Zidovudine

Name: Zidovudine

Warning

Zidovudine has caused severe blood problems including a decrease in red blood cells (anemia) and white blood cells (neutropenia). They occur more frequently in people with advanced HIV disease (AIDS). Blood problems may require blood transfusions or stopping your medication. Your doctor will order blood tests to monitor for this. Keep all medical appointments. Seek immediate medical attention if you develop signs of anemia (unusual tiredness, breathing problems, weakness, bluish fingernails/lips, pale skin, fast heartbeat). Low white blood cells can make you more likely to get serious (sometimes fatal) infections. Seek immediate medical attention if you develop signs of infection such as fever, chills, persistent cough, breathing problems, or sore throat.

This medication may also cause muscle problems (myopathy). Seek immediate medical attention if you develop symptoms of myopathy (such as wasting or decrease in muscle size, muscle weakness/pain/tenderness, weight loss).

Rarely, zidovudine has caused a severe (sometimes fatal) liver and blood problem (lactic acidosis). Tell your doctor immediately if you develop symptoms of liver problems (persistent nausea, stomach/abdominal pain, dark urine, yellowing eyes/skin) or lactic acidosis (rapid breathing, drowsiness, muscle aches).

Indications

Treatment Of HIV-1

RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Prevention Of Maternal-Fetal HIV-1 Transmission

RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission [see DOSAGE AND ADMINISTRATION]. The indication is based on a dosing regimen that included 3 components:

  1. antepartum therapy of HIV-1-infected mothers
  2. intrapartum therapy of HIV-1-infected mothers
  3. post-partum therapy of HIV-1-exposed neonate

Points to consider prior to initiating RETROVIR in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:

  • In most cases, RETROVIR for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.
  • Prevention of HIV-1 transmission in women who have received RETROVIR for a prolonged period before pregnancy has not been evaluated.
  • Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy with RETROVIR during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks gestation.

Zidovudine FDA Warning

WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS 

  • Hematologic toxicity including neutropenia and severe anemia have been associated with the use of zidovudine.
  • Symptomatic myopathy associated with prolonged use of zidovudine.
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including zidovudine. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. 

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Interactions for Zidovudine

The following drug interactions are based on studies using zidovudine.1 Drug interaction studies not performed using lamivudine/zidovudine or abacavir/lamivudine/zidovudine.227 229 When fixed combinations are used, consider interactions associated with each drug in the fixed combination.227 229

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 trough 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 warranted;1 231 monitor for zidovudine-associated adverse effects200

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 unlikely204

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

Simeprevir

Clinically important interactions not expected187

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

Stability

Storage

Oral

Capsules

Zidovudine: 15–25°C; protect from moisture.1

Solution

Zidovudine: 15–25°C.1

Tablets

Zidovudine: 15–25°C.1

Lamivudine/zidovudine (Combivir): 2–30°C.227

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

Parenteral

Concentrate for IV Infusion

Zidovudine: 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

zidovudine Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Fever, chills, or sore throat
  • pale skin
  • unusual tiredness or weakness
Rare
  • Abdominal or stomach discomfort
  • confusion
  • convulsions (seizures)
  • diarrhea
  • fast, shallow breathing
  • general feeling of discomfort
  • loss of appetite
  • mood or mental changes
  • muscle pain, tenderness, weakness, or cramping
  • nausea
  • shortness of breath
  • sleepiness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Difficulty having a bowel movement (stool)
  • general feeling of discomfort or illness
  • headache (severe)
  • lack or loss of strength
  • muscle soreness
  • trouble with sleeping
  • vomiting
  • weight loss
Less common
  • Bluish-brown colored bands on nails
  • changes in skin color
Incidence not known
  • Acid or sour stomach
  • belching
  • burning, tingling, numbness, or pain in the hands, arms, feet, or legs
  • heartburn
  • indigestion
  • muscle or bone pain
  • sensation of pins and needles, stabbing pain
  • stomach cramps
  • stomach pain
  • yellow eyes or skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Zidovudine Dosage and Administration

Adults - Treatment of HIV-1 Infection

Oral Dosing

The recommended oral dose of Zidovudine capsules is 300 mg twice daily in combination with other antiretroviral agents.

Pediatric Patients (Aged 4 Weeks to Less than 18 Years)

Healthcare professionals should pay special attention to accurate calculation of the dose of Zidovudine capsules, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors.

Prescribers should calculate the appropriate dose of Zidovudine capsules for each child based on body weight (kg) and should not exceed the recommended adult dose.

Before prescribing Zidovudine capsules, children should be assessed for the ability to swallow capsules. If a child is unable to reliably swallow a Zidovudine capsule, the Zidovudine syrup formulation should be prescribed.

The recommended oral dosage in pediatric patients aged 4 weeks to less than 18 years and weighing greater than or equal to 4 kg is provided in Table 1. Zidovudine syrup should be used to provide accurate dosage when capsules are not appropriate.

Table 1: Recommended Pediatric Oral Dosage of Zidovudine Capsules
Body Weight
(kg)
Total Daily Dose
Dosage Regimen and Dose
Twice Daily
Three Times Daily
4 to <9
24 mg/kg/day
12 mg/kg
8 mg/kg
≥9 to <30
18 mg/kg/day
9 mg/kg
6 mg/kg
≥30
600 mg/day
300 mg
200 mg

Alternatively, dosing for Zidovudine capsules can be based on body surface area (BSA) for each child. The recommended oral dose of Zidovudine capsules is 480 mg per m2 per day in divided doses (240 mg per m2 twice daily or 160 mg per m2 three times daily). In some cases the dose calculated by mg per kg will not be the same as that calculated by BSA.

Prevention of Maternal-Fetal HIV-1 Transmission

The recommended dosage regimen for administration to pregnant women (greater than 14 weeks of pregnancy) and their neonates is:

Maternal Dosing

100 mg orally 5 times per day until the start of labor [see Clinical Studies (14.3)]. During labor and delivery, intravenous Zidovudine should be administered at 2 mg per kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg per kg per hour (total body weight) until clamping of the umbilical cord.

Neonatal Dosing

Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered Zidovudine intravenously. See Table 2.

Table 2. Recommended Neonatal Dosages of Zidovudine
Route
Total Daily Dose
Dose and Dosage Regimen
 Oral
8 mg/kg/day
2 mg/kg every 6 hours
 Intravenous
6 mg/kg/day
1.5 mg/kg infused over 30 minutes, every 6 hours

Patients with Severe Anemia and/or Neutropenia

Significant anemia (hemoglobin less than 7.5 g per dL or reduction greater than 25% of baseline) and/or significant neutropenia (granulocyte count less than 750 cells per mm3 or reduction greater than 50% from baseline) may require a dose interruption until evidence of marrow recovery is observed [see Warnings and Precautions (5.1)]. In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoietin level and patient tolerance.

Patients with Renal Impairment

In patients maintained on hemodialysis or peritoneal dialysis or with creatinine clearance (CrCl) by Cockcroft-Gault less than 15 mL per min, the recommended oral dosage is 100 mg every 6 to 8 hours. [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment

There are insufficient data to recommend dose adjustment of Zidovudine capsules in patients with impaired hepatic function or liver cirrhosis. Frequent monitoring of hematologic toxicities is advised [see Use in Specific Populations (8.7)].

Dosage Forms and Strengths

Zidovudine Capsules USP, 100 mg are white/white size ‘3’ hard gelatin capsules imprinted with ‘D’ on white cap and ‘01’ on white body with black edible ink.

Drug Interactions

Antiretroviral Agents

Stavudine

Concomitant use of Zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro.

Nucleoside Analogues Affecting DNA Replication

Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of Zidovudine against HIV-1; concomitant use of such drugs should be avoided.

Doxorubicin

Concomitant use of Zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro.

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of Zidovudine.

Overdosage

Acute overdoses of Zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with Zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of Zidovudine while elimination of its primary metabolite, 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced. If overdose occurs, the patient should be monitored for evidence of toxicity and given standard supportive treatment as required.

Contraindications

Potentially life-threatening hypersensitivity to zidovudine or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Neutrophil count <750/mm3 or hemoglobin <7.5 g/dL (4.65 mmol/L)

Dosing Geriatric

Refer to adult dosing.

Reconstitution

Solution for injection should be removed from the vial and diluted with D5W to a concentration ≤4 mg/mL.

Administration

Oral: Administer around-the-clock to promote less variation in peak and trough serum levels; may be administered without regard to meals

IV: Avoid rapid infusion or bolus injection. Do not administer IM

Infuse over 1 hour; infuse over 30 minutes in neonates; in pregnant women, infuse loading dose over 1 hour followed by continuous infusion.

Storage

IV: Store undiluted vials at 15°C to 25°C (59°F to 77°F). Protect from light. When diluted in D5W, solution is physically and chemically stable for 24 hours at room temperature and 48 hours if refrigerated at 2°C to 8°C (36°F to 46°F). Attempt to administer diluted solution within 8 hours if stored at room temperature or 24 hours if refrigerated at 2°C to 8°C (36°F to 46°F) to minimize potential for microbial-contaminated solutions (vials are single-use and do not contain preservative).

Tablets, capsules, syrup: Store at 15°C to 25°C (59°F to 77°F). Protect capsules from moisture.

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