Neonatal Intensive Care Drug Manual

Start therapy within 4 hours of birth.

If neonates are unable to take oral zidovudine

Switch to oral once the neonate is tolerating oral feeds.

• 
  Very low risk monotherapy – 2 weeks
  
• 
  Low risk monotherapy – 4 weeks
  
• 
  High risk / combination therapy – 4 weeks
  

ECMO: no information.

Renal: see monitoring and interactions.

Hepatic: see monitoring and adverse reactions.

IV

IV: Draw up 1mL (10mg of zidovudine) and add 9mL of glucose 5% to make a final volume of 10mL with a final concentration of 1mg/mL. [1]

IV: infusion over 30 minutes - 1 hour.

The panel should be repeated within 2-4 weeks of commencement of therapy and then every 3-4 months. [2-4]

Zidovudine infusions should not be given to patients with abnormally low neutrophils or haemoglobin levels. [5]

Co-administration of zidovudine with drugs that are nephrotoxic, cytotoxic, or which interfere with red blood cell and white blood cell number or function (e.g. ganciclovir, amphotericin B or interferon) may increase the risk of toxicity. If concomitant therapy with any of these drugs is necessary then extra care should be taken in monitoring renal function and haematological parameters. 

Ribavirin antagonizes in vitro antiviral activity of zidovudine and so concomitant use should be avoided.

Doxorubicin - simultaneous use of doxorubicin and zidovudine should be avoided. Doxorubicin may inhibit the phosphorylation of zidovudine to its active form.

Phenytoin - phenytoin blood levels have been reported to be low in some patients receiving zidovudine. Monitor phenytoin levels if neonate is receiving both medications. [5]

Clarithromycin - oral clarithromycin reduces the absorption of zidovudine. This can be avoided by separating the doses by at least 2 hours. [5]

Y site: aciclovir, amikacin, amphotericin B, aztreonam, cefepime, ceftazidime, ceftriaxone, cimetidine, clindamycin, dexamethasone, dobutamine, dopamine, erythromycin lactobionate, fluconazole, gentamicin, heparin, imipenem, linezolid, lorazepam, metoclopramide, morphine, nafcillin, oxacillin, piperacillin, piperacillin-tazobactam, potassium chloride, ranitidine, remifentanil, rocuronium, tobramycin, trimethoprim-sulfamethoxazole, and vancomycin.

Note: This is not an exhaustive list. Please refer to the relevant resources eg. Micromedex, Australian Injectable Drugs Handbook for detailed information.

Y site: lansoprazole, meropenem

After dilution, the drug solution is stable for 24 hours if stored below 25°C or in refrigerator. Protect from light. [5]

Retrovir IV vials: hydrochloric acid, sodium hydroxide, water for injection.

Fixed drug combinations should be avoided in infants with renal and hepatic insufficiency.

The risk of mother to child transmission of HIV can be significantly reduced by postnatal antiretroviral therapy in addition to antenatal management. [8] The Pediatric AIDS Clinical Trials Group Protocol 076 Study Group showed 67.5% reduction in the relative risk of perinatal HIV transmission by administering Zidovudine during antenatal, intrapartum period and to neonates for 6 weeks. [LOE II] [9] Petra et al reported significant reduction in perinatal HIV transmission (8.9 vs 14.2%) if ART prophylaxis was administered to neonates in addition to intrapartum maternal ART in a group of women who did not receive antenatal ART. [LOE II] [10] A retrospective analysis using data from the New York State Department of Health showed a transmission 9.3% if postnatal zidovudine prophylaxis was commenced within 48 hours compared with 26.6% in the absence of ZDV prophylaxis. [LOE III-1] [11] In a resource-rich setting with use of standard antenatal ART in mother, 4 weeks postnatal neonatal zidovudine prophylaxis was comparable to 6 weeks regimen. [LOE III-3] [12] In pregnant women who did not receive antenatal prophylaxis, two and three drug anti-retroviral regimens are more effective than Zidovudine alone in reducing risk of HIV transmission. [LOE II] [13]

Zidovudine is generally well tolerated in neonates including preterm infants. In a cohort of 112 neonates with mean GA 37 weeks, Smith et al reported anaemia in 39%, neutropenia in 39% and thrombocytopenia in 3% of the infants. Hyperbilirubinemia occurred in 42% and elevated ALT and AST in 3 and 1% infants respectively. [7] In a cohort of 76 preterm neonates (24-34 weeks) who received Zidovudine for 6 weeks, Capparelli reported that risk of severe anaemia requiring transfusion (45%) which is similar to rates in infants of similar gestation. The incidence of other haematological abnormalities was low (neutropenia 11%; thrombocytopenia 13%) and no death attributable to zidovudine was reported. [14] In a cohort of 374 HIV-exposed, uninfected infants, there was no association between in utero exposure to ARV regimens at any time during pregnancy and any Bayley-III outcome at 9-15 months. [15]

Metabolized primarily in the liver to zidovudine glucuronide and renally excreted. Boucher et al. studied the pharmacokinetics of ZDV in full-term infants during the first months of life and found reduced ZDV elimination in those younger than 14 days, with CL averaging 10.9 mL/min/kg and t1/2 averaging 3.12 hours. In full-term infants, ZDV elimination increases rapidly during the first weeks of life. [16] In 15 preterm neonates (GA 26-31 weeks), Mirochnick et al found lower ZDV clearance (2.5 ml/kg/min) and longer half-life (7 hours) compared to term infants. The clearance of ZDV increases and the half-life decreases with postnatal age. [17] Postnatal age was the best predictor of Zidovudine clearance with other factors being gestational at birth, and serum creatinine. Protein binding is approximately 25%. Zidovudine distributes into cells by passive diffusion and is relatively lipophilic. The CSF: plasma ratio was 0.24. The relationship between serum concentration and clinical efficacy is unclear. The oral syrup is well-absorbed, but only 65% bioavailable due to significant first-pass metabolism. The serum half-life in term newborns is 3 hours, declining to 2 hours after 2 weeks of age (half-life of intracellular zidovudine triphosphate in 9 hours). In preterm infants less than 33 weeks gestation, plasma half-life during the first two weeks of life ranges from 5 to 10 hours, decreasing to 2 to 6 hours afterward. [14, 17]

1. 
   Murray KL, Wright D, Laxton B, Miller KM, Meyers J, Englebright J. Implementation of standardized pediatric i.v. medication concentrations. Am J Health Syst Pharm. 2014;71:1500-8.
   
2. 
   AIDSinfo and Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children: Guidelines for the use of antiretroviral agents in Pediatric HIV infection. AIDSinfo, Rockville, MD, Mar01, 2016. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf.
   
3. 
   Palasanthiran P, Starr M, Jones C, Giles M. Management of Perinatal Infections. Australian society for infectious diseases 2014. https://www.asid.net.au/documents/item/368 Downloaded 29/05/2020.
   
4. 
   AIDS info: Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Accessed on 1st April 2019. Available at: https://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0.
   
5. 
   Product Information: RETROVIR(R) oral capsules, oral syrup, intravenous injection, zidovudine oral capsules, oral syrup, intravenous injection. Viv Healthcare (per FDA), Research Triangle Park, NC, Feb 2017.
   
6. 
   Alimenti A, Burdge DR, Ogilvie GS, Money DM, Forbes JC. Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr Infect Dis J. 2003;22:782-9.
   
7. 
   Smith C, Forster JE, Levin MJ, Davies J, Pappas J, Kinzie K, Barr E, Paul S, McFarland EJ, Weinberg A. Serious adverse events are uncommon with combination neonatal antiretroviral prophylaxis: a retrospective case review. PLoS One. 2015;10:e0127062.
   
8. 
   Hurst SA, Appelgren KE, Kourtis AP. Prevention of mother-to-child transmission of HIV type 1: the role of neonatal and infant prophylaxis. Expert Rev Anti Infect Ther. 2015;13:169-81.
   
9. 
   Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331:1173-80.
   
10. 
    Petra Study T. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet. 2002;359:1178-86.
    
11. 
    Wade NA, Birkhead GS, Warren BL, Charbonneau TT, French PT, Wang L, Baum JB, Tesoriero JM, Savicki R. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med. 1998;339:1409-14.
    
12. 
    Ferguson W, Goode M, Walsh A, Gavin P, Butler K. Evaluation of 4 weeks' neonatal antiretroviral prophylaxis as a component of a prevention of mother-to-child transmission program in a resource-rich setting. Pediatr Infect Dis J. 2011;30:408-12.
    
13. 
    Nielsen-Saines K, Watts DH, Veloso VG, Bryson YJ, Joao EC, Pilotto JH, Gray G, Theron G, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata MM, Ceriotto M, Machado D, Bethel J, Morgado MG, Dickover R, Camarca M, Mirochnick M, Siberry G, Grinsztejn B, Moreira RI, Bastos FI, Xu J, Moye J, Mofenson LM, Team NHPP. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012;366:2368-79.
    
14. 
    Capparelli EV, Mirochnick M, Dankner WM, Blanchard S, Mofenson L, McSherry GD, Gay H, Ciupak G, Smith B, Connor JD, Pediatric ACTGI. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr. 2003;142:47-52.
    
15. 
    Sirois PA, Huo Y, Williams PL, Malee K, Garvie PA, Kammerer B, Rich K, Van Dyke RB, Nozyce ML, Pediatric HCS. Safety of perinatal exposure to antiretroviral medications: developmental outcomes in infants. Pediatr Infect Dis J. 2013;32:648-55.
    
16. 
    Boucher FD, Modlin JF, Weller S, Ruff A, Mirochnick M, Pelton S, Wilfert C, McKinney R, Jr., Crain MJ, Elkins MM, et al. Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. Journal of Pediatrics. 1993;122:137-44.
    
17. 
    Mirochnick M, Capparelli E, Dankner W, Sperling RS, van Dyke R, Spector SA. Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus. Antimicrob Agents Chemother. 1998;42:808-12.
    
18. 
    British HIV Association guidelines for the management of HIV in pregnancy and postpartum 2018 (2019 second interim update). https://www.bhiva.org/file/5bfd30be95deb/BHIVA-guidelines-for-the-management-of-HIV-in-pregnancy.pdf Accessed on 19 May 2020.
    
19. 
    Gilleece DY, Tariq DS, Bamford DA, Bhagani DS, Byrne DL, Clarke DE, Clayden MP, Lyall DH, Metcalfe DR, Palfreeman DA, Rubinstein DL, Sonecha MS, Thorley DL, Tookey DP, Tosswill MJ, Utting MD, Welch DS, Wright MA. British HIV Association guidelines for the management of HIV in pregnancy and postpartum 2018. HIV Med. 2019;20 Suppl 3:s2-s85.