Intravenous acetaminophen: Its role and its benefits

Acetaminophen has been the topic of several Pharmacology Consult columns in Infectious Diseases in Children in past years because it is one of the most commonly used medications in pediatrics. Recently, acetaminophen has been discussed in the lay news and literature, reflecting concerns over this medication’s potential for serious hepatotoxicity from inappropriate dosing and use by individuals and caregivers of children.

Numerous prescription and over-the-counter products are available that contain acetaminophen, and this contributes to its inappropriate use. In the medical news again, acetaminophen is now available as a new dosage form. Ofirmev (Cadence Pharmaceuticals), IV acetaminophen, was labeled by the FDA in late 2010 and is labeled for use as a 15-minute IV infusion in children aged 2 years and older. Ofirmev is indicated for adults, with indications for management of mild-moderate pain, moderate-severe pain with adjunctive opioid analgesics (adults), and for fever reduction. Labeled dosing includes 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours (maximum of 75 mg/kg/24 hours).

Clinical study data

Data used to support the labeling of Ofirmev, as described in the product insert, include adult clinical studies, with additional, supportive pediatric safety and pharmacokinetic data from other studies. Published small clinical efficacy studies of IV acetaminophen in infants (aged 1 month and older) and children include uses for preoperative, intraoperative and postoperative pain (inguinal hernia repair, tonsillectomy, dental surgery) and fever (single-dose). In these studies, acetaminophen administered intravenously had comparable analgesic effects as intramuscular meperidine, propacetamol (a pro-drug formulation of acetaminophen available in some European countries) or rectally administered acetaminophen. The pharmacokinetics of intravenously administered acetaminophen has been studied in infants (including preterm) and children, although Ofirmev is labeled for use only at 2 years of age and older. The maximum blood concentration after administration of IV acetaminophen occurs at the end of the 15-minute infusion, with peak analgesic effects in 60 minutes.

Other acetaminophen dosages

Acetaminophen has an advantage of availability in numerous dosage forms, including oral and rectal dosage forms. As acetaminophen is commonly used in infants and children for its analgesic and antipyretic effects, it is available as numerous oral products, including liquids, chewable tablets and tablets/capsules. Acetaminophen is also available as rectal suppositories, in several strengths.

However, rectal administration of acetaminophen has been criticized for altered pharmacokinetics, including significant interpatient variability (as much as a ninefold difference) in absorption and plasma levels. Some children may not attain therapeutic levels with rectal administration of acetaminophen, and peak plasma levels occur longer as compared with use of oral dosage forms. Dosing and dosing intervals of acetaminophen differ with oral and rectal administration in neonates.

In 2001, the AAP cautioned on the use and potential toxicity (potential for more frequent administration) of rectally administered acetaminophen. Recently, several authors evaluated three comparative antipyretic pediatric studies of orally and rectally administered acetaminophen (Goldstein, 2008). No difference in various efficacy measures (temperature decrease one study, three studies post-dose and maximum temperature decline) was found between oral or rectal administration. These studies are limited, however, by small patient numbers, lack of blinding (two studies) and comparison of single-dose therapy only.

Other IV agents

Another commonly used antipyretic agent, ibuprofen, also recently became available (in 2009) as an intravenously administered dosage form. Caldolor (Cumberland Pharmaceuticals) is labeled for use only in adults for treatment of mild-moderate pain, moderate-severe pain as an adjunct to opioid analgesics, and for treatment of fever. Another nonsteroidal anti-inflammatory drug available as an IV dosage form is ketorolac, which is not labeled for use in infants and children, and is limited by its higher propensity to cause gastrointestinal bleeding.

Potential of IV acetaminophen

IV acetaminophen has the potential for several benefits over products. Ofirmev is the only intravenously antipyretic/analgesic product available that is specifically labeled for use in children as young as 2 years of age. Some studies of its use in infants have been published, and more are currently ongoing. Acetaminophen has the advantage of product availability in numerous dosage forms and strengths, including several strengths of rectal suppositories. Rectal administration of acetaminophen has been shown to have large interpatient variability in absorption and bioavailability. This may negate its clinical usefulness in some patients, and may also increase the potential for therapeutic miss-adventuring.

In the hospital setting, where drug efficacy and safety can be more closely followed, use of rectal acetaminophen is likely to continue to have a role. Ofirmev offers an advantage of another route of administration for acetaminophen. IV administration of acetaminophen can be potentially beneficial for infants and children in the following scenarios: postsurgical; NPO status for a variety of reasons; vomiting; intractable diarrhea; or other contraindications to oral or rectal drug administration. More predictable blood levels from IV administration may also have the potential benefit of increased clinical analgesia, as compared with more variable absorption from orally and rectally administered acetaminophen. These advantages should be tempered with product cost, however. The rectal route of administration can be useful in pediatrics for other drugs as well.

Acetaminophen oral and rectal dosage forms are very inexpensive (eg, pennies per dose). Ofirmev’s cost to hospital pharmacy departments is approximately $10 per vial. Ofirmev is available only as a single-use (use within 6 hours of opening), 1,000-mg vial. Thus, frequent use of Ofirmev in infants and children with established IV access (where oral or rectal administration may be feasible) has the potential to sharply increase hospital pharmacy drug costs. Many hospital pharmacy departments and pharmacy/therapeutic committees are currently debating the most efficient and cost-effective use of this new agent.

For more information:

• AAP. Pediatrics. 2001;108:1020-1024.
• Duggan ST. Drugs. 2009;69:101-113.
• Goldstein LH. Arch Pediatr Adolesc Med. 2008;162:1042-1045.

Edward A. Bell, PharmD, BCPS, is a Professor of Clinical Sciences at Drake University College of Pharmacy, Blank Children’s Hospital and Clinics in Des Moines, Iowa.

Disclosure: Bell reports no relevant financial disclosures.