NEODOSE

INDICATIONS

• Closure of patent ductus arteriosus (PDA): NSAIDs (indomethacin and ibuprofen) are the standard drugs for closure of PDA. However, there are risks to NSAIDs and there is a high rate of spontaneous closure; therefore, treatment should be limited to select preterm newborns with symptomatic PDA. Acetaminophen may be a treatment option in those having NSAID failure or contraindications to NSAIDs. IV acetaminophen may be an option in those who have a contraindication to feeding, or who have feeding intolerance. Oral acetaminophen appears as effective as ibuprofen, but long-term safety trials are needed .
  • IV acetaminophen vs placebo: More preterm infants experienced closed ductus arteriosus in the acetaminophen group compared with placebo group (HR 0.49 (95% CI, 0.25 to 0.97)) in a double-blind, randomized, phase I to II study (n=48). Ductal closure was observed at a mean postnatal age of 177+/-338 hours the acetaminophen group and 336 + /-517 hours for the placebo group. The mean gestational age and birth weight were 28.4 weeks and 1.22 kg in the acetaminophen group and 28.3 weeks and 1.12 kg in the placebo group. The dosage was 20 mg/kg IV for 1 dose, followed by 7.5 mg/kg/dose IV every 6 hoursfor 4 days of acetaminophen.
  • Acetaminophen vs Ibuprofen vs Indomethacin: Acetaminophen IV is as effective as indomethacin IV and ibuprofen(at standard doses) IV in the closure of PDA in preterm infants(gestational age less than 28 weeks) with hemodynamically significant PDA in a randomized study(n = 300).After the first treatment course, the closure rates were 80 % , 77 % , and 81 % for acetaminophen, ibuprofen, and indomethacin, respectively.Adverse effects(increase in serum creatinine and serum BUN and decrease in platelet count and urine output) were significantly more with ibuprofen and indomethacin than acetaminophen.Bilirubin significantly increased with ibuprofen.The mean weights were 1.1 kg, 1 kg, and 1.1 kg in the infants treated with acetaminophen, ibuprofen, and indomethacin, respectively
  • Oral acetaminophen vs. oral ibuprofen: In an open – label, randomized trial(n = 80), there was no difference in ductal closure rate(72.5 % vs 77.5 % ) in preterm infants(30 weeks or less gestational age; 1250 g or less) administered a first course of oral acetaminophen compared with oral ibuprofen within 48 to 96 hours after birth with hemodynamically significant PDA.The doses were 15 mg/kg/dose every 6 hours for 3 days of acetaminophen and 10 mg/kg followed by 5 mg/kg/dose 24 and 48 hours later of ibuprofen; each dose was administered via an orogastric tube and flushed with 1 to 2 mL of sterile water.Reopening and subsequent closure with a second course occurred in 24.1 % versus 16.1 % of patients.Bilirubin levels and renal and liver function tests before and after the first and second course of each drug did not differ significantly within or between groups.
  • Case-series: Several case -series demonstrate ductal closure in preterm infants(n = 30; 23 to 36 weeks gestational age; 590 to 990 g birth weight).Dose regimens were either 15 mg/kg/dose every 6 hours for 3 days or 10 mg/kg/dose every 8 hours for 3 days.Treatment durations were extended up to 7 days for persistent hemodynamically PDA.
• Fever reduction and treatment of mild to moderate pain: The decision to use acetaminophen should be weighed against the epidemiological evidence of an association between acetaminophen use and asthma, atopy, rhinoconjunctivitis, or eczema; although causality has not been established. The IV route may be considered when the oral or rectal route is not possible. Routine prophylactic use of acetaminophen at the time of vaccination is not recommended because of a potential reduction in antibody response.

FDA APPROVED INDICATION

Management of mild to moderate pain and moderate to severe pain with adjunctive opioid analgesics in children 2 years or older. Indicated in fever in neonates or older :

CONTRAINDICATIONS/PRECAUTIONS

Intravenous formulation contraindicated in patients with severe hepatic impairment or severe active liver disease. Hypersensitivity reactions, including life-threatening anaphylaxis, have been reported. Rare but serious skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, have been associated with the use of acetaminophen. Reactions may occur after one use or at any time. Discontinue use immediately if rash or other hypersensitivity symptoms occur. Use with caution in patients with hepatocellular insufficiency, severe renal insufficiency, glucose 6 phosphate dehydrogenase deficiency, chronic malnutrition, or dehydration/hypovolemia. A modest reduction in blood pressure and heart rate may occur in neonates (preterm and full-term) after IV administration of acetaminophen. Neonates with pre-existing low arterial pressure may be at greater risk for hypotension. Epidemiological evidence demonstrated an association between acetaminophen use and asthma , rhinoconjunctivitis, eczema and atopy . Confirmatory studies are needed; however, in a meta-analysis, the odds ratio (OR) was 1.6 (95% CI, 1.48 to 1.74) for the risk of asthma in children among users of acetaminophen in the year prior to asthma diagnosis and the first year of life and 1.96 (95% CI, 1.5 to 2.56) for the risk of wheezing and acetaminophen use in the previous year of life. In 2 observational studies, the OR was 3.61 (95% CI, 1.33 to 9.77) for atopy and acetaminophen exposure before the age of 15 months, and up to 2.39 (95% CI, 2.24 to 2.55) for rhinoconjunctivitis symptoms or 1.99 (95% CI, 1.82 to 2.16) for eczema symptoms and acetaminophen exposure in the previous 12 months in adolescents.:

Injection site events (pain and site reactions; 15%) and vomiting (5%) occur with IV acetaminophen . Rash, fever, thrombocytopenia, leukopenia, and neutropenia have been reported in children . Serious skin reactions have been reported from patients who were rechallenged with acetaminophen and had a recurrence of a serious skin reaction. Hypothermia did not develop in 99 neonates (93 normothermic and 6 with fever) administered IV acetaminophen. Although data are limited for neonates, in children liver toxicity occurs with excessive doses or after prolonged administration (greater than 48 hours) of therapeutic doses. Hepatotoxicity occurred in less than 0.01% of children administered therapeutic doses of acetaminophen, in a systemic review (n=32,424; studies=62). The estimated risk for minor or major hepatic events was 0.031% (95% CI, 0.015% to 0.057%). No significant increases in liver enzymes were observed after a median duration of 60 hours (6 to 480 hours) and a median of 9 (2 to 80) doses of IV acetaminophen (20 mg/kg loading dose; 10 mg/kg (every 6 hours for more than 36 weeks postmenstrual age (PMA), every 8 hours for 31 to 36 weeks PMA, and every 12 hours for less than 31 weeks postmenstrual age) in 189 infants (1 day to 182 days of age; 30 to 55 weeks PMA), in a retrospective analysis. Acute liver failure occurred in an 11-month-old boy who received therapeutic doses of oral acetaminophen for a prolonged duration (10 days)! :

BLACK BOX WARNING

Prevent acetaminophen injection dosing errors, which may result in accidental overdose and death, by confirming that doses in milligrams (mg) are not confused with doses in milliliters (mL); that patients under 50 kg receive weight-based doses; that infusion pumps are programmed correctly; and that the total dose of acetaminophen from all routes and from all sources does not exceed daily limits. Life-threatening cases of acute hepatic failure leading to liver transplant or death have been linked with acetaminophen use. In most cases of hepatic injury, acetaminophen doses exceeded maximum daily limits and often involved the use of more than 1 acetaminophen-containing product.

ADMINISTRATION

• Intravenous: Intravenous: Administer IV over 15 minutes (10 mg/mL). Withdraw appropriate dose and administer in bottle, bag, or IV syringe; dose should be administered within 6 hours. Exercise caution when calculating the dose in milligrams and administering the dose in milliliters. The administered volume in a neonate should always be 7.5 mL or less.

MONITORING

Assess for signs of pain. Monitor temperature. Assess liver function. Serum acetaminophen concentration is obtained only to assess toxicity.