiretrovirals in addition to zidovudine.202 (See Prevention of Perinatal HIV Transmission under Uses.)

Adults

Treatment of HIV Infection
Oral

600 mg daily in divided doses.1 200 Usually given in a dosage of 200 mg 3 times daily or 300 mg twice daily.200

Combivir (adults weighing ≥30 kg): 1 tablet twice daily.200 227

Trizivir: 1 tablet twice daily.200 229

IV

1 mg/kg 5 to 6 times daily (5 to 6 mg/kg daily).231 Higher dosage may be associated with greater improvement of neurologic symptoms in patients with preexisting neurologic disease.231

Prevention of Perinatal HIV Transmission
HIV-infected Pregnant Women
IV

At start of labor, 2 mg/kg given by IV infusion over 1 hour followed by 1 mg/kg per hour given by continuous IV infusion until delivery.1 202 231

Indicated in all HIV-infected pregnant women in labor (unless contraindicated), regardless of viral load or current antiretroviral regimen.202 (See Prevention of Perinatal HIV Transmission under Uses.) If oral zidovudine is part of current antiretroviral regimen, substitute with IV zidovudine until after delivery;202 continue other antiretrovirals in the woman’s antiretroviral regimen on schedule as much as possible during labor.202

Used in conjunction with oral or IV zidovudine prophylaxis regimen in the neonate.202

Postexposure Prophylaxis of HIV
Occupational Exposure
Oral

200 mg 3 times daily or 300 mg twice daily.199

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.199 467 470

Nonoccupational Exposure
Oral

200 mg 3 times daily or 300 mg twice daily.198

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.198

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

Infants and children ≥4 weeks of age: Maximum 600 mg daily.1

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Data insufficient to recommend dosage adjustment for patients with mild to moderate hepatic impairment or liver cirrhosis;1 dosage reduction may be necessary and frequent monitoring for hematologic toxicities is advised.231

Combivir and Trizivir: Do not use in patients with hepatic impairment.227 229

Renal Impairment

Treatment of HIV Infection
Oral

Adults with severe renal impairment (Clcr <15 mL/minute): Dosage reduction recommended.1 Use 100 mg every 6–8 hours in those with end-stage renal disease maintained on hemodialysis or peritoneal dialysis.1

Combivir and Trizivir: Do not use in patients with Clcr <50 mL/minute.227 229

IV

Adults with severe renal impairment (Clcr <15 mL/minute): Dosage reduction recommended.1 Use 1 mg/kg every 6–8 hours in those with end-stage renal disease maintained on hemodialysis or peritoneal dialysis.231

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 231

Cautions for Zidovudine

Contraindications

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

Warnings/Precautions

Warnings

Hematologic Effects

Hematologic toxicity (including neutropenia and severe anemia) reported, especially in patients with advanced HIV-1 disease.1 2 3 29 30 38 62 64 65 82 106 107 134 139 231 260 332 Pancytopenia reported; pancytopenia usually reversible following discontinuation of zidovudine.1 231

Blood cell counts and indices of anemia (e.g., hemoglobin, mean corpuscular volume) should be determined prior to and monitored during zidovudine therapy.1 50 64 181 231 332 Patients with advanced HIV disease or low baseline blood cell counts and indices of anemia should be monitored frequently1 231 (at least every 2 weeks);181 231 periodic monitoring1 231 (once monthly for the first 3 months and then, if stable, once every 3 months) recommended for patients with asymptomatic or early symptomatic HIV infection.181

Substantial anemia (hemoglobin <7.5 g/dL or >25% reduction from baseline) and/or neutropenia (granulocyte count <750/mm3 or >50% reduction from baseline) may require dose interruption until there is evidence of bone marrow recovery.1 231 Dose interruption does not necessarily eliminate need for transfusion.1 231 If bone marrow recovery occurs following dose interruption, reinitiation may be appropriate using adjunctive measures (e.g., epoetin alfa), depending on hematologic indices and patient tolerance.1 231

Musculoskeletal Effects

Myopathy and myositis with pathologic changes, similar to that produced by HIV-1 disease, associated with long-term zidovudine use.1 231

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving NRTIs (including zidovudine) alone or in conjunction with other antiretrovirals.1 227 229 Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors.1 227 229 Has been reported in patients with no known risk factors.1 227 229

Use particular caution in patients with known risk factors for liver disease.1 227 229

Interrupt therapy 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).1 227 229

Considerations in Patients Coinfected with HIV and HCV

Exacerbation of anemia reported in patients coinfected with HIV and HCV receiving zidovudine, interferon alfa, and ribavirin concomitantly.1 (See Specific Drugs under Interactions.)

Hepatic decompensation, sometimes fatal, reported in patients coinfected with HIV and HCV receiving antiretroviral therapy concomitantly with interferon alfa (or peginterferon alfa) with or without ribavirin.1 231 298 (See Specific Drugs under Interactions.)

Other Warnings and Precautions

Use of Fixed Combinations

Do not use multiple zidovudine-containing preparations concomitantly.1 227 229

When fixed combination containing lamivudine and zidovudine (Combivir) used, consider cautions, precautions, and contraindications associated with both drugs.227

When fixed combination containing abacavir, lamivudine, and zidovudine (Trizivir) used, consider cautions, precautions, and contraindications associated with all 3 drugs.229

Combivir and Trizivir: Use caution in patients with bone marrow compromise evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5 g/dL.227 229 (See Hematologic Effects under Cautions.)

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.1

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 jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.1

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

Specific Populations

Pregnancy

Retrovir, Combivir, Trizivir: Category C.1 231

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 231

Based on efficacy studies and extensive experience, zidovudine is the preferred NRTI for use in pregnant women.202 Zidovudine and lamivudine is a preferred dual NRTI option for use in multiple-drug antiretroviral regimens in pregnant women; the preferred dual NRTI option in those who are antiretroviral-naive.202

Pregnancy registry data indicate no increased risk for congenital abnormalities among infants born to women who receive zidovudine during pregnancy compared with general population.202 453

Lactation

Zidovudine distributed into human milk.1 231

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Pediatric Use

Well tolerated in neonates and children.1 91 92 114 163 231 244 245 458 However, usual zidovudine dosage used in full-term neonates may be excessive in premature neonates.201 530 (See Pediatric Dosage under Dosage and Administration.)

Major adverse effects reported in children are similar to those reported in adults1 91 92 114 163 244 245 and include bone marrow toxicity resulting in anemia and/or neutropenia.1 91 92 114 155 231 244 245

Combivir: Do not use in children or adolescents weighing <30 kg.227

Trizivir: Do not use in pediatric patients or in adolescents weighing <40 kg.229

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 231 No substantial differences in response relative to younger adults identified.1 231

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 231

Hepatic Impairment

Possibility of increased risk of hematologic toxicity in patients with severe hepatic impairment.1 231

Use with caution in patients with known risk factors for liver disease.1 231

Combivir and Trizivir: Do not use in patients with impaired hepatic function.227 229

Renal Impairment

Dosage adjustment recommended in patients with severe renal impairment (Clcr <15 mL/minute).1 231 (See Renal Impairment under Dosage and Administration.)

Combivir and Trizivir: Do not use in patients with Clcr <50 mL/minute.227 229

Common Adverse Effects

Headache, malaise, fever, cough, GI effects (anorexia, nausea, vomiting).1 231

Interactions for Zidovudine

Specific Drugs

Drug

Interaction

Comments

Abacavir

No clinically important pharmacokinetic interactions216

In vitro evidence of synergistic antiretroviral effects216

Acetaminophen

Pharmacokinetic interactions unlikely156

Acyclovir

Increased toxicity reported;15 has been used concomitantly without increased toxicity61 181

Antifungals, azoles

Fluconazole: Increased zidovudine AUC1 231 457

Fluconazole: Monitor for zidovudine-associated adverse effects;457 routine zidovudine dosage adjustments not warranted;1 231 consider reducing zidovudine dosage if substantial anemia or other severe zidovudine adverse effects occur231

Antimycobacterials, rifamycins

Rifabutin: Pharmacokinetic interactions unlikely409

Rifampin: Decreased zidovudine AUC1 150 231

Rifampin: Routine zidovudine dosage adjustments not warranted1 231

Atazanavir

No change in zidovudine AUC; possible decreased minimum zidovudine concentrations200

No in vitro evidence of antagonistic antiretroviral effects203

Clinical importance unknown200

Atovaquone

Increased zidovudine AUC; no change in atovaquone pharmacokinetics1 231 242

Possible increased hematologic toxicity242

Routine zidovudine dosage adjustments not warranted1 231

Buprenorphine

No clinically important pharmacokinetic interactions200

Dosage adjustments not needed200

Cidofovir

No pharmacokinetic interaction with cidofovir; however, cidofovir must be given concomitantly with probenecid and probenecid can reduce zidovudine clearance243

Manufacturer of zidovudine states routine zidovudine dosage adjustments not warranted if zidovudine given with probenecid;1 231 manufacturer of cidofovir recommends zidovudine be temporarily discontinued or dosage reduced by 50% on days that cidofovir and probenecid are given243

Co-trimoxazole

Pharmacokinetic interactions unlikely333

Darunavir

Ritonavir-boosted darunavir: Pharmacokinetic interaction not expected204

No in vitro evidence of antagonistic antiretroviral effects204

Delavirdine

No pharmacokinetic interactions212

In vitro evidence of additive or synergistic antiretroviral effects1 212 406

Didanosine

Decreased zidovudine concentrations and AUC;217 no effect on didanosine concentrations or AUC217

In vitro evidence of synergistic antiretroviral effects281

Doxorubicin

In vitro evidence of antagonism1 231 534

Avoid concomitant use1 231

Efavirenz

No effect on zidovudine peak concentrations or AUC213

In vitro evidence of additive or synergistic antiretroviral effects213 406

Dosage adjustment not needed213

Emtricitabine

Increased zidovudine peak concentration and AUC; no effect on emtricitabine peak concentrations or AUC218

In vitro evidence of additive to synergistic antiretroviral effects218

Pharmacokinetic interaction not considered clinically important218

Enfuvirtide

In vitro evidence of additive to synergistic antiretroviral effects223

Etravirine

No in vitro evidence of antagonistic antiretroviral effects214

Fosamprenavir

Increased amprenavir AUC;205 increased zidovudine concentrations and AUC205

In vitro evidence of synergistic antiretroviral effects205

Ganciclovir or valganciclovir

No clinically important pharmacokinetic interactions200

Potential increased risk of hematologic toxicity196 197 200 278 524

Concomitant use not recommended;196 278 524 advise patients that concomitant use may not be tolerated by some individuals and may result in severe granulocytopenia (neutropenia)1 165 197 233 521

Indinavir

Slightly increased indinavir concentrations and AUC; slightly increased zidovudine AUC, decreased zidovudine peak concentrations206

In vitro evidence of synergistic antiretroviral effects206

Interferon (interferon alfa, peginterferon alfa)

Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with HIV and HCV receiving antiretroviral agents and interferon alfa (or peginterferon alfa) with or without ribavirin1 231 298

Increased risk of hematologic toxicity (e.g., neutropenia, thrombocytopenia) and hepatic toxicity in patients receiving interferon alfa (or peginterferon alfa), ribavirin, and zidovudine1 231 298 395 399

In vitro evidence of synergistic antiretroviral effects34 57 351 395 396 397 398 399

Monitor for adverse effects1 231 298 395 399

If zidovudine used in patients receiving interferon alfa (or peginterferon alfa) with or without ribavirin, closely monitor for toxicities, especially hepatic decompensation; consider discontinuing zidovudine as medically appropriate; consider discontinuing or reducing dosage of interferon alfa (or peginterferon alfa) and/or ribavirin if worsening toxicities, including hepatic decompensation (Child-Pugh >6) occur1 231 298

Lamivudine

No clinically important pharmacokinetic interactions1 219 231

In vitro evidence of synergistic antiretroviral effects219

Dosage adjustments not needed1

Lopinavir/ritonavir

Possible decreased zidovudine concentrations207

Clinical importance unknown207

Macrolides (clarithromycin)

Decreased zidovudine AUC1

Routine zidovudine dosage adjustments not warranted1

Maraviroc

No effect on zidovudine pharmacokinetics224

No in vitro evidence of antagonistic antiretroviral effects224

Megestrol acetate

Slight decrease in zidovudine AUC102

Not considered clinically important102

Methadone

Increased zidovudine AUC; no change in methadone pharmacokinetics1 200 231 350

Routine zidovudine dosage adjustments not warranted; monitor for zidovudine-associated adverse effects1 200 231

Myelosuppressive or cytotoxic agents

Increased risk of hematologic toxicity1 29 176 231 332

Use with caution29 176 332

Nelfinavir

Decreased zidovudine peak concentrations and AUC;1 208 231 no effect on nelfinavir concentrations1 231

In vitro evidence of synergistic antiretroviral effects208

Routine zidovudine dosage adjustments not warranted1 231

Nevirapine

Decreased zidovudine concentrations and AUC215

In vitro evidence of additive to synergistic antiretroviral effects1 215 406

Oxazepam

Pharmacokinetic interactions unlikely353

Phenytoin

Pharmacokinetic interactions; alteration in pharmacokinetics of both drugs reported1 231

Use caution; monitor closely1 231

Probenecid

Increased zidovudine peak plasma concentrations and AUC1 231

Routine zidovudine dosage adjustments not warranted1 231

Raltegravir

In vitro evidence of additive to synergistic antiretroviral effects225

Ribavirin

In vitro evidence that ribavirin can reduce phosphorylation of zidovudine;37 60 200 no evidence of pharmacokinetic or pharmacodynamic interaction (e.g., loss of virologic suppression of HIV or HCV) in patients coinfected with HIV and HCV receiving zidovudine and ribavirin1

Exacerbation of anemia reported in patients coinfected with HIV and HCV receiving ribavirin and zidovudine concomitantly1

Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with HIV and HCV receiving antiretroviral agents and interferon alfa (or peginterferon alfa) with or without ribavirin1 298

Avoid concomitant use if possible or closely monitor virologic response and hematologic toxicities200

If zidovudine used in patients receiving interferon alfa (or peginterferon alfa) with or without ribavirin, closely monitor for toxicities, especially hepatic decompensation; consider discontinuing zidovudine as medically appropriate; consider discontinuing or reducing dosage or interferon (or peginterferon) and/or ribavirin if worsening toxicities, including hepatic decompensation (Child-Pugh >6) occur1 298

Rilpivirine

Pharmacokinetic interaction not expected226

No in vitro evidence of antagonistic antiretroviral effects226

Ritonavir

Decreased zidovudine concentrations and AUC; no effect on ritonavir concentrations or AUC1 209 231

In vitro evidence of additive antiretroviral effects209

Dosage adjustments not needed1 231

Saquinavir

In vitro evidence of additive or synergistic antiretroviral effects210

Stavudine

In vitro and in vivo evidence of antagonism1 8 200 220 231

Do not use concomitantly1 200 201 220 231

Tenofovir

In vitro evidence of additive to synergistic antiretroviral effects221

Tipranavir

Ritonavir-boosted tipranavir: Decreased zidovudine AUC; may also decrease tipranavir concentrations and AUC211

In vitro evidence of additive antiretroviral effects211

Clinical importance unknown211

Appropriate dosages for concomitant use with ritonavir-boosted tipranavir not established200

Valproic acid

Increased zidovudine AUC1 231

Routine zidovudine dosage adjustments not warranted; monitor for zidovudine toxicities1 200 231

Consider reduction in zidovudine dosage if patient experiences severe anemia or other severe events1 231

Zidovudine Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; peak plasma concentrations achieved within 0.5–1.5 hours.1 2 4 110 111 115 116 117 119 Bioavailability is 64%.1

Commercially available tablets, capsules, and oral solution are bioequivalent.1

Fixed-combination tablet containing lamivudine 150 mg and zidovudine 300 (Combivir) is bioequivalent to one 150-mg lamivudine tablet and one 300-mg zidovudine tablet given simultaneously.227

Fixed-combination tablet containing abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg (Trizivir) is bioequivalent to one 300-mg abacavir tablet, one 150-mg lamivudine tablet, and one 300-mg zidovudine tablet given simultaneously.20 229

Food

Extent of absorption (AUC) not affected by food.1

Special Populations

Zidovudine AUC increased in patients with renal impairment.1 177 231

Zidovudine pharmacokinetics in pediatric patients >3 months of age similar to that in adults; 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 Bioavailability is greater in neonates ≤14 days of age and is reported to be 89%.1

Pharmacokinetics of zidovudine in pregnant women similar to that reported in nonpregnant adults.1 231

Distribution

Extent

Widely distributed.1 32 231

Distributed into CSF; 1 32 67 114 148 177 231 ratio of CSF/plasma concentrations reported in adults or children with HIV infection is 0.15–2.1.1 32 67 114 115 148 177 231

Distributed into semen.110 145 159 160

Crosses human placenta and is distributed into amniotic fluid, cord blood, and fetal blood120 185 261 262 528 and fetal liver, muscle, and CNS tissue.185

Distributed into milk.1 177 231

Plasma Protein Binding

<38%.1 177 231

Elimination

Metabolism

Rapidly metabolized via glucuronidation in the liver.4 22

Intracellularly, zidovudine is phosphorylated and converted by cellular enzymes to the active 5′-triphosphate metabolite.1 4 7 18 25 46 177 231

Elimination Route

Eliminated principally in urine via both glomerular filtration and tubular secretion.1 22 32 110 115 116 231

Zidovudine not removed by hemodialysis or peritoneal dialysis1 231

Half-life

Adults: 0.5–3 hours.1 2 32 30 119 177 231

Neonates and infants: 3.1 hours in neonates ≤14 days of age, 1.9 hours in infants 14 days to 3 months of age, or 1.5 hours in pediatric patients 3 months to 12 years of age.1 231

Special Populations

Patients with liver disease: Mean half-life 1.8 hours.103

Patients with severe renal impairment: Mean half-life 1.4 hours.1 113

Stability

Storage

Oral

Capsules

15–25°C; protect from moisture.1

Solution

15–25°C.1

Tablets

Retrovir: 15–25°C.1

Combivir: 2–30°C.227

Trizivir: 25°C (may be exposed to 15–30°C).229

Parenteral

Concentrate for IV Infusion

15–25°C; protect from light.231

After dilution in 5% dextrose, physically and chemically stable for 24 hours when stored at room temperature and for 48 hours when refrigerated at 2–8°C.231

To minimize risk of microbial contamination, administer diluted solutions within 8 hours if stored at room temperature or within 24 hours if refrigerated.231

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Admixture in biologic or colloidal fluids (e.g., blood products, protein solutions) not recommended.231

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Dobutamine HCl

Ranitidine HCl

Variable

Meropenem

Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Allopurinol sodium

Amifostine

Amikacin sulfate

Amphotericin B

Amphotericin B cholesteryl sulfate complex

Anidulafungin

Aztreonam

Ceftazidime

Ceftriaxone sodium

Cisatracurium besylate

Clindamycin phosphate

Co-trimoxazole

Dexamethasone sodium phosphate

Dobutamine HCl

Docetaxel

Dopamine HCl

Doripenem

Doxorubicin HCl liposome injection

Erythromycin lactobionate

Etoposide phosphate

Filgrastim

Fluconazole

Fludarabine phosphate

Gemcitabine HCl

Gentamicin sulfate

Granisetron HCl

Heparin sodium

Imipenem–cilastatin sodium

Linezolid

Lorazepam

Melphalan HCl

Metoclopramide HCl

Morphine sulfate

Nafcillin sodium

Ondansetron HCl

Oxacillin sodium

Oxytocin

Paclitaxel

Pemetrexed disodium

Pentamidine isethionate

Phenylephrine HCl

Piperacillin sodium–tazobactam sodium

Potassium chloride

Ranitidine HCl

Remifentanil HCl

Sargramostim

Teniposide

Thiotepa

Tobramycin sulfate

Vancomycin HCl

Vinorelbine tartrate

Variable

Meropenem

Actions

  • Analog of thymidine.2 4 12 18 29 39

  • Pharmacologically related to, but structurally different from, other NRTIs (e.g., abacavir, didanosine, emtricitabine, lamivudine, stavudine); also differs pharmacologically and structurally from other currently available antiretrovirals.1 2

  • A prodrug that is inactive until converted intracellularly to zidovudine triphosphate.1 16 25

  • Active in vitro against HIV-11 4 5 7 18 25 30 231 and HIV-2.189 260 382

  • Inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1 2 4 16 18 19 25 30 79 231

  • Strains of HIV-1 with reduced susceptibility to zidovudine have been produced in vitro and have emerged during therapy with the drug.1 141 142 151 189 190 231 260 264 265 296 305 358 359 360 361 362 363 364 365 366 367 402 446 448 525

  • Strains of HIV resistant to zidovudine may be cross-resistant to some other NRTIs (e.g., didanosine, lamivudine, stavudine).219 220 290 303 362 366 446 450

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.226

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.1

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.226

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200 217

  • Possibility of neutropenia and/or anemia; transfusions or drug discontinuance may be needed.1 231 Importance of having blood cell counts closely monitored.1 231

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 231

  • If taking zidovudine, importance of not taking another zidovudine-containing preparation.1 If taking Combivir, importance of not taking another lamivudine- or zidovudine-containing preparation.227 If taking Trizivir, importance of not taking another abacavir-, lamivudine-, or zidovudine-containing preparation.229

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription 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.1 231 Advise HIV-infected women not to breast-feed.1 231

  • Advise pregnant patients that long-term consequences of in utero exposure and infant exposure to zidovudine unknown, including the possible risk of cancer.1 231

  • Importance of advising patients of other important precautionary information.1 231 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Zidovudine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg

Retrovir

ViiV

Solution

10 mg/mL*

Retrovir Syrup

ViiV

Zidovudine Oral Solution

Tablets, film-coated

300 mg*

Retrovir

ViiV

Zidovudine Tablets

Parenteral

For injection concentrate, for IV infusion only

10 mg/mL

Retrovir I.V. Infusion

ViiV

Zidovudine Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

300 mg with Abacavir Sulfate 300 mg (of abacavir) and Lamivudine 150 mg

Trizivir

ViiV

300 mg with Lamivudine 150 mg

Combivir

ViiV

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Combivir 150-300MG Tablets (VIIV HEALTHCARE): 30/$488.01 or 60/$949.93

Lamivudine-Zidovudine 150-300MG Tablets (TEVA PHARMACEUTICALS USA): 30/$425.99 or 90/$1,249.97

Retrovir 100MG Capsules (VIIV HEALTHCARE): 180/$520.99 or 540/$1,533.95

Retrovir 300MG Tablets (VIIV HEALTHCARE): 60/$479.97 or 180/$1,439.90

Retrovir 50MG/5ML Syrup (VIIV HEALTHCARE): 240/$71.99 or 720/$205.98

Trizivir 300-150-300MG Tablets (VIIV HEALTHCARE): 60/$1,562.95 or 180/$4,374.97

Zidovudine 300MG Tablets (CAMBER PHARMACEUTICALS): 60/$169.98 or 180/$467.93

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 18, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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79. St Clair MH, Richards CA, Spector T et al 3′-azido-3′-deoxythymidine triphosphate as an inhibitor and substrate of purified human immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother. 1987; 31:1972-7.

80. Terasaki T, Pardridge WM. Restricted transport of 3′-azido-3′deoxythymidine and dideoxynucleosides through the blood-brain barrier. J Infect Dis. 1988; 158:630-2. [PubMed 2842410]

81. Hirsch MS. Azidothymidine. J Infect Dis. 1988; 157:427-31. [IDIS 239514] [PubMed 3278063]

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83. Helbert M, Robinson D, Peddle B et al. Acute meningo-encephalitis on dose reduction of zidovudine. Lancet. 1988; 1:1249-52. [IDIS 242636] [PubMed 2897518]

84. Harris PJ, Caceres CA. Azidothymidine in the treatment of AIDS. N Engl J Med. 1988; 318:250. [IDIS 237401] [PubMed 3422108]

85. Richman DD, Fischl MA, Nusinoff-Lehrman S et al. Azidothymidine in the treatment of AIDS. N Engl J Med. 1988; 318:251.

86. Creigh-Kirk T, Doi P, Andrews E et al. Survival experience among patients with AIDS receiving zidovudine: follow-up of patients in a compassionate plea program. JAMA. 1988; 260:3009-15. [IDIS 247723] [PubMed 3263514]

87. Bartlett JA. HIV therapeutics: an emerging science. JAMA. 1988; 260:3051-2. [IDIS 247728] [PubMed 3054186]

88. The Swiss Group for Clinical Studies on the Acquired Immunodeficiency Syndrome (AIDS). Zidovudine for the treatment of thrombocytopenia associated with human immunodeficiency virus (HIV): a prospective study. Ann Intern Med. 1988; 109:718-21. [IDIS 248244] [PubMed 3190058]

89. Helbert M, Fletcher T, Peddle B et al. Zidovudine-associated myopathy. Lancet. 1988; 2:689-90. [IDIS 245718] [PubMed 2901551]

90. Schmitt FA, Bigley JW, McKinnis R et al. Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complex. N Engl J Med. 1988; 319:1573-8. [IDIS 248650] [PubMed 3059187]

91. Blanche S, Caniglia M, Fischer A et al. Zidovudine therapy in children with acquired immunodeficiency syndrome. Am J Med. 1988; 85(Suppl 2A):203-7. [IDIS 247154] [PubMed 3165604]

92. Pizzo PA, Eddy J, Falloon J et al. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med. 1988; 319:889-96. [IDIS 246133] [PubMed 3166511]

93. O’Dowd MA, McKegney FP. Manic syndrome associated with zidovudine. JAMA. 1988; 260:3587. [IDIS 248573] [PubMed 3193583]

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