Zidovudine

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

Special Alerts:

[Posted 03/01/2011] ISSUE: FDA updated the public about an ongoing safety review of abacavir and a possible increased risk of heart attack. There has been conflicting information on the potential increased risk of heart attack with abacavir (Ziagen) treatment. An increased risk of heart attack (myocardial infarction or MI) has been seen in several observational studies and one randomized controlled trial (RCT) with abacavir. However, an increased risk of heart attack has not been seen in other RCTs and the safety database maintained by the drug manufacturer.

FDA conducted a meta-analysis of 26 randomized clinical trials that evaluated abacavir. This meta-analysis did not show an increased risk of MI associated with the use of abacavir. FDA will continue to communicate any new safety information to the public as it becomes available.

BACKGROUND: Abacavir is an antiviral medication used in combination with other antiretroviral drugs [abacavir and lamivudine (Epzicom); abacavir, lamivudine, and zidovudine (Trizivir)] for the treatment of HIV-1 infection.

RECOMMENDATION: Healthcare professionals should continue to prescribe abacavir according to the professional label. Patients should not stop taking their abacavir without first talking to their healthcare professional. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for zidovudine to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

• 
  

  Hematologic toxicity reported, particularly in patients with advanced disease.^{1 231} (See Hematologic Effects under Cautions.)

  
  


• 
  

  Symptomatic myopathy reported.^{1 231} (See Musculoskeletal Effects under Cautions.)

  
  


• 
  

  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.^{1 231} (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  
  


• 
  

  If using Trizivir, consider that abacavir has been associated with serious and sometimes fatal hypersensitivity reactions.¹⁰

  
  

Introduction

Antiretroviral; nucleoside reverse transcriptase inhibitor (NRTI).^{1 4 7 12 16 18 29 39 47 231 260 296}

Uses for Zidovudine

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.^{1 231 279 466}

An alternative (not a preferred) NRTI for use in multiple-drug antiretroviral regimens for initial therapy in adults.²⁷⁹

Fixed-combination preparation containing zidovudine and lamivudine (Combivir) used in conjunction with other antiretrovirals.²⁷¹

Fixed-combination preparation containing zidovudine, abacavir, and lamivudine (Trizivir) used for triple NRTI treatment;¹⁰ can be used alone or in conjunction with other antiretrovirals.¹⁰ If using Trizivir, consider that data are limited regarding use of the fixed combination in patients with higher viral loads (>100,000 copies/mL) at baseline.¹⁰

Because of inferior antiretroviral activity, a triple NRTI regimen of abacavir, lamivudine, and zidovudine is not recommended for initial therapy.²⁷⁹

Prevention of Maternal-fetal Transmission of HIV

Prevention of maternal-fetal transmission of HIV.^{1 231 279 455}

A regimen that includes combination antiretroviral therapy or prophylaxis in the pregnant women, intrapartum therapy, and zidovudine prophylaxis in the newborn is recommended for the prevention of perinatal HIV transmission.⁴⁵⁵ Antiretroviral therapy or antiretroviral prophylaxis for prevention of perinatal HIV transmission during the antepartum period recommended for all pregnant HIV-infected women in the US; zidovudine should be included in the regimen when feasible.⁴⁵⁵ Intrapartum zidovudine in conjunction with other antiretroviral agents is recommended in all pregnant HIV-infected women.⁴⁵⁵ Administration of zidovudine for 6 weeks is recommended for all HIV-exposed infants.⁴⁵⁵

If intrapartum/newborn zidovudine is used for prevention of perinatal HIV transmission in women in labor who received no prior antiretroviral therapy, some clinicians would add single-dose intrapartum/newborn nevirapine (a nevirapine dose given to the mother at onset of labor and a nevirapine dose given to the neonate).⁴⁵⁵

If a single-dose nevirapine regimen in conjunction with intrapartum/newborn zidovudine is used for prevention of perinatal HIV transmission in women in labor who received no prior antiretroviral therapy, some clinicians suggest that consideration be given to adding a zidovudine and lamivudine regimen in the mother to reduce development of nevirapine resistance.⁴⁵⁵

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 98 149 194 224 337 338 339 340 341 342 343 344 418 464 465} Used in conjunction with other antiretrovirals.⁴⁶⁴

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.⁵⁰³ Used in conjunction with other antiretrovirals.⁵⁰³

Zidovudine Dosage and Administration

Administration

Administer orally or by intermittent or continuous IV infusion.^{1 231} Should not be administered by rapid or bolus IV injection, IM injection, or sub-Q injection.²³¹

Oral Administration

Administer single-entity preparations (Retrovir) and fixed-combination preparations (Combivir, Trizivir) orally without regard to meals.^{1 10 271}

To reduce risk of esophageal irritation and ulceration, zidovudine capsules should be administered while the 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

Because dosage of zidovudine and lamivudine cannot be adjusted individually, the fixed-combination containing zidovudine and lamivudine (Combivir) should not be used in individuals requiring dosage adjustment, including children <12 years of age, patients with impaired renal function (i.e., Cl_cr <50 mL/minute), patients with impaired hepatic function, and patients who experience dose-limiting adverse effects.²⁷¹

Because dosage of the drugs cannot be adjusted individually, the fixed-combination containing abacavir, lamivudine, and zidovudine (Trizivir) should not be used in pediatric patients; adolescents or adults with low body weight (i.e., <40 kg); patients with impaired renal function (i.e., Cl_cr <50 mL/minute); patients with impaired hepatic function; or patients who experience dose-limiting adverse effects.¹⁰

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 The appropriate dose should be withdrawn from the vial and diluted in 5% dextrose injection to provide a solution containing ≤4 mg/mL.²³¹

Rate of Administration

Intermittent IV infusions should be infused at a constant rate over 60 minutes.²³¹

In neonates, intermittent IV infusions should be infused at a constant rate over 30 minutes.²³¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Used in conjunction with other antiretrovirals for treatment of HIV infection or for postexposure prophylaxis of HIV;^{1 231 271} may be used alone or in conjunction with other antiretrovirals for prevention of maternal-fetal transmission of HIV.^{1 231} The fixed-combination preparation containing zidovudine, abacavir, and lamivudine may be used alone or in conjunction with other antiretrovirals.¹⁰

Dosage of Combivir and Trizivir expressed as number of tablets.^{10 271}

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

Modification of zidovudine dosage is necessary in adults or pediatric patients who develop anemia and/or neutropenia.^{1 91 92 229 231 244 245 451} Substantial anemia (hemoglobin <7.5 g/dL or a reduction >25% from baseline) and/or neutropenia (granulocyte count <750/mm³ or a reduction >50% from baseline) may require dose interruption until evidence of bone marrow recovery occurs.^{1 231} If bone marrow recovery occurs following interruption of therapy, reinitiation of zidovudine therapy may be appropriate.^{1 231} (See Hematologic Effects under Cautions.)

Pediatric Patients

Treatment of HIV Infection

To avoid medication errors, use extra care in calculating the dose, transcribing the medication order, dispensing the prescription, and providing dosing instructions.¹

Oral

Premature neonates: 2 mg/kg every 12 hours; 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.^{455 466}

Neonates and infants <6 weeks of age: 2 mg/kg every 6 hours.⁴⁶⁶

Zidovudine Dosage in Pediatric Patients ≥6 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, for pediatric patients ≥6 weeks of age, 240 mg/m² twice daily or 160 mg/m² 3 times daily.¹

Combivir: 1 tablet twice daily in adolescents ≥12 years of age.^{271 466}

Trizivir: 1 tablet twice daily in adolescents weighing ≥40 kg.^{10 466}

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.^{455 466}

Neonates and infants <6 weeks of age: 1.5 mg/kg every 6 hours.⁴⁶⁶

Infants and children 6 weeks to 12 years of age: 120 mg/m² by intermittent IV infusion every 6 hours; alternatively, 20 mg/m² per hour by continuous IV infusion.⁴⁶⁶

Prevention of Maternal-fetal Transmission of HIV

Postexposure Prophylaxis

Oral

Premature neonates: Initiate therapy with 2 mg/kg every 12 hours; frequency of administration may be increased to every 8 hours at 2 weeks of age in neonates with >30 to <35 weeks gestation at birth or at 4 weeks of age in those with <30 weeks gestation at birth.^{455 466} Zidovudine is continued through 6 weeks of age.⁴⁵⁵

Neonates ≥35 weeks at gestation: 2 mg/kg every 6 hours starting within 6–12 hours after birth and continued through 6 weeks of age.^{1 231 455 458}

Used in conjunction with intrapartum zidovudine in the mother.⁴⁶⁶

IV

Premature neonates: Initiate therapy with 1.5 mg/kg every 12 hours; frequency of administration may be increased to every 8 hours at 2 weeks of age in neonates with ≥30 to <35 weeks gestation at birth or at 4 weeks of age in those with <30 weeks gestation at birth.^{455 466} Zidovudine is continued through 6 weeks of age.⁴⁵⁵

Neonates ≥35 weeks at gestation: 1.5 mg/kg every 6 hours starting within 6–12 hours after birth.^{1 231 455} Zidovudine is continued through 6 weeks of age.⁴⁵⁵

Used in conjunction with intrapartum zidovudine in the mother.⁴⁶⁶

Adults

Treatment of HIV Infection

Oral

600 mg daily in divided doses.^{1 3 279 466 483 484 485 486 487 488 489 490 497} Usually given in a dosage of 200 mg 3 times daily or 300 mg twice daily.^{3 279 466}

Combivir: 1 tablet twice daily.^{271 279}

Trizivir: 1 tablet twice daily.^{10 279} Patient should weigh ≥40 kg.¹⁰

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 Maternal-fetal Transmission of HIV

Oral

IV

At start of labor, 2 mg/kg over 1 hour followed by 1 mg/kg per hour given by continuous IV infusion until the umbilical cord is clamped.^{1 231 455}

Used in conjunction with a 6-week zidovudine regimen in the neonate.^{466 455}

Postexposure Prophylaxis of HIV†

Occupational Exposure†

Oral

200 mg 3 times daily or 300 mg twice daily.⁴⁶⁴

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.^{464 467 470}

Nonoccupational Exposure†

Oral

200 mg 3 times daily or 300 mg twice daily.⁵⁰³

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.⁵⁰³

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

Children 6 weeks to 12 years of age: Maximum 200 mg every 8 hours.¹

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Insufficient clinical experience to recommend dosage adjustment for patients with mild to moderate hepatic impairment or liver cirrhosis; a reduction in dosage may be necessary in these patients and frequent monitoring for hematologic toxicities advised.^{1 231}

Renal Impairment

Treatment of HIV Infection

Oral

100 mg every 6 to 8 hours for patients with end-stage renal disease maintained on hemodialysis or peritoneal dialysis.¹

IV

1 mg/kg every 6 to 8 hours for patients 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 clinically important hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to zidovudine or any ingredient in the formulation.^{1 231}

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Hematologic Effects

Use with caution in patients who have compromised bone marrow function (i.e., hemoglobin concentration <9.5 g/dL or granulocyte count <1000/mm³).^{1 231}

Anemia and/or neutropenia reported; these events are especially important in patients with advanced symptomatic HIV disease.^{1 2 3 4 29 30 33 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 frequently^{1 231} (at least every 2 weeks);^{181 231} periodic monitoring^{1 231} (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

If anemia and/or neutropenia occurs, interruption of zidovudine therapy and/or dosage adjustment may be necessary.^{1 231} In patients who develop substantial anemia, interruption of zidovudine therapy does not necessarily eliminate the need for transfusions.^{1 231}

Musculoskeletal Effects

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

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving zidovudine.^{1 271} Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors.^{1 271} Has been reported in patients with no known risk factors.^{1 271}

Use with caution in patients with known risk factors for liver disease.^{1 271}

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 marked increases in serum aminotransferase concentrations).^{1 271}

General Precautions

Do not use multiple zidovudine-containing preparations concomitantly.^{1 271}

Incidence of adverse effects increases with disease progression; monitor patients carefully, especially as disease progression occurs.^{1 231}

Use of Fixed Combinations

When used in fixed combination with lamivudine (Combivir), consider the cautions, precautions, and contraindications associated with lamivudine.²⁷¹

When used in fixed combination with abacavir and lamivudine (Trizivir), consider the cautions, precautions, and contraindications associated with the concomitant agents.¹⁰

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

Specific Populations

Pregnancy

Category C.^{1 231} Antiretroviral Pregnancy Registry at 800-258-4263.^{1 231}

The preferred NRTI for use in antiretroviral regimens in pregnant women based on efficacy studies and extensive experience.²⁷⁹ Pregnancy registry data indicate no increased risk for congenital abnormalities among infants born to women who receive zidovudine during pregnancy compared with general population.^{453 455}

Lactation

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

Pediatric Use

Studied in neonates perinatally exposed to HIV and in HIV-infected pediatric patients >3 months of age.^{1 231}

The major adverse effects reported in children are similar to those reported in adults^{1 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}

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}

Renal Impairment

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

Common Adverse Effects

Adults: Headache, malaise, anorexia, nausea, vomiting.^{1 231}

Children: Fever, cough, GI disorders.¹

Interactions for Zidovudine

Specific Drugs

Drug	Interaction	Comments
Abacavir	Pharmacokinetic interactions unlikely161 In vitro evidence of synergistic antiretroviral effects161
Acetaminophen	Pharmacokinetic interactions unlikely156
Acyclovir	Increased toxicity reported;15 has been used concomitantly without increased toxicity61 181
Antifungals, azoles (fluconazole)	Increased zidovudine AUC with fluconazole1 231 457	Routine dosage adjustment not needed;1 231 monitor for zidovudine-associated adverse effects457 Consider reduction in zidovudine dosage if patient experiences severe anemia or other severe events1 231
Antimycobacterials, rifamycins (rifabutin, rifampin)	Pharmacokinetic interactions unlikely with rifabutin409 Decreased zidovudine AUC with rifampin1 150 231
Atazanavir	No change in zidovudine AUC, but possible decreased zidovudine concentrations279 In vitro evidence of additive antiretroviral effects507	Clinical importance unknown279
Atovaquone	Increased zidovudine AUC; no change in pharmacokinetics of atovaquone1 231 242 Possible increased hematologic toxicity242	Routine dosage adjustments not needed1 231
Cidofovir	No pharmacokinetic interaction with cidofovir; cidofovir must be given concomitantly with probenecid and probenecid can reduce zidovudine clearance243	Temporarily discontinue zidovudine or reduce zidovudine dosage by 50% on days that cidofovir and probenecid are given243
Co-trimoxazole	Pharmacokinetic interactions unlikely333
Cytotoxic/Myelosuppressive agents	Increased risk of hematologic toxicity1 29 176 231 332	Use with caution29 176 332
Darunavir	Ritonavir-boosted darunavir: Pharmacokinetic interaction unlikely510
Delavirdine	Pharmacokinetic interactions unlikely284 In vitro evidence of additive or synergistic antiretroviral effects1 175 284 391 406
Didanosine	Pharmacokinetic interactions unlikely279 422 In vitro evidence of synergistic antiretroviral effects281
Doxorubicin	In vitro evidence of antagonism1 227 231	Concomitant use should be avoided1 231
Efavirenz	Pharmacokinetic interactions unlikely175 In vitro evidence of synergistic antiretroviral effects1 175 284 391 406	Dosage adjustment not needed175
Emtricitabine	In vitro evidence of additive or synergistic antiretroviral effectsb
Fosamprenavir	Studies using amprenavir indicate possible increased amprenavir AUC;d possible increased zidovudine plasma concentrations and AUCd In vitro evidence of synergistic antiretroviral effectsd
Ganciclovir	No clinically important pharmacokinetic interactions279 Increased risk of hematologic toxicity196 197 201 213 278 279	Concomitant use not recommended196 197 201 213 278
Indinavir	In vitro evidence of additive or synergistic antiretroviral effects166 215 480 481 482
Interferon (interferon alfa, peginterferon alfa)	Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with hepatitis C virus (HCV) and HIV who are receiving interferon alfa, ribavirin, and antiretroviral agents1 f Increased risk of hematologic toxicity (e.g., neutropenia, thrombocytopenia) and hepatic toxicity in patients receiving interferon alfa or peginterferon alfa, ribavirin, and zidovudine1 231 395 399 f In vitro evidence of synergistic antiretroviral effects34 57 351 395 396 397 398 399	Monitor for adverse effects1 231 395 399 f 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 appropriate; if worsening toxicities (e.g., hepatic decompensation Child-Pugh >6) are observed, consider discontinuing or reducing dosage of interferon or peginterferon alfa and/or ribavirin1 f
Lamivudine	Pharmacokinetic interactions unlikely1 231 In vitro evidence of synergistic antiretroviral effects347
Lopinavir	Possible decreased zidovudine concentrations508	Clinical importance unknown508
Megestrol acetate	Slight decrease in zidovudine AUC102	Not considered clinically important102
Methadone	Increased zidovudine AUC; no change in pharmacokinetics of methadone1 231 279 350	Routine dosage adjustment not needed; monitor for zidovudine toxicity1 231 279
Nelfinavir	Decreased zidovudine peak plasma concentrations and AUC; no effect on nelfinavir pharmacokinetics1 215 231 In vitro evidence of additive or synergistic antiretroviral effects166 215 480 481 482	Routine dosage adjustment not needed1 215 231
Nevirapine	Decreased plasma zidovudine concentrations391 In vitro evidence of synergistic antiretroviral effects1 175 284 391 406
Oxazepam	Pharmacokinetic interactions unlikely353
Phenytoin	Pharmacokinetic interactions; alteration in pharmacokinetics of both drugs reported1 231	Use with caution; monitor closely1 231
Probenecid	Increased zidovudine peak plasma concentrations and AUC1 231	Routine dosage adjustment not needed1 231
Ribavirin	Ribavirin can reduce phosphorylation of zidovudine;37 60 279 no evidence of pharmacokinetic or pharmacodynamic interaction in patients coinfected with HCV and HIV1 Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with HCV and HIV who are receiving interferon alfa or peginterferon alfa, ribavirin, and antiretroviral agents1 f	Concomitant use should be avoided if possible or closely monitor virologic response and hematologic toxicities 279 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 appropriate; if worsening toxicities (e.g., hepatic decompensation Child-Pugh >6) are observed, consider discontinuing or reducing dosage of interferon and/or ribavirin1 f
Ritonavir	Decreased zidovudine peak plasma concentrations and AUC; no effect on ritonavir pharmacokinetics1 231 481 In vitro evidence of additive or synergistic antiretroviral effects166 215 480 481 482	Routine dosage adjustment not needed1 231
Saquinavir	In vitro evidence of additive or synergistic antiretroviral effects166 215 480 481 482
Stavudine	In vitro evidence of antagonism1 165 231	Concomitant use not recommended1 231 279
Tipranavir	Ritonavir-boosted tipranavir: Decreased zidovudine AUC279 e In vitro evidence of additive antiretroviral effectse	Clinical importance unknowne Appropriate dosages for concomitant use with ritonavir-boosted tipranavir not established279 e
Valproic acid	Increased zidovudine AUC1 231	Routine dosage adjustment not needed; monitor for zidovudine toxicity1 231 279 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

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 are similar to those reported in nonpregnant adults.^{1 231}

Distribution

Extent

Widely distributed.^{1 32 231}

Distributed into CSF; ^{1 32 67 114 148 177 231} the 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}