NEODOSE

INDICATIONS

• Neonatal herpes simplex virus (HSV) infections, known or suspected : Acyclovir treatment should be initiated in all infants, including HIV-positive, with herpes disease. In asymptomatic neonates born to women with active herpes lesions, initiation of acyclovir is dependent on risk of transmission to the neonate . Adverse effects (AE) were common, but severe AEs were rare with a median dose of acyclovir 60 mg/kg/day IV in a retrospective review of Pediatrix Medical Group data (n=89 newborn infants).
  • Dose Regimen: Based on results from a clinical trial, the standard dose and dosing interval is 20 mg/kg IV every 8 hours (60 mg/kg/day). Although mortality rate was reduced when compared with the 30 mg/kg/day (10 mg/kg/dose every 8 hours) regimen, the 60 mg/kg/day regimen still demonstrated a 24-month mortality rate of 31% among infants with disseminated HSV disease and 6% among infants with CNS HSV disease. Furthermore, the dose did not improve the rates of normal infant development. Investigators of a small population pharmacokinetic study proposed the following frequencies for a 20 mg/kg dose: every 12 hours for infants less than 30 weeks postmenstrual age (PMA) (n=13 ), every 8 hours for infants 30 to less than 36 weeks PMA (n=9), and every 6 hours for infants 36 to 41 weeks PMA (n=6) to achieve a surrogate pharmacodynamic acyclovir target concentration of 3 mg/L or more. This target concentration theoretically would achieve CSF concentrations of 1 mg/L or more. Safety and efficacy were not evaluated with these regimens. One infant experienced an elevated serum creatinine, which was considered related to acyclovir. Doses greater than 80 mg/kg/day (range 87 to 158 mg/kg/day) were administered to 47% of neonates (15 out of 32 infants).
• Gastric Lactobezoar: A gastric lactobezoar was successfully treated after 4 doses of Acyclovir 10 mg/kg/dose via nasogastric (NG) tube every 6 hours in a 1 month of age full-term infant. Each dose was diluted in 50 mL of normal saline and administered over 30 minutes, then the NG tube was clamped for 2 hours, followed by aspiration at 3 and 6 hours after the dose.
• Lung Disease, Non-Cystic Fibrosis: Evidence is limited and does not support the use of oral or inhaled Acyclovir for non-cystic fibrosis lung disease such as primary ciliary dyskinesia, chronic lung disease of infancy, pneumonia, asthma, atelectasis, inhalation injury, or lower respiratory tract infection in pediatric patients or neonates. A 6-day course of I Acyclovir (16 to 32 mg/kg/day) started before the age of 36 hours did not improv mortality, the incidence of bronchopulmonary dysplasia, or lung function in a randomized double-blind, placebo-control trial (n=391; weight range 500 to 999 g). Furthermore harm was demonstrated in 10 ventilated premature infants with chronic lung disease an treated with intratracheally administered Acyclovir for 7 days.
• Neonatal HSV infection, Chronic suppressive therapy: Based on data reported from 2 parallel, phase III, double-blind, placebo-controlled studies (n=45 with CNS disease; n=29 with skin, eye, mouth (SEM) disease), 6 months of suppressive oral acyclovir therapy (300 mg/m2/dose 3 times a day) started immediately after IV treatment for CNS HSV disease was associated with better neurological outcomes when compared with placebo. Of the 28 infants with CNS disease assessed at 12 months (acyclovir=16; placebo=12), Bayley Scales of Infant Development (2nd Edition) Mental Scores were significantly higher in patients receiving acyclovir compared with patients receiving placebo (88.24 vs 68.12; p=0.046). In patients with SEM disease receiving 6 months of suppressive oral acyclovir therapy started immediately after IV treatment, the time to 2 recurrences of skin lesions was 1.7 months longer in the treatment group compared with placebo. Of the 15 infants with SEM disease assessed at 12 months, there were no differences in Bayley scores between acyclovir and placebo. An absolute neutrophil count of 500 cells/mm3 or less was reported in 20% to 25% of patients receiving acyclovir compared with 5% to 7% receiving placebo; no patient had complications associated with neutropenia.
• Varicella-zoster virus infections with CNS and pulmonary involvement: Acyclovir treatment is recommended in infants with varicella-zoster infection having CNS or pulmonary involvement.

• administration: Rapid rate of infusion may lead to renal tubular damage.
• hematologic: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, including fatal cases, has been reported in immunocompromised patients.
• Neurologic: Encephalopathic changes (eg, lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures, or coma) have been reported; use with caution in patients with underlying neurologic abnormalities, significant hypoxia, or serious renal, hepatic, or electrolyte abnormalities
• Renal:
  • Impaired renal function may occur and is dependent upon rate of administration; risk is increased in patients with preexisting renal disease and dehydration, and with concomitant use of other nephrotoxic drugs.
  • Precipitation of acyclovir crystals in renal tubules may occur and can result in acute renal failure; accompany administration with adequate hydration.
  • Renal failure, including fatal cases, has been reported.

ADVERSE EFFECTS

• Common Adverse Effects: Common adverse events include nausea, vomiting, and rash
• Cardiovascular: Hypotension requiring inotropes (9%) occurred in a retrospective review of Pediatrix Medical Group data (n=89 newborn infants treated for herpes simplex virus disease).
• Hepatic: Elevations of hepatic transaminases (1% to 2%).
• Hematologic: Leukopenia (16%) and thrombocytopenia (25%), which occurred within a median of 1 to 2 days, were common in a retrospective review of Pediatrix Medical Group data (n=89 newborn infants treated with high-dose acyclovir for herpes simplex virus disease). Neutropenia occurred in 6% of infants, most of whom were treated with granulocyte colonystimulating factor. Severe hematologic events were rare (0% to 3%). Among infants receiving high-dose acyclovir for neonatal HSV disease, the major toxicity was neutropenia (absolute neutrophil count less than 1000/mm3), which was observed in 20% of neonates. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, resulting in death, have been reported in some immunocompromised patients receiving acyclovir. Overall, hematologic abnormalities occurred in less than 1% .
• Immunologic: Development of certain acyclovir-resistant viruses may cause severe disease in infants.
• Neurological: Seizures (9%) occurred in a retrospective review of Pediatrix Medical Group data (n=89 newborn infants treated with high-dose acyclovir for herpes simplex virus disease).
• Neurological: Mild elevations of creatinine concentrations (2%) were reported in a retrospective review of Pediatrix Medical Group data (n=89 newborn infants treated with high-dose acyclovir for herpes simplex virus disease). Renal failure, in some cases fatal, has been reported.
• Vascular: Phlebitis at the injection site occurred in 9% of patients.

ADMINISTRATION

• Intravenous route: Administer as IV infusion over 1 hour at a concentration of 7 mg/mL or less in D5W or NS.
• Oral route: take with or without food; for suspension, shake well before measuring each dose.
• Extravasation Management: Neonatal data are limited to pooled data from 10 case reports/case series (n=237) and are not specific to acyclovir extravasation; subcutaneous saline irrigation with or without hyaluronidase infiltration was commonly used. No standardized management was established. An option for more severe injuries (stages 3 and 4) is subcutaneous irrigation with saline, but this is not advocated as standard treatment. Conservative management is appropriate for mild extravasation (stages 1 and 2). Although not neonatal-specific, the following are recommendations for extravasation of acidic or alkaline agents (acyclovir is alkaline with a pH of 11):
  • General
    • Stop and disconnect infusion; do not remove the cannula or needle
    • Attempt to gently aspirate as much extravasated agent as possible; avoid manual pressure
    • Remove cannula or needle
    • Dry heat and elevation
    • Closely monitor for signs of coagulation and ischemia
    • Avoid attempt a pH neutralization(acyclovir – pH 11)
    • Monitor and consider the need for surgica management such as surgical flushing with normal saline or debridement and excision of necrotic tissue(especially if pain persists for 1 to 2 weeks).In cases of compartment syndrome, surgical decompression may be required
  • Refractor Events:
    • Hyaluronidase 15 units intradermall along injection site and edematous area. Give as five, 0.2 – mL intradermal injections along extravasation site and edematous tissue.
  • Inadvertent Intraarterial Administration:
    • Leave inadvertent intraarterial line i place for diagnostics
    • Systemic heparin titrated to therapeutic anticoagulant effect.
    • Stellate ganglion block

MONITORING

• Laboratory: Monitor renal function at baseline and at least once weekly, particularly in patients with preexisting renal dysfunction on prolonged therapy.