RETROVIR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for RETROVIR (RETROVIR).
Nucleoside analog reverse transcriptase inhibitor; after intracellular phosphorylation to a triphosphate metabolite, it incorporates into viral DNA and causes chain termination, inhibiting HIV reverse transcriptase.
| Metabolism | Extensively metabolized via glucuronidation to zidovudine glucuronide (inactive); minor metabolism via cytochrome P450 (CYP3A4) to 3'-amino-3'-deoxythymidine (AMT). |
| Excretion | Renal excretion of unchanged drug accounts for approximately 14% of the dose; major metabolite is zidovudine 5'-glucuronide (GZDV), which is excreted renly. Fecal excretion is minimal (<1%). |
| Half-life | Terminal elimination half-life is 0.5–3 hours (mean ~1.1 hours) in adults; prolonged in renal impairment (up to 8 hours) and neonates (up to 13 hours). |
| Protein binding | 34–38% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | 1.4–1.6 L/kg; indicates extensive distribution into total body water and tissues, including CNS (CSF concentrations ~50% of plasma). |
| Bioavailability | Oral bioavailability is 60–70% (range 50–80%) due to first-pass metabolism. |
| Onset of Action | Oral: time to peak plasma concentration 0.5–1.5 hours; clinical antiviral effect begins within days. IV: immediate systemic availability. |
| Duration of Action | Duration of action is 4–6 hours based on dosing interval (every 4–6 hours for oral). Sustained suppression requires consistent dosing; intracellular zidovudine triphosphate half-life is approximately 3–4 hours. |
300 mg orally twice daily or 200 mg orally three times daily; intravenous: 1-2 mg/kg every 4 hours around the clock.
| Dosage form | INJECTABLE |
| Renal impairment | Creatinine clearance 15-50 mL/min: 300 mg every 12-24 hours; <15 mL/min: 300 mg every 24 hours; hemodialysis: 100 mg every 6-8 hours; peritoneal dialysis: 100 mg every 6-8 hours. |
| Liver impairment | Child-Pugh Class A: no adjustment; Class B: reduce dose by 50% or consider alternative; Class C: contraindicated or use with extreme caution. |
| Pediatric use | Neonates (≥6 weeks): 8 mg/kg/day divided every 6 hours; Infants/Children (<30 kg): 8-12 mg/kg/day divided every 6 hours; Dose not to exceed 600 mg daily. |
| Geriatric use | Monitor renal function closely; start at lower end of dosing range due to age-related decline in renal function; consider creatinine clearance adjustment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for RETROVIR (RETROVIR).
| Breastfeeding | Zidovudine is excreted into human breast milk. The milk-to-plasma (M/P) ratio is approximately 0.6–1.0. Concentrations in milk are similar to or slightly lower than maternal plasma concentrations. In the United States, HIV-infected mothers are advised not to breastfeed to avoid postnatal transmission of HIV. If used for other indications (e.g., off-label), caution is advised due to potential for infant toxicity and viral transmission. |
| Teratogenic Risk | Zidovudine (Retrovir) is classified as FDA Pregnancy Category C. There is evidence of fetal risk based on animal studies, but human data are limited. First trimester: No increased risk of major malformations has been consistently demonstrated in human studies, but transplacental passage occurs. Second and third trimesters: Use is associated with reduced vertical transmission of HIV. However, animal studies have shown carcinogenicity and teratogenicity at high doses. Mitochondrial toxicity has been reported in some infants exposed in utero. Overall, the benefit of preventing HIV transmission generally outweighs the theoretical risk. |
■ FDA Black Box Warning
Hematologic toxicity including neutropenia and severe anemia, especially in patients with advanced HIV disease; prolonged use associated with mitochondrial toxicity; risk of lactic acidosis and severe hepatomegaly with steatosis, which may be fatal.
| Serious Effects |
Life-threatening hypersensitivity to zidovudine or any component of the formulation; co-administration with stavudine or doxorubicin (antagonistic); do not use for postpartum HIV prevention in mothers with HIV RNA >400 copies/mL due to resistance risk.
| Precautions | Bone marrow suppression (anemia, neutropenia); lactic acidosis and hepatomegaly with steatosis; myopathy; immune reconstitution syndrome; risk of hepatotoxicity in co-infected patients; monitor hematologic parameters frequently. |
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| Fetal Monitoring | Maternal: Complete blood count (CBC) and hepatic function tests should be monitored frequently, especially during the first month of therapy and periodically thereafter due to risk of anemia, neutropenia, and hepatotoxicity. Lactic acid levels if symptoms of lactic acidosis occur. Fetal/neonatal: Ultrasound for fetal growth and anatomy; monitor for signs of mitochondrial dysfunction, including neurologic abnormalities, growth retardation, and hematologic toxicity in the newborn. Perform neonatal CBC at birth. |
| Fertility Effects | Animal studies have shown no significant effects on fertility at clinical doses. Human data are limited, but zidovudine is not known to impair fertility in men or women. However, HIV infection itself may affect fertility, confounding assessment. |