Less Pain1-5 Less Opioids2,3 Improved Patient Satisfaction2,4

Gastric function and absorption

SUPPORTING DATA FROM A PHARMACOKINETIC STUDY IN ORTHOPEDIC SURGERYPetring et al28

STUDY DESIGN: This was a randomized, double-blind pharmacokinetic study involving 15 patients undergoing orthopedic surgery with spinal anesthesia. Patients were randomized to receive a single dose of intramuscular morphine 10 mg (n=8) or a single dose of intramuscular ketorolac 30 mg (n=7) for post-op pain. As a measure of liquid gastric emptying, oral acetaminophen solution at 20 mg/kg was administered to each patient at 2 time points, at least 12 hours before scheduled surgery (pre-op) and 30 minutes after the first administration of morphine or ketorolac (post-op).

Efficacy of acetaminophen was not assessed in this study.

Post-op gastric impairment can impact absorption of analgesics

Following surgery, compromised gastric function has been shown to diminish the absorption of oral analgesics

Mean pre-op and post-op plasma concentrations of oral acetaminophen

Mean pre-op and post-op plasma concentrations of oral acetaminophen
  • Post-op plasma concentrations of oral acetaminophen (used as a measure of liquid gastric emptying) were significantly lower than pre-op values (P<0.001) in patients who received a single dose of morphine following surgery
  • Post-op maximum concentration (Cmax) and time to reach maximum concentration (Tmax) of oral acetaminophen could not be determined following morphine administration due to a marked delay in absorption

SUPPORTING DATA FROM A PHARMACOKINETIC STUDY IN CARDIAC SURGERYBerger et al29

STUDY DESIGN: This was a prospective pharmacokinetic study conducted in patients with adequate hemodynamic status undergoing cardiac surgery (n=16), patients with hemodynamic failure undergoing cardiac surgery (n=23), and healthy volunteers who served as controls (n=6) to assess intestinal absorption as a function of hemodynamic status. To test the role of pyloric opening and assess intestinal absorption, 1 g of acetaminophen in liquid formulation was administered on post-op days 1 and 3 through a nasogastric or postpyloric tube.

Efficacy was not assessed in this study.

Opioid-related pyloric narrowing or closure led to decreased concentrations of oral acetaminophen

Peak plasma levels of oral acetaminophen on day 1

Peak plasma concentrations of oral acetaminophen on day 1
  • Oral acetaminophen absorption was decreased following nasogastric, but not postpyloric, administration on day 1 post surgery

Several factors may diminish gastric function following surgery28-31

In the period immediately following surgery, gastroparesis and delayed gastric emptying may be caused by:

  • Surgery
  • Opioids
  • Anesthesia
  • Pre-op fasting
  • Post-op stress

SUPPORTING DATA FROM A PHARMACOKINETIC STUDY IN HEALTHY SUBJECTSDevarakonda et al32

STUDY DESIGN: This was a randomized, single-blind, two-way, repeated-dose study in healthy adults to assess how opioids alter the pharmacokinetics of orally administered acetaminophen. Participants were randomly assigned to receive either 4 repeat doses of oral acetaminophen 1 g with IV placebo every 6 hours (n=11) or 4 repeat doses of IV acetaminophen 1 g with 2 placebo tablets every 6 hours (n=11). Both groups received 2 doses of IV morphine at 0.125 mg/kg at hours 6 and 12. The observed pharmacokinetic profiles of oral and IV acetaminophen were compared with their predicted profiles.

Efficacy was not assessed in this study.

Impact of morphine on the absorption of oral acetaminophen

A two-way, repeated-dose study in healthy adults assessed how opioids alter the pharmacokinetics of orally or intravenously administered acetaminophen

Group A: Oral acetaminophen plasma concentrations

Group A: Oral acetaminophen plasma concentrations Group A: Oral acetaminophen plasma concentrations APAP, acetaminophen; AUC0-6, area under the curve from 0 to 6 hours; C6, concentration at 6 hours; Cmax, maximum concentration; SD, standard deviation; Tmax, time to reach maximum concentration. aAUC following each dose of APAP.
  • Group A: 4 repeat doses of oral acetaminophen 1 g with IV placebo and 2 doses of IV morphine at 0.125 mg/kg (n=11)
  • Peak plasma levels of oral acetaminophen were diminished following IV morphine administration
    • Time to reach maximum concentration (Tmax) was prolonged, and area under the curve from 0 to 6 hours (AUC0-6) was reduced

Group B: IV acetaminophen plasma concentrations

Group B: IV acetaminophen plasma concentrations Group B: IV acetaminophen plasma concentrations APAP, acetaminophen; AUC0-6, area under the curve from 0 to 6 hours; C6, concentration at 6 hours; Cmax, maximum concentration; SD, standard deviation; Tmax, time to reach maximum concentration. aAUC following each dose of APAP.
  • Group B: 4 repeat doses of IV acetaminophen 1 g with tablet placebo and 2 doses of IV morphine at 0.125 mg/kg (n=11)
  • Peak plasma levels of IV acetaminophen were similar before, during, and after IV morphine administration
    • AUC0-6 was also similar

Safety Considerations

  • Acetaminophen is contraindicated in patients with
    • known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation
    • severe hepatic impairment or severe active liver disease
Scroll down for additional important safety information

Indications and Usage

OFIRMEV® (acetaminophen) injection is indicated for the management of mild to moderate pain in adult and pediatric patients 2 years and older, the management of moderate to severe pain with adjunctive opioid analgesics in adult and pediatric patients 2 years and older, and the reduction of fever in adult and pediatric patients.

Important Safety Information

WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY

Take care when prescribing, preparing, and administering OFIRMEV® (acetaminophen) injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that:

  • the dose in milligrams (mg) and milliliters (mL) is not confused;
  • the dosing is based on weight for patients under 50 kg;
  • infusion pumps are properly programmed; and
  • the total daily dose of acetaminophen from all sources does not exceed maximum daily limits.

OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product.

Contraindications

  • Acetaminophen is contraindicated in patients with
    • known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation.
    • severe hepatic impairment or severe active liver disease.

Warnings and Precautions

  • Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death. Do not exceed the maximum recommended daily dose of acetaminophen. The maximum recommended daily dose of acetaminophen includes all routes of acetaminophen administration and all acetaminophen-containing products administered, including combination products. Dosing errors could result in accidental overdose and death.
  • Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia, or severe renal impairment (creatinine clearance ≤ 30 mL/min).
  • Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Discontinue OFIRMEV immediately at the first sign of skin rash.
  • Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors, which could result in accidental overdose and death.
  • Hypersensitivity and anaphylaxis associated with the use of acetaminophen have been reported. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. Discontinue OFIRMEV immediately upon occurrence of signs or symptoms associated with allergy or hypersensitivity. Do not use OFIRMEV in patients with acetaminophen allergy.
  • The antipyretic effects of OFIRMEV may mask fever.

Adverse Reactions

  • Serious adverse reactions may include hepatic injury, serious skin reactions, allergy, and hypersensitivity.
  • The most common adverse reactions in patients treated with OFIRMEV were nausea, vomiting, headache, and insomnia in adult patients and nausea, vomiting, constipation, and pruritus in pediatric patients.

To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt Hospital Products, Inc. at 1-800-778-7898 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see additional Important Safety Information, including Boxed Warning, in the Full Prescribing Information.