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

Pharmacokinetics

SUPPORTING DATA FROM A PHARMACOKINETIC STUDY IN HEALTHY SUBJECTSData on file33

STUDY DESIGN: The primary objective of this study was to determine the comparative exposure of OFIRMEV and oral acetaminophen (liquid formulation). This was an open-label, single-center, randomized, 4-period crossover pharmacokinetic study involving healthy adult males (N=38). Subjects received a total of 8 doses each of OFIRMEV 1 g every 6 hours (q6h), OFIRMEV 1 g every 4 hours (q4h), oral acetaminophen 1 g q6h, and oral acetaminophen 1 g q4h divided among 4 treatment periods. OFIRMEV was administered as a 15-minute infusion. Results after the first dose of the 6-hour dosing regimen for OFIRMEV and oral acetaminophen are shown below.

Efficacy was not assessed in this study.

OFIRMEV demonstrated higher Cmax at 15 minutes34

Mean plasma concentrations of OFIRMEV 1 g and oral acetaminophen 1 g33

Mean plasma concentrations of OFIRMEV 1 g and oral acetaminophen 1 g Cmax, maximum concentration; Tmax, time to reach maximum concentration.
  • Maximum concentration (Cmax) occurred at the end of the 15-minute IV infusion of OFIRMEV34
  • Overall exposure (area under the curve) after a single dose of OFIRMEV was similar to that after a single dose of oral acetaminophen34
  • No significant accumulation was seen with repeated dosing (data not shown)33

Safety Considerations

  • 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

SUPPORTING DATA FROM A PHARMACOKINETIC STUDY IN HEALTHY SUBJECTSSingla et al35

STUDY DESIGN: This was a three-way crossover, single-center, single-dose pharmacokinetic study of 6 healthy adult males. Each received 3 single-dose treatments of IV, oral, and rectal acetaminophen, separated by a washout period of 24 hours. Treatment dosage was 1 g IV and oral acetaminophen, and 1300 mg rectal.* IV acetaminophen was administered over 15 minutes commencing at 0 hours. Cerebrospinal fluid (CSF) and blood draws were performed prior to study medication administration and at 8 additional time points for 6 hours in each treatment period.

No treatment-related adverse events were reported in this study. Of the 12 reported adverse events, headache (postdural puncture headache in particular) was the most common event.

Efficacy was not assessed in this study.

* Rectal acetaminophen data reflect standardization of the 1300-mg dose to 1 g (linear kinetics).

Greater peak plasma levels and overall cerebrospinal fluid levels with IV acetaminophen

Mean plasma concentrations

Mean plasma concentrations
  • Peak plasma concentrations with IV acetaminophen were 76% higher than with oral acetaminophen (P<0.001) and 256% higher than with rectal acetaminophen (P<0.001)

Mean CSF concentrations

Mean CSF concentrations CSF, cerebrospinal fluid. aRectal acetaminophen data reflect standardization of the 1300-mg dose to 1 g (linear kinetics).
  • Overall CSF levels (area under the curve) with IV acetaminophen were 75% higher than with oral acetaminophen (P<0.01) and 142% higher than with rectal acetaminophen (P<0.001)

Adverse events reported in this study

No treatment-related adverse events were reported in this study. Of the 12 reported adverse events, headache (postdural puncture headache in particular) was the most common event.

Safety Considerations

  • 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)
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.