Clinical Pharmacokinetic and Health Economic Data on OFIRMEV® (Acetaminophen) Injection Presented at 15th Annual Pain Medicine Meeting of ASRA

CHESTERFIELD, United Kingdom, Nov. 18, 2016 /PRNewswire/ -- Mallinckrodt Pharmaceuticals (NYSE: MNK), a leading global specialty pharmaceutical company, today announced results from a clinical pharmacokinetic (PK) study examining the effect of IV morphine on the absorption of orally administered acetaminophen.

The company also revealed findings from three retrospective claims-based analyses providing health economic insights on use of IV acetaminophen versus oral acetaminophen for managing post-operative pain in patients undergoing spine surgery, cholecystectomy (removal of the gall bladder) or hysterectomy.

Study results will be presented today in moderated ePoster sessions at the 15^th Annual Pain Medicine Meeting of the American Society of Regional Anesthesiology and Pain Medicine (ASRA) in San Diego.

"We are encouraged that these studies can provide clinicians, pharmacists, and hospital administrators additional clinical and health economic data, further differentiating IV acetaminophen from oral acetaminophen," said Tunde Otulana, Chief Medical Officer at Mallinckrodt. "These studies help underscore the relevant pharmacokinetic profile and the health economic value of OFIRMEV in the management of acute pain in the surgical setting."

Clinical Pharmacokinetic Study  
"Morphine Impacts the Absorption of Co-Administered Oral Acetaminophen and Results in Altered Pharmacokinetics in Healthy Subjects" [Devarakonda K, Lu L, Chen Y, Wu S, Hill L, Brant J], a randomized, single-blind, two-way, parallel, single-site, repeat-dose study in healthy subjects examined the effect of IV morphine, which is associated with delayed gastric emptying, on the intestinal absorption of orally administered acetaminophen. The study also assessed the comparative effects of IV morphine co-administered with IV acetaminophen as a secondary endpoint.

The study enrolled 50 healthy subjects; 23 completed the study and 22 were included in the final analysis. Study subjects were randomized to receive:

• Oral acetaminophen: Four repeat doses of 1,000 mg (two tablets, 500 mg/tablet) at hours -6, 0, 6 and 12 plus a dummy (placebo) IV infusion of saline at the same time points; or
• IV acetaminophen (OFIRMEV): Four doses of 1,000 mg (1,000 mg/100 mL) delivered as an infusion at hours -6, 0, 6 and 12 plus two placebo tablets at the same time points;

IV morphine infusions were received by both groups: (0.125 mg/kg in 100 mL saline) at hours 0 and 6.

The study showed that concurrent administration of morphine with oral acetaminophen resulted in reduced maximum serum concentrations and overall drug exposure of acetaminophen. There was significantly greater variability of response between subjects with oral administration. Following the final dose of oral acetaminophen, when morphine was unlikely to still be exerting an effect on gastric function, significantly increased acetaminophen blood levels – greater than the first and subsequent doses – were also observed. Concurrent administration of morphine with IV acetaminophen, however, did not significantly alter critical PK (C_max¹, AUC², T_max³) parameters of acetaminophen.  

Health Economic Study – Spine Surgery
"Comparative Analysis of Length of Stay, Hospitalization Costs, Opioid Use, and Discharge Status Among Spine Surgery Patients with Postoperative Pain Management Including IV versus Oral Acetaminophen" [Hansen RN, Pham A, Böing EA, Lovelace B, Wan GJ, Miller TE] examined the impact of IV acetaminophen (OFIRMEV) versus oral acetaminophen – when administered in addition to other pain medications – on length of stay (LOS), hospitalization costs and average morphine equivalent dose (MED) on patients undergoing spine surgery starting on the day of surgery and continuing up to the third postoperative day. This retrospective cohort analysis of the Premier Inc. inpatient hospital database from January 2012 to September 2015 included 112,586 spine surgery patients from U.S. hospitals, with 51,835 patients (46%) receiving IV acetaminophen.

The study showed that, compared to oral acetaminophen, use of IV acetaminophen as part of an analgesic management program for post-spine surgical pain was associated with a significant decrease in hospital LOS and hospitalization costs, and significantly lower doses of opioids.

The study was conducted in collaboration with researchers from the University of Washington School of Pharmacy and Duke University School of Medicine.

Health Economic Study – Cholecystectomy  
"Reduced Length of Stay and Hospitalization Costs Among Inpatient Cholecystectomy Patients with Postoperative Pain Management: IV versus Oral Acetaminophen" [Pham A, Hansen RN, Böing EA, Lovelace B, Wan GJ, Thomas DA, Fontes M] examined the impact of IV acetaminophen (OFIRMEV) versus oral acetaminophen – when administered in addition to other pain medications – on LOS, hospitalization costs and average MED starting on the day of surgery and continuing up to the third postoperative day. This retrospective cohort analysis of the Premier Inc. inpatient hospital database from January 2012 to September 2015 included 61,017 cholecystectomy surgery patients from U.S. hospitals, with 31,133 patients (51%) receiving IV acetaminophen.

This study showed that, compared to oral acetaminophen, use of IV acetaminophen in managing post-cholecystectomy pain was associated with a significant decrease in hospital LOS and hospitalization costs, and significantly lower doses of opioids.

The study was conducted in collaboration with researchers from the University of Washington School of Pharmacy and Yale University School of Medicine.

Health Economic Study – Hysterectomy 
"Reduced Length of Stay and Hospitalization Costs Among Inpatient Hysterectomy Patients with Postoperative Pain Management Including IV Versus Oral Acetaminophen" [Pham A, Hansen RN, Lovelace B, Böing EA, Wan GJ, Urman R] examined the impact of IV acetaminophen (OFIRMEV) versus oral acetaminophen – when administered in addition to other pain medications – on LOS, hospitalization costs and average MED starting on the day of surgery and continuing up to the third postoperative day. This retrospective cohort analysis of the Premier Inc. inpatient hospital database from January 2012 to September 2015 included 22,828 hysterectomy patients from U.S. hospitals, with 14,811 patients (65%) receiving IV acetaminophen.

This study showed that, compared to oral acetaminophen, use of IV acetaminophen in managing post-hysterectomy pain was associated with a significantly shorter hospital LOS and lower hospitalization costs.

The study was conducted in collaboration with researchers from the University of Washington School of Pharmacy, Harvard Medical School and Brigham & Women's Hospital.

Health Economic Study Limitations

• The differences observed between IV and oral acetaminophen patients on outcomes (e.g., LOS, hospitalization costs, MED, discharge to skilled nursing facilities, bowel obstruction, nausea/vomiting, respiratory depression) could be explained by unmeasured confounders. Investigators attempted to account for this through the use of instrumental variable regression, adjusting models for potentially confounding variables, but unmeasured factors might still play a role in the associations reported.
• The medication use data in the Premier database reflects the amount and dose charged rather than what was administered. However, systematic differences in billing of other pain medications between patients who did or did not receive IV acetaminophen is not suspected.
• The population of patients seen in Premier hospitals is not randomly sampled although the database represents 20 percent of all hospitalizations in the U.S. Therefore, these results may not be generalizable outside of Premier hospitals.

ABOUT OFIRMEV (Acetaminophen) Injection 
OFIRMEV is the first and only IV formulation of acetaminophen to be approved and currently marketed in the United States. The U.S. FDA approved OFIRMEV in November 2010. OFIRMEV is available to hospitals and outpatient and ambulatory surgical centers across the U.S.

INDICATIONS AND USAGE 
OFIRMEV (acetaminophen) Injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. 

IMPORTANT RISK INFORMATION

WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY

Take care when prescribing, preparing, and administering OFIRMEV 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 (IV) 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 (e.g., due to dehydration or blood loss), 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.
• 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.
• The antipyretic effects of OFIRMEV may mask fever.

ADVERSE REACTIONS

• Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity, and anaphylaxis.
• Common adverse reactions in adults include nausea, vomiting, headache, and insomnia. Common adverse reactions in pediatric patients include nausea, vomiting, constipation, pruritus, agitation, and atelectasis.

USE IN SPECIFIC POPULATIONS

• Pregnancy Category C. OFIRMEV should be given to a pregnant woman only if clearly needed.
• Breastfeeding: While studies with OFIRMEV have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration.
• Pediatric Use: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients < 2 years of age.

For additional Important Risk Information, including complete boxed warning, see Full Prescribing Information.

ABOUT MALLINCKRODT 
Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical and biopharmaceutical products and therapies, as well as nuclear imaging products. Areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and hemostasis products; and central nervous system drugs. The company's core strengths include the acquisition and management of highly regulated raw materials and specialized chemistry, formulation and manufacturing capabilities. The company's Specialty Brands segment includes branded medicines; its Specialty Generics segment includes specialty generic drugs, active pharmaceutical ingredients and external manufacturing; and the Nuclear Imaging segment includes nuclear imaging agents. To learn more about Mallinckrodt, visit www.mallinckrodt.com.

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¹ The maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose
² The total drug exposure over time
³ The time at which the C_max is observed

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SOURCE Mallinckrodt Pharmaceuticals

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