Zidovudine is an antiviral medicine that inhibits the replication of the HIV virus by inhibiting viral RNA dependent DNA polymerase.

It is used in the following situations:

• HIV-1 infection:

  • It is used in the treatment of HIV-1 infection along with other antiretroviral agents

• Perinatal HIV-1 transmission:

  • It is used in the prevention of mother to fetus HIV-1 transmission

• Off Label Usage of Zidovudine in Adults:

  • HIV-1 nonoccupational postexposure prophylaxis

Zidovudine Dose in Adults

• Patients should receive Intravenous therapy only until oral therapy can be administered.

Dose in the Prevention of perinatal HIV transmission:

• Zidovudine should be given by continuous IV infusion near delivery in the following cases:
  • in women with known or suspected HIV RNA >1,000 copies/mL
  • Unknown HIV RNA status
  • Use may be advised in women with HIV RNA between 50 and 999 copies/mL.
• Oral zidovudine should be discontinued during intrapartum IV infusion if the patient was receiving oral therapy previously.
• Other antiretroviral agents should be continued orally.
• Zidovudine IV is not used in women receiving combination antiretroviral therapy who have HIV RNA <50 copies/mL near delivery and there are no worries related to adherence to the regimen.

  • Intravenous (preferred route):

    • During labor and delivery:
      • A loading dose of 2 mg/kg is given
      • It is followed by a continuous IV infusion of 1 mg/kg/hour until clamping of the umbilical cord.
      • For scheduled cesarean delivery, IV zidovudine is started 3 hours before surgery.
      • In cases of unscheduled cesarean delivery, consider giving the loading dose then proceeding to delivery.

  • Oral (if Intravenous, not possible):

    • A loading dose of 600 mg, then 400 mg every 3 hours.

Dose in the treatment of HIV-1 infection:

• 300 mg orally BID daily
• 1 mg/kg/dose Intravenous administered every 4 hours around-the-clock (6 doses daily)
• It is used in combination with other antiretroviral agents.

Off Label Dosage in the treatment of HIV-1 nonoccupational postexposure prophylaxis 

Oral:

• CrCl ≥60 mL/minute:

  • Zidovudine is not given

• CrCl <60 and ≥15 mL/minute:

  • 300 mg twice daily with other antiretroviral agents.
  • Initiate therapy within 72 hours of exposure and continue for 4 weeks.

• CrCl <15 mL/minute:

  • Adjust dose based on renal function along with other antiretroviral agents. I
  • initiate therapy within 72 hours of exposure and continue for 28 days

Zidovudine Dose in Childrens

Dose in the treatment of HIV-1 infection:

• Infants (born at or near term ≥35 weeks postconception, and PNA ≥4 weeks) weighing ≥4 kg, Children, and Adolescents:

  • The 3-times-daily dosing is approved by the FDA but rarely practiced
  • Twice daily dosing is recommended in the current pediatric HIV guidelines.

    • Weight-directed dosing:

      • 4 to <9 kg:

        • 12 mg/kg/dose orally twice daily or 8 mg/kg/dose 3 times daily.

      • 9 to <30 kg:

        • 9 mg/kg/dose orally twice daily or 6 mg/kg/dose 3 times daily.

      • ≥30 kg:

        • 300 mg orally twice daily or 200 mg 3 times daily.

• Body Surface Area-directed dosing:

  • 240 mg/m /dose every 12 hours,
  • Range is 180 - 240 mg/m² /dose every 12 hours(Maximum dose is 300 mg/dose) or
    • 160 mg/m /dose every 8 hours
    • Maximum dose is 200 mg/dose.

Note: Use the Intravenous route only until oral therapy can be administered:

• Infants ≥3 months and Children:

  • 120 mg/m² /dose I/V QID
  • The maximum dose given is 160 mg/dose

• Adolescents ≥30 kg:

  • 1 to 2 mg/kg is given  Intravenous every 4 hours around the clock

Dose in the prevention of HIV-1 perinatal transmission:

• Dosing targets completion of courses started at birth
• If the neonate is diagnosed as HIV positive then stop empiric dosing and transition to a treatment regimen and monitoring.
• The duration of zidovudine, in general, is 6 weeks, although it is variable, and depends on additional antiretrovirals, risk of transmission, serology testing, and chosen strategy.

• Infants born prematurely (GA <35 weeks):

  • Neonatal; standard infant doses may be excessive in infants who were born prematurely.

• Infants <6 weeks (GA ≥35 weeks)

  • Weight-directed dosing:

    • 4 mg/kg/dose orally every 12 hours.

  • Fixed weight-band dosing regimen:

    • 2 to <3 kg: 10 mg orally given every 12 hours.
    • 3 to <4 kg: 15 mg orally given every 12 hours.
    • 4 to <5 kg: 20 mg given every 12 hours.
• 3 mg/kg/dose Intravenous can be given if oral therapy intolerable every 12 hours.

Dose in the treatment of HIV-1 nonoccupational postexposure prophylaxis:

• Initiate therapy within 3 days of exposure
• Continue for 28 days & use it in combination with other antiretroviral agents.

• Infants (PCA ≥35 weeks and PNA ≥4 weeks of age) and Children:

  • 4 to <9 kg: 12 mg/kg/dose given orally twice daily.
  • 9 to <30 kg: 9 mg/kg/dose given orally twice daily.
  • ≥30 kg: 300 mg given orally twice daily.

• Adolescents:

  • 300 mg orally twice daily.

• Dosing adjustment for hematologic toxicity:

  • Stop if foolowing occurs :
    • Significant anemia (Hgb <7.5 g/dL or >25% decrease from baseline)
    • Significant neutropenia (ANC <750 cells/mm or >50% decrease from baseline)
    • The dose may be restarted when bone marrow recovers using appropriate adjunctive therapy (eg, epoetin alfa).

Pregnancy Risk Factor: C

• Zidovudine crosses the human placenta
• Zidovudine is metabolized by the placenta to its active metabolite.
• There has not been an increase in overall birth defects risk after first-trimester exposure.
• Preterm births are more likely with maternal antiretroviral treatment (ART). However, stillbirths are possible. Low birth weight and gestational age can increase the chances of preterm delivery.
• It is important to continue maternal ART and not withhold it.
• All infants who have been exposed to antiretroviral medication should be followed up for a long time.
• The use of nucleoside-reverse transcriptase inhibitors, or NRTI (Nucleoside Reverse Transcriptase Inhibitors) can lead to lactic acidosis or hepatic steatosis due to mitochondrial toxicity.
• NRTIs are generally well tolerated, and the potential risks of their use outweigh the benefits.
• Zidovudine is an alternative NRTI to HIV-infected pregnant women, according to the Health and Human Services (HHS), Perinatal HIV Guidelines.
  • antiretroviral-naive,
  • People who have received antiretroviral treatment in the past and are now starting again
  • Patients who are unable to tolerate or respond poorly to the current treatment.
  • Patients who are trying to conceive.
• Females who get pregnant while taking zidovudine may continue using it if the viral suppression is successful and the regimen is well tolerated.
• Adjustment is not required.
• Zidovudine is recommended in combination with lamivudine by the Health and Human Services (HHS), Perinatal HIV Guidelines. This is to be used as a replacement NRTI backbone in starting treatment in pregnant women who are antiretroviral-naive.
• Zidovudine should always be administered IV at delivery to females who have HIV RNA levels greater than 1,000 copies/mL. This includes females who are known or suspected to have HIV RNA levels above 1000 copies/mL.
• All pregnant women with HIV should receive ART to lower their viral load and reduce the chance of perinatal transmission.
• Monitoring during pregnancy is more common than monitoring in adults who are not pregnant.
• The ART can be modified after delivery, but should not be stopped after delivery.

Use Zidovudine while breastfeeding

• Breast milk contains Zidovudine.

Zidovudine dose in renal disease:

• CrCl ≥15 mL/minute:

  • No dosage adjustment required.

• CrCl <15 mL/minute:

  • Manufacturer’s labeling:

    • 100 mg orally given every 6 to 8 hours

  • Alternate dosing:

    • 100 mg orally given 3 times daily or 300 mg once daily (HHS [adult] 2017)
  • 1 mg/kg Intravenous every 6 to 8 hours

• ESRD on intermittent hemodialysis (IHD) (administer dose after dialysis on dialysis days):

  • Manufacturer’s labeling:

    • 100 mg orally given  every 6 to 8 hours

  • Alternate dosing:

    • 100 mg orally given 3 times daily or 300 mg once daily (HHS [adult] 2017)
  • 1 mg/kg Intravenous given every 6 to 8 hours

• Peritoneal dialysis (PD):

  • 100 mg orally given every 6 to 8 hours
  • 1 mg/kg Intravenous given every 6 to 8 hours

• Continuous renal replacement therapy (CRRT):

  • No adjustment required

Zidovudine dose in liver disease:

• There are no specific dosage adjustments given in the manufacturer's labeling (has not been studied).
• However, the adjustment may be required due to extensive hepatic metabolism.

Common Side Effects of Zidovudine Include:

• Central Nervous System:

  • Headache
  • Malaise

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Nausea
  • Anorexia
  • Vomiting

• Hematologic & Oncologic:

  • Macrocytosis
  • Anemia

• Hepatic:

  • Hepatomegaly

• Respiratory:

  • Cough

• Miscellaneous:

  • Fever

Less Common Side Effects of Zidovudine Include:

• Cardiovascular:

  • Cardiac Failure
  • ECG Abnormality
  • Edema
  • Left Ventricular Dilation

• Central Nervous System:

  • Hyporeflexia
  • Irritability
  • Nervousness
  • Chills
  • Fatigue
  • Insomnia
  • Neuropathy

• Endocrine & Metabolic:

  • Weight Loss
  • Increased Amylase

• Gastrointestinal:

  • Diarrhea
  • Constipation
  • Stomatitis
  • Abdominal Cramps
  • Abdominal Pain
  • Dyspepsia
  • Increased Serum Lipase

• Genitourinary:

  • Hematuria

• Hematologic & Oncologic:

  • Lymphadenopathy
  • Neutropenia
  • Splenomegaly
  • Thrombocytopenia

• Hepatic:

  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Alanine Aminotransferase,

• Neuromuscular & Skeletal:

  • Asthenia
  • Arthralgia
  • Musculoskeletal Pain
  • Myalgia

• Otic:

  • Ear Sign Or Symptom

• Respiratory:

  • Nasal Congestion
  • Rhinorrhea
  • Abnormal Breath Sounds
  • Wheezing

Side effects (Frequency not defined):

• Local:

  • Injection site reaction (IV)
  • Irritation at the injection site (IV)
  • Pain at the injection site (IV)

Contraindication to Zidovudine Include:

• Hypersensitivity to zidovudine, or any component of the formulation, could be life-threatening
• Hemoglobin 7.5g/dL or neutrophil count 750/mm (4.65 mmol/L).

Warnings and precautions​​​​​​​

• Hematologic toxicities: [US Boxed Warning]

  • Use of advanced HIV-1 disease has been associated with hemomatologic toxicities, such as neutropenia, severe anemia and even severe anemia.
  • The duration of the use and the amount of bone marrow reserves may influence the severity of toxic effects. 
  • Hemoglobin loss can be seen as soon as 2 to 4 weeks after treatment. Neutropenia usually takes place between 6 and 8 weeks.
  • Pancytopenia can be seen (usually reversible).
  • Patients with bone marrow impairment (granulocytes 1,000 cell/mm or hemoglobin >9.5 g/dL) should be cautious.
  • Keep track of your blood pressure
  • Patients with anemia or neutropenia may need to be dose interrupted.

• Immune reconstitution syndrome:

  • The immune reconstitution syndrome can occur in patients who have received HIV treatment.
  • This may lead to an inflammatory response to an indolent, residual opportunistic virus.
  • Further evaluation and treatment may be necessary.

• Lactic acidosis/ hepatomegaly:

  • With nucleoside analogs, severe hepatomegaly and steatosis with lactic acidosis have been reported. Some cases even proved fatal.
  • Obesity or female obesity may increase the risk.
  • Stop treatment for any patient with clinical or laboratory findings suggesting lactic acidosis, hepatotoxicity or transaminase elevation (hepatomegaly or steatosis may or may not be associated).

• Lipoatrophy

  • It can cause subcutaneous fat loss, particularly in the face, legs, and buttocks. 
  • The severity and incidence of lipoatrophy are affected by cumulative exposure. They may not be reversible.
  • After switching to a regimen without zidovudine, improvement can take several months or years.
  • Monitor patients for signs of lipoatrophy and consider switching to a non-zidovudine-containing regimen if lipoatrophy occurs.

• Myopathy

  • Myopathy and myositis can be caused by prolonged use.
  • The pathological changes that are observed are similar to those caused by HIV-1.

• Hepatic impairment

  • Patients with hepatic impairment might have higher serum levels, which could increase the risk of hematologic toxicities.

• Renal impairment

  • Patients with CrCl >15 mL/minute should be cautious; dosage adjustment is recommended.

Zidovudine: Drug Interaction

Monitor:

• CBC with differential (more frequent monitoring required in patients with poor bone marrow reserve)
• LFTs
• serum creatinine
• HIV viral load and CD4 count.

How to administer Zidovudine?

• Give orally without regard to meals.

Intravenous:

• Avoid rapid infusion or bolus injection.
• Do not administer IM.
• Infuse over 1 hour
• in pregnant women, infuse loading dose over 1 hour followed by continuous infusion.

Mechanism of action of Zidovudine:

• Zidovudine, a thymidine analogue, interferes with HIV's RNA-dependent DNA polymerase and inhibits viral replication.
• It inhibits nucleoside reverse transcriptionase.

Absorption: Oral:

• Well absorbed

Distribution:

• Significant penetration into the CSF

V :

• 1 to 2.2 L/kg

Protein binding:

• 25% to 38%

Metabolism:

• Mainly Hepatic via glucuronidation to inactive metabolites, including GZDV; extensive first-pass effect

Bioavailability: Oral:

• Similar for tablets, capsules, and syrup
• Neonates <14 days: 89%
• Infants 14 days to 3 months: 61%
• Infants 3 months to Children 12 years: 65%

Half-life elimination: Terminal:

• Premature neonate: 6.3 hours
• Full-term neonates: 3.1 hours
• Infants 14 days to 3 months: 1.9 hours
• Infants 3 months to Children 12 years: 1.5 hours
• Adults: 0.5 to 3 hours (mean 1.1 hours)

Time to peak, serum:

• 30 to 90 minutes

Excretion:

• Oral: Via Urine (72% to 74% as metabolites, 14% to 18% as unchanged drug)
• IV: Via Urine (45% to 60% as metabolites, 18% to 29% as unchanged drug)

International Brands of Zidovudine:

• Adovi
• Antivir
• Aviral
• Avirzid
• Azidomine
• Kedu
• Latus AZT
• Retrovir
• Retrovir AZT
• Retrovir-AZT
• Revodine
• Timivudin
• Zidic-C
• Zidin
• Zido-H
• Zidomat
• Zidovir
• Zydowin
• ALTI-Zidovudine
• APO-Zidovudine
• NOVO-AZT
• Retrovir

Zidovudine Brands in Pakistan: