An integrated safety analysis of intravenous ibuprofen (Caldolor(®)) in adults

Stephen R Southworth, Emily J Woodward, Alex Peng, Amy D Rock, Stephen R Southworth, Emily J Woodward, Alex Peng, Amy D Rock

Abstract

Intravenous (IV) nonsteroidal anti-inflammatory drugs such as IV ibuprofen are increasingly used as a component of multimodal pain management in the inpatient and outpatient settings. The safety of IV ibuprofen as assessed in ten sponsored clinical studies is presented in this analysis. Overall, 1,752 adult patients have been included in safety and efficacy trials over 11 years; 1,220 of these patients have received IV ibuprofen and 532 received either placebo or comparator medication. The incidence of adverse events (AEs), serious AEs, and changes in vital signs and clinically significant laboratory parameters have been summarized and compared to patients receiving placebo or active comparator drug. Overall, IV ibuprofen has been well tolerated by hospitalized and outpatient patients when administered both prior to surgery and postoperatively as well as for nonsurgical pain or fever. The overall incidence of AEs is lower in patients receiving IV ibuprofen as compared to those receiving placebo in this integrated analysis. Specific analysis of hematological and renal effects showed no increased risk for patients receiving IV ibuprofen. A subset analysis of elderly patients suggests that no dose adjustment is needed in this higher risk population. This integrated safety analysis demonstrates that IV ibuprofen can be safely administered prior to surgery and continued in the postoperative period as a component of multimodal pain management.

Keywords: NSAID; critical care; fever; multimodal pain management; perioperative analgesia; surgical pain.

Figures

Figure 1
Figure 1
Disposition of patients. Notes:aIncludes all adults, aged 18 years and older in Phase II-IV studies; bControl includes placebo and active comparator; cForty patients were treated for both pain and fever in Promes et al;18 dTypes of surgical procedures are summarized in Table 2. Abbreviations: IV, intravenous; N, number.
Figure 2
Figure 2
Age distribution by decade. Abbreviation: IV, intravenous.
Figure 3
Figure 3
Mean hematology parameters by study day for IV ibuprofen and placebo-treated patients over five days of treatment. Notes: Day 0= pre-treatment baseline. The sample size for the mean of each treatment group is given for each day. (A) Average hematocrit (HCT, %). (B) Average hemoglobin (HGB, g/dL). (C) Average platelet counts (PLT, cells ×109/L). Abbreviations: HCT, hematocrit; HGB, hemoglobin; IV, intravenous; PLT, platelet counts.
Figure 4
Figure 4
Mean renal parameters by study day for IV ibuprofen and placebo-treated patients over five days of treatment. Notes: Day 0= pretreatment baseline. The sample size for the mean of each treatment group is given for each day. (A) Average blood urea nitrogen (BUN, mg/dL). (B) Average serum creatinine (SCr, mg/dL). Abbreviations: BUN, blood urea nitrogen; SCr, serum creatinine; IV, intravenous.
Figure 5
Figure 5
Timing of the initiation of IV ibuprofen therapy in placebo-controlled, surgical pain studies. Notes: IV ibuprofen therapy was initiated intraoperatively (prior to wound closure) in Southworth et al and Kroll et al. IV ibuprofen therapy was initiated prior to incision (proximal to the induction of anesthesia) in Singla et al. Abbreviation: IV, intravenous.

References

    1. Caldolor (Ibuprofen) Injection [Package Insert] Nashville, TN: Cumberland Pharmaceuticals Inc.; 2014.
    1. Ketorolac Tromethamine Injection [Package Insert] Lake Zurich, IL: Fresenius Kabi USA, LLC; 2013.
    1. Dyloject™ (Diclofenac Sodium) Injection [Package Insert] Lake Forest, IL: Hospira, Inc.; 2014.
    1. Gallelli L, Galasso O, Falcone D, et al. The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial. Osteoarthritis Cartilage. 2013;21(9):1400–1408.
    1. Conaghan PG. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int. 2012;32(6):1491–1502.
    1. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96(13):7563–7568.
    1. Van Hecken A, Schwartz JI, Depre M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol. 2000;40(10):1109–1120.
    1. Garcia Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med. 1998;158(1):33–39.
    1. Castellsague J, Riera-Guardia N, Calingaert B, et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project) Drug Saf. 2012;35(12):1127–1146.
    1. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011;8(9):e1001098.
    1. Gallelli L, Colosimo M, Pirritano D, et al. Retrospective evaluation of adverse drug reactions induced by nonsteroidal anti-inflammatory drugs. Clin Drug Investig. 2007;27(2):115–122.
    1. Zusman M. The Absolute Visual Analogue Scale (AVAS) as a measure of pain intensity. Aust J Physiother. 1986;32(4):244–246.
    1. Morris PE, Promes JT, Guntupalli KK, Wright PE, Arons MM. A multi-center, randomized, double-blind, parallel, placebo-controlled trial to evaluate the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for the treatment of fever in critically ill and non-critically ill adults. Crit Care. 2010;14(3):R125.
    1. Krudsood S, Tangpukdee N, Wilairatana P, et al. Intravenous ibuprofen (IV-ibuprofen) controls fever effectively in adults with acute uncomplicated Plasmodium falciparum malaria but prolongs parasitemia. Am J Trop Med Hyg. 2010;83(1):51–55.
    1. Southworth S, Peters J, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain. Clin Ther. 2009;31(9):1922–1935.
    1. Kroll PB, Meadows L, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (iv-ibuprofen) in the management of postoperative pain following abdominal hysterectomy. Pain Pract. 2011;11(1):23–32.
    1. Singla N, Rock A, Pavliv L. A multi-center, randomized, double-blind placebo-controlled trial of intravenous-ibuprofen (IV-ibuprofen) for treatment of pain in post-operative orthopedic adult patients. Pain Med. 2010;11(8):1284–1293.
    1. Promes JT, Safcsak K, Pavliv L, Voss B, Rock A. A prospective, multicenter, randomized, double-blind trial of IV ibuprofen for treatment of fever and pain in burn patients. J Burn Care Res. 2011;32(1):79–90.
    1. Bergese SD, Candiotti K, Ayad SS, Soghomonyan S, Gan TJ. The shortened infusion time of intravenous ibuprofen part 1: a multicenter, open-label, surveillance trial to evaluate safety and efficacy. Clin Ther. 2015;37(2):360–367.
    1. Gan TJ, Candiotti K, Turan A, et al. The shortened infusion time of intravenous ibuprofen, part 2: a multicenter, open-label, surgical surveillance trial to evaluate safety. Clin Ther. 2015;37(2):368–375.
    1. Cumberland Pharmaceuticals Inc A pilot study to determine the efficacy of intravenous ibuprofen for pain control following arthroscopic knee surgery. [Accessed June 30, 2015]. Available from: . NLM identifier: NCT01650519.
    1. Cumberland Pharmaceuticals Inc Efficacy of intravenous ibuprofen compared to intravenous ketorolac for pain control following arthroscopic knee surgery. [Accessed June 30, 2015]. Available from: . NLM Identifier: NCT01901393.
    1. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63(10):1979–1984.
    1. Kaufman E, Epstein JB, Gorsky M, Jackson DL, Kadari A. Preemptive analgesia and local anesthesia as a supplement to general anesthesia: a review. Anesth Prog. 2005;52(1):29–38.
    1. Slater D, Kunnathil S, McBride J, Koppala R. Pharmacology of non-steroidal antiinflammatory drugs and opioids. Semin Intervent Radiol. 2010;27(4):400–411.
    1. Cashman JN. The mechanisms of action of NSAIDs in analgesia. Drugs. 1996;52(Suppl 5):13–23.
    1. Dirig DM, Isakson PC, Yaksh TL. Effect of COX-1 and COX-2 inhibition on induction and maintenance of carrageenan-evoked thermal hyperalgesia in rats. J Pharmacol Exp Ther. 1998;285(3):1031–1038.
    1. Yaksh TL, Dirig DM, Conway CM, Svensson C, Luo ZD, Isakson PC. The acute antihyperalgesic action of nonsteroidal, anti-inflammatory drugs and release of spinal prostaglandin E2 is mediated by the inhibition of constitutive spinal cyclooxygenase-2 (COX-2) but not COX-1. J Neurosci. 2001;21(16):5847–5853.
    1. Freshwater JD, Svensson CI, Malmberg AB, Calcutt NA. Elevated spinal cyclooxygenase and prostaglandin release during hyperalgesia in diabetic rats. Diabetes. 2002;51(7):2249–2255.
    1. Hodkinson DJ, Khawaja N, O’Daly O, et al. Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen. Pain. 2015;156(7):1301–1310.
    1. Bjorkman R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiol Scand Suppl. 1995;103:1–44.
    1. Bjorkman R, Hallman KM, Hedner J, Hedner T, Henning M. Nonsteroidal antiinflammatory drug modulation of behavioral responses to intrathecal N-methyl-D-aspartate, but not to substance P and aminomethyl-isoxazole-propionic acid in the rat. J Clin Pharmacol. 1996;36(12 Suppl):20S–26S.
    1. Jalota L, Kalira V, George E, et al. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ. 2011;342:d1110.
    1. Wininger SJ, Miller H, Minkowitz HS, et al. A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther. 2010;32(14):2348–2369.
    1. Zhou TJ, Tang J, White PF. Propacetamol versus ketorolac for treatment of acute postoperative pain after total hip or knee replacement. Anesth Analg. 2001;92(6):1569–1575.
    1. Moller PL, Juhl GI, Payen-Champenois C, Skoglund LA. Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery. Anesth Analg. 2005;101(1):90–96. table of contents.
    1. American Society of Anesthesiologists Task Force on Acute Pain Management Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248–273.
    1. Gallelli L, Galasso O, Urzino A, et al. Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis. Clin Drug Investig. 2012;32(12):827–833.
    1. Kaye AD, Baluch A, Scott JT. Pain management in the elderly population: a review. Ochsner J. 2010;10(3):179–187.
    1. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105–S120.
    1. Kolodzie K, Apfel CC. Nausea and vomiting after office-based anesthesia. Curr Opin Anaesthesiol. 2009;22(4):532–538.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner