Caldolor™                                                                  Pharmacy & Therapeutics Committee              ...
Caldolor™MECHANISM OF ACTIONBoth ketorolac and ibuprofen are nonsteroidal antiinflammatory drugs (NSAIDs) and work by inhi...
Caldolor™Black Box Warnings (Details) [3,7]Ketorolac -  WARNING  Ketorolac tromethamine, a nonsteroidal anti-inflammatory ...
Caldolor™ADVERSE DRUGS REACTIONSTable 5a: ADRs in clinical trials of IV ibuprofen [3]                      Table 5b: ADRs ...
Caldolor™Table 5d: Common ADRs of ibuprofen (any form) [6]                            Table 5e: Common ADRs of ketorolac (...
Caldolor™                                                                                                                 ...
Caldolor™                                                                                                                 ...
Caldolor™EfficacyTo date, there have been no published trials directly comparing IV ketorolac to IV ibuprofen. Only one tr...
Caldolor™    All NSAIDs are also capable of inducing acute kidney injury. Ketorolac specifically has been associated with ...
Caldolor™REFERENCES   1. Alexander R, El-Moalem HE, Gan TJ. Comparison of the morphine-sparing effects of diclofenac sodiu...
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Caldolor™ Monograph

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Caldolor™ Monograph

  1. 1. Caldolor™ Pharmacy & Therapeutics Committee IBUPROFEN INJECTION (CALDOLOR™) FORMULARY ADDITION REQUEST COMPARATIVE REVIEWGENERIC NAME: Ibuprofen InjectionPROPRIETARY NAME: Caldolor™FDA APPROVAL DATE: June 11, 2009THERAPEUTIC CLASS: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)COMPARATIVE MEDICATION(S): Ketorolac Tromethamine (Toradol®) Injection, USPREQUESTER: ********************FORMULARY STATUS Open Formulary (No Restrictions)REQUESTED:RATIONALE FOR REQUEST: Improved or greater efficacy compared to current formulary agentsDISCLOSURE STATEMENT:This drug review will compare ibuprofen injection (Caldolor™) and ketorolac tromethamine (Toradol ®) via intravenous injection inadults. In this review, ―IV ibuprofen‖ refers specifically to Caldolor™ and ―ketorolac‖ refers to intravenous injection of ketorolactromethamine. This review does not include ibuprofen lysine injection (NeoProfen®), another intravenous ibuprofen formationuse in premature infants to close a clinically significant patent ductus arteriosus.INDICATION(S)Table 1: FDA-approved indications for ketorolac and IV ibuprofen [3,7] Ketorolac IV Ibuprofen Adult Fever X Moderate to severe pain as an adjunct to X opioid analgesics Short term (≤5 days) management of X moderately severe acute painDOSINGTable 2: Adult dosing for FDA-approved indications [6,8] Ketorolac IV Ibuprofen Adult Short term (≤5 days) management of moderately severe acute pain: IV: Fever: IV: 400 mg x1, then 400 mg q4-6h prn or 100-200 mg IV q4h prn 30 mg x1, or 30 mg q6h (Max 120 mg/day) (Maximum duration of treatment (Max 3.2 g/day). Infused over at least 30 minutes. is 5 days) Moderate to severe pain as an adjunct to opioid analgesics: 400-800 g IV q6h prn (Max 3.2 g/day). Infused over at least 30 minutes. Renal adjustment For patients ≥65 yrs, <50 kg, or with renal impairment: IV: 15 mg x1, or New-onset anuria or oliguria: Hold dose until renal function returns to 15 mg q6h (Max 60 mg/day) (Maximum duration of treatment is 5 days) normal Advanced renal impairment: Contraindicated
  2. 2. Caldolor™MECHANISM OF ACTIONBoth ketorolac and ibuprofen are nonsteroidal antiinflammatory drugs (NSAIDs) and work by inhibiting cyclooxygenase (COX)and subsequently prostaglandin synthesis. [6,8] Both ketorolac and ibuprofen are considered reversible, nonselective inhibitors ofthe two COX isoforms (COX-1 and COX-2). The COX-1 isoform is constitutively expressed and is involved in platelet activation,gastrointestinal protection, and kidney function. [21] The COX-2 isoform is inducible and is produced as part of the inflammatoryresponse. While ketorolac and ibuprofen are both classified as nonselective NSAIDs, ketorolac is significantly more selective forthe COX-1 isoform (294:1 for ketorolac and 2.6:1 for ibuprofen). [20] Based on its actions, it has been hypothesized that selectiveinhibition of the COX-1 isoform is responsible for the adverse effects of these agents, namely the risk of gastrointestinal bleed. [20]More recently, others have suggested that a more complex process is likely involved. [21]PHARMACOKINETICSTable 3: Pharmacokinetic properties of ketorolac and IV ibuprofen [6,8] Ketorolac IV Ibuprofen Protein binding >99% >99% Metabolism Hepatic, extensive via oxidation and conjugation Hepatic, extensive via oxidation and conjugation Active metabolites No No Half-life elimination ~5.5 hra 2-3 hrs Excretion Urine (92%), mostly inactive metabolites Urine (79%), mostly inactive metabolitesa Increased by 30-50% in the elderly (age ≥65), and up to 19 hours in renal impairment (CrCl <60 mL/min/1.73m 2)CONTRAINDICATIONS / WARNINGS / PRECAUTIONSTable 4: Contraindications, warnings, and precautions with ketorolac and IV ibuprofen [6,8] Ketorolac IV Ibuprofen Contraindications Hypersensitivity [X] X Asthma & allergic reactions to NSAIDs [X] X CABG, peri-operatively [X] [X] Active history of peptic ulcer disease [X] Recent history of GI bleeding or perforation [X] Advanced renal disease [X] Prophylaxis before major surgery [X] Suspected or confirmed cerebrovascular bleeding [X] Hemorrhagic diathesis [X] Incomplete hemostasis or high risk of bleeding [X] Concurrent ASA or other NSAIDs [X] Concurrent probenecid or pentoxifylline X Epidural or intrathecal administration [X] Labor & delivery [X] Breast-feeding [X] Use for ≥5 days [X] Concerns related to adverse effects Cardiovascular thrombotic events X [X] Gastrointestinal effects X [X] (Risk of ulceration, bleeding, and perforation) Hepatic effects X X (Elevated LFTs, severe hepatic reactions) Anaphylactoid reactions X X Serious skin reactions X X Hematological effects X X (Coagulopathy) Ophthalmological effects X (Vision disturbances) Disease-related concerns Renal insufficiency X X Hypertension X X Congestive heart failure and edema X X Masking inflammation and fever X Pre-existing asthma X Aseptic meningitis X Concerns regarding specific populations Pregnancy X X Elderly [X] XX – Indicates CI/warning/precaution is listed for this drug[X] – Indicates a black box warning
  3. 3. Caldolor™Black Box Warnings (Details) [3,7]Ketorolac - WARNING Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days) management of moderately severe acute pain that requires analgesia at the opioid level. It is NOT indicated for minor or chronic painful conditions. Ketorolac tromethamine is a potent NSAID analgesic, and its administration carries many risks. The resulting NSAID-related adverse events can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will result in increasing the risk of developing serious adverse events. Gastrointestinal Effects Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding, and/or perforation. Therefore, ketorolac tromethamine is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Renal Effects Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion. Risk of Bleeding Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis, and those at high risk of bleeding. Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery, and is CONTRAINDICATED intraoperatively when hemostasis is critical because of the increased risk of bleeding. Hypersensitivity Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of ketorolac tromethamine injection. Ketorolac tromethamine is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine or allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Intrathecal or Epidural Administration Ketorolac tromethamine is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol content. Labor, Delivery and Nursing The use of ketorolac tromethamine in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions. The use of ketorolac tromethamine is CONTRAINDICATED in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates. Concomitant Use with NSAIDs Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risk of inducing serious NSAID- related side effects. DOSAGE AND ADMINISTRATION Ketorolac Tromethamine Tablets Ketorolac tromethamine tablets are indicated only as continuation therapy to ketorolac tromethamine IV/IM, and the combined duration of use of ketorolac tromethamine IV/IM and ketorolac tromethamine tablets is not to exceed 5 (five) days, because of the increased risk of serious adverse events. The recommended total daily dose of ketorolac tromethamine tablets (maximum 40 mg) is significantly lower than for ketorolac tromethamine IV/IM (maximum 120 mg). Special Populations Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight, and for patients with moderately elevated serum creatinine. IV/IM doses of ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients. Ketorolac tromethamine injection is indicated as a single dose therapy in pediatric patients; Not to exceed 30 mg for IM administration and 15 mg for IV administration.IV Ibuprofen - WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Risk Non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. Caldolor is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. Gastrointestinal Risk NSAIDs increase the risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomachor intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
  4. 4. Caldolor™ADVERSE DRUGS REACTIONSTable 5a: ADRs in clinical trials of IV ibuprofen [3] Table 5b: ADRs in clinical trials of IV ibuprofen [3] Post-operative Patients with Adverse Reactions Observed in ≥3% of Patients with Adverse Reactions Observed in ≥3% of Patients in any Patients in any Caldolor Treatment Group in Pain Studies * Caldolor Treatment Group in All-Cause Fever Study Caldolor Caldolor 400 mg 800 mg Placebo 100 mg 200 mg 400 mg Placebo Event (N=134) (N=304) (N=287) Event (N=30) (N=30) (N=31) (N=28) 118 260 258 27 25 23 25 Any reaction Any reaction (88%) (86%) (90%) (87%) (83%) (74%) (89%) 77 161 179 5 6 11 4 Nausea Anemia (22%) (15%) (62%) (17%) (20%) (36%) (14%) 30 46 50 7 7 8 7 Vomiting Eosinophilia (22%) (15%) (17%) (23%) (23%) (26%) (25%) 10 49 44 4 4 6 5 Flatulence Hypokalemia (7%) (16%) (15%) (13%) (13%) (19%) (18%) 12 35 31 3 4 2 Headache Hypoproteinemia 0 (9%) (12%) (11%) (10%) (13%) (7%) 13 13 16 2 2 4 2 Hemorrhage Neutropenia (10%) (4%) (6%) (7%) (7%) (13%) (7%) 8 13 5 3 Dizziness Blood urea increased 0 0 0 (6%) (4%) (2%) (10%) 1 9 4 2 3 Edema, Peripheral Hypernatremia 0 0 (<1%) (3%) (1%) (7%) (10%) 7 10 10 3 Urinary retention Hypertension 0 0 0 (5%) (3%) (3%) (10%) 5 7 6 3 1 3 1 Anemia Hypoalbuminemia (4%) (2%) (2%) (10%) (3%) (10%) (4%) 4 6 3 3 3 2 2 Decreased hemoglobin Diarrhea (3%) (2%) (1%) (10%) (10%) (7%) (7%) 6 4 2 3 1 2 Dyspepsia Pneumonia, bacteria 0 (4%) (1%) (<1%) (10%) (3%) (7%) 4 4 4 3 2 1 1 Wound hemorrhage Blood LDH increase (3%) (1%) (1%) (10%) (7%) (3%) (4%) 4 2 3 2 1 Abdominal discomfort 0 Thrombocytopenia 0 (3%) (<1%) (10%) (7%) (3%) 4 2 1 4 Cough Bacteremia 0 0 0 (3%) (<1%) (<1%) (13%) 5 3 8 Hypokalemia (4%) (<1%) (3%)*All patients received concomitant morphine during these studies.Table 5c: ADRs in clinical trials of ketorolac [7] Adverse Reactions Observed in ≥3% of Patients Receiving Ketorolac Tromethamine in Clinical Trials Event Incidence Headache 17% GI pain 13% Dyspepsia 12% Nausea 12% Diarrhea 7% Dizziness 7% Drowsiness 6% Edema 4%
  5. 5. Caldolor™Table 5d: Common ADRs of ibuprofen (any form) [6] Table 5e: Common ADRs of ketorolac (any form) [8] Cardiovascular Cardiovascular Hypotension (intravenous, up to 10%) Edema (1% to 10%) Dermatologic Hypertension (1% to 10%) Rash (oral, 3% to 9%) Dermatologic Endocrine metabolic Injection site pain (injection, 1% to 10%) Hypernatremia (intravenous, up to 10%) Pruritus (1% to 10%) Hypoalbuminemia (intravenous, 3% to 10%) Rash (1% to 10%) Hypoproteinemia (intravenous, up to 13%) Sweating (1% to 10%) Serum lactate dehydrogenase level elevated (intravenous, 3% to 10%) Gastrointestinal Gastrointestinal Abdominal pain (1% to 10%) Flatulence (injection, 7% to 16%) Constipation Heartburn (oral, 3% to 9%) Diarrhea Nausea (oral, 3% to 9%; intravenous, 53% to 57%) Flatulence (1% to 10%) Vomiting (oral, 1% to 3%; intravenous, 15% to 22%) Heartburn (1% to 10%) Hematologic Indigestion (1% to 10%) Thrombocytosis (intravenous, 3% to 10%) Nausea (greater than 10%) Immunologic Stomatitis (1% to 10%) Bacteremia (injection, 13%) Vomiting (1% to 10%) Neurologic Hematologic Dizziness (oral, 3% to 9%; intravenous 4% to 6%) Anemia (1% to 10%) Headache (oral, 1% to 3%; intravenous, 9% to 11%) Purpura (1% to 10%) Renal Neurologic Serum blood urea nitrogen raised (intravenous, up to 10%) Dizziness (1% to 10%) Urinary retention (intravenous, 3% to 5%) Headache (greater than 10%) Respiratory Somnolence (1% to 10%) Bacterial pneumonia (intravenous, 3% to 10%) Opthalmic Burning sensation in eye, Transient (ophthalmic, 20% to 40%) Corneal edema (ophthalmic, 1% to 10%) Eye irritation (ophthalmic, 1% to 10%) Iritis (ophthalmic, 1% to 10%) Keratitis (ophthalmic, 1% to 10%) Respiratory Nasal irritation (nasal, 15%) Pain Rhinalgia (nasal, 13%)DRUG INTERACTIONSAlthough all NSAIDs, including ketorolac and ibuprofen, are metabolized extensively by the liver, the precise enzymes involves inthe process have not been fully determined. Many of the interactions listed below are theoretical.Table 6: Labeled drug interactions with ketorolac and IV ibuprofen [6,8]Interacting Medication Ketorolac IV Ibuprofen Effect NSAIDs can increase BPACE Inhibitors / ARBs X X Risk of renal impairmentAnticoagulants/Antiplatelets X X NSAIDs also have some anticoagulant effect and increase risk of bleedingAntiepileptics X Increased risk of seizure(phenytoin, carbamazepine)Diuretics X X Renal failureLithium X X Reduced renal lithium clearanceMethotrexate X X Reduced renal methotrexate clearanceProbenecid X Reduced renal ketorolac clearancePsycoactive drugs X Hallucinations
  6. 6. Caldolor™ REVIEW DATE: April 2012COMPARATIVE ANALYSISTable 7: Randomized controlled trials of IV ibuprofen Subjects c Indication Comparator Treatment arms Max Duration Efficacy SafetyPromes et. al. (2011) [15]Burn patients w/ 2nd- and 3rd- Fever and Placebo Ibuprofen 800 mg IV q6h a 5 days Reduction in AUC-T° over 0-24 hrs (P=0.008). Trend towards more total ADEs in IVdegree thermal (non-electrical) Pain Placebo (20 doses) Non-significant reduction in AUC-T° over total ibuprofen arm (p=0.41). No differences inburns to >10% TBSA (N=61) treatment time 0-120 hrs (p=0.475). No specific ADEs between IV ibuprofen and difference in VAS/VRS pain scores. placebo.Southworth et. al. (2009) [18]Elective orthopedic or abdominal Pain (post-op) Placebo Ibuprofen 400 mg IV q6h 48 hours Morphine requirements reduced by 22% in the No statistically significant differences insurgery (N=406) Ibuprofen 800 mg IV q6h (8 doses) 800 mg arm (p=0.03). reported ADEs. Placebo + Morphine IV PRNSingla et. al. (2010) [17]Elective orthopedic surgery Pain (post-op) Placebo Ibuprofen 800 mg IV q6h b 28 hours Morphine requirements reduced by 30.9% Significant increase in vomiting in ibuprofen(N=185) Placebo (5 doses) (p<0.001). Three different AUC-VAS measures arm (p=0.031). were reduced by 20-30% (p<0.001). + Morphine IV PRNKroll et. al. (2010) [9]Elective abdominal hysterectomy Pain (post-op) Placebo Ibuprofen 800 mg IV q6h 48 hours Morphine requirements reduced by 19% No statistically significant differences in(N=319) Placebo (8 doses) (p<0.001). VAS scores at rest and with reported ADEs. movement showed statistically significant + Morphine IV PRN reductions throughout the study period.Morris et. al. (2010) [12]Hospitalized patients with fever Fever Placebo Ibuprofen 100 mg IV q4h 24 hours Proportion of patients <101°F at 4 hours post- No statistically significant differences in>101°F from any cause (N=120) Ibuprofen 200 mg IV q4h (6 doses) dose and AUC-T° over 0-24 hrs were statistically reported ADEs. Ibuprofen 400 mg IV q4h significantly for all active treatment arms Placebo (p<0.05). Mean temp decrease in 400 mg arm was 4.40°F, 1.37°F more than placebo.Krudsood et. al. (2010) [10]Malaria. Patients were excluded Fever Placebo Ibuprofen 400 mg IV q6h 72 hours Reductions in AUC-T° over 0-24 hrs (p=0.002), Delay in parasite clearance in ibuprofen armif they had sxs of severe malaria Placebo (12 doses) 0-4 hrs (p<0.0001), and 0-72 hrs (p=0.0176). (p=0.0024).or any other significant medical Time to <37°C was 3 hrs in the ibuprofen groupproblems. (N=60) and 20 hrs in the placebo group.a Additional antipyretic treatment was restricted only during the first 24 hours. From hr 24-120, any antipyretic therapy, except for other NSAIDs, could be used.b First dose was given pre-operativelyC Exclusion criteria:The exclusion criteria were very similar throughout all six studies. Exclusions included:  Renal impairment or dialysis (determined by CrCl, SCr, urine output, or recent need of dialysis)  Increased risk of bleed, General (including thrombocytopenia, coagulopathy)  Increased risk of bleed, GI (patients with recent h/o GI bleed requiring medical intervention)  Increased risk of bleed, Intracranial (Recent head trauma, AVM, aneurysm, CNS mass lesion)  Anemia  Asthma (active and clinically significant)  Use of warfarin, lithium, or combination of and ACE-inhibitor and furosemide  Pregnant or nursing  H/o sensitivity to any component of IV ibuprofen, NSAIDs, aspirin or related compounds, or COX-2 inhibitorsAdditionally, in trials studying the drug’s analgesic effects, allowance for prior use of analgesics, muscle relaxants, and sedatives varied but were generally restricted. Patients with a known tolerance to opioid analgesicswere also excluded. In trials studying the drug’s antipyrectic effects, allowance for prior use of antipyretics was also varied but was generally restricted.
  7. 7. Caldolor™ REVIEW DATE: April 2012Table 8: Selected randomized controlled trials of ketorolac Subjects a Indication Comparator Treatment arms Max Duration Efficacy SafetySevarino et. al. (1994) [16]Elective intra-abdominal Pain (post-op) Placebo Ketorolac 30 mg IV x1, then 15 mg IV q6h x4 36 hours Ketorolac groups required an average of No statistically significantgynecologic surgery Ketorolac 60 mg IV x1, then 30 mg IV q6h x4 (5 doses) 20% less morphine over the study period differences in reported ADEs.(N=62) Placebo (NSS). VAS pain scores were significantly reduced w/ ketorolac between hours 4-12 + Morphine IV PRN post-op (p<0.05)Chen et. al. (2009) [4]Elective colorectal Pain (post-op) Placebo Morphine (1 mg/mL) + Placebo PCA 72 hours Morphine requirements reduced by 18.3% Placebo group had a 5.25 timesresection (N=102) Morphine (1 mg/mL) + Ketorolac (1.2 mg/mL) PCA (n/a) over 0-72 hrs post-op. Statistically greater risk of post-operative significant usage decreases were noted only ileus. Bolus 2 mL; Lockout 10 min (settings adjusted q6h) over post-op hours 0-12 and 12-24. No statistical differences in VAS scores.Alexander et. al. (2002) [1]Hip or knee replacement Pain (post-op) Placebo Ketorolac 60 mg IV x1, pre-op 24 hours Reduction in VAS/VPS scores at post-op hr In the ketorolac arm, over post-opsurgery (N=102) Diclofenac 75 mg IV x1, pre-op (n/a) 0 (p=0.009) and hr 8 (p=0.026) in ketorolac hrs 0-24, 31% fewer patients had Placebo arm. Morphine requirements over hrs 0-24 PONV (p<0.05) and 39% fewer post-op were reduced by 9% in ketorolac patients had pruritis (p<0.01). Morphine IV PCA, post-op arm.Parker et. al. (1994) [14]Hysterectomy (N=198) Pain (post-op) Placebo Ketorolac 60 mg IV x1, then 30 mg IV q6h 72 hours Statistically significant reduction in PCA Reduced incidence of nausea in Placebo (12 doses) usage during the first evening post-surgery the ketorolac group (p not (p<0.05). reported). Morphine or Merperidine IV PCAPONV – Post-operative nausea & vomitinga Exclusion criteria:  The exclusion criteria were very similar throughout all four studies. Exclusions included:  Renal impairment  Increased risk of bleed, General (including coagulopathy or anticoagulant use)  Increased risk of bleed, GI (patients with recent h/o gastric ulceration)  Asthma  H/o sensitivity to NSAIDs or opioid analgesics  Allowance for prior use of analgesics varied but was generally restricted
  8. 8. Caldolor™EfficacyTo date, there have been no published trials directly comparing IV ketorolac to IV ibuprofen. Only one trial was located thatcompared any formulations of ibuprofen and ketorolac. The study by Neighbor et. al. compared IM ketorolac and oral ibuprofenfor the treatment of pain in patients presenting to an emergency department. [13] The study of 119 patients found no significantdifference in either drugs ability to relieve pain.Since its approval in 1989, ketorolac has been included in several pain management guidelines; in particular, those from theAmerican Society of Anesthesiologists (ASA). [2] The most recent ASA guidelines make specific reference to ketorolac and itsuse as part of a multimodal analgesic treatment plan, citing the high level of evidence supporting its use (category A1 evidence—the ASA’s highest evidence level). Several studies have been conducted since its approval which demonstrate the drug’seffectiveness, especially as an adjunct to opioid analgesics. A MEDLINE search for human clinical trials using intravenouslyadministered ketorolac returns 90 such studies, many of which show favorable outcomes for ketorolac. The studies selected anddisplayed in Table 8 were chosen based on their similarity to the trials of IV ibuprofen. Specifically, the study by Sevarino et. al.bears the most resemblance methodologically to the IV ibuprofen trials. [16] That study found a 20 percent reduction in morphineusage in patients receiving ketorolac and a statistically significant improvement in reported pain scores. But while the injectableformulation of ketorolac has over two decades of research and clinical experience to support its indication, there is significantlyless data to support the claims for IV ibuprofen.Three studies were the basis for IV ibuprofen’s FDA approval for pain management. [9,16,17] The studies had very similar designsoverall: they were all placebo-controlled trials, the subjects were all patients undergoing elective surgery, and all patients werealso given morphine as needed. Analgesic efficacy was determined by visual analog scale (VAS) or verbal pain scale (VPS) andby comparing the amount of morphine used by patients receiving placebo and those receiving IV ibuprofen. In all three studies,patients receiving IV ibuprofen required around 20 to 30 percent less morphine than patients receiving a placebo. Unfortunately,since these studies are so similar and the patient populations are so specific, it is difficult make their conclusions generalizable toother forms of pain (e.g. visceral pain, pain from traumatic injury, etc.).There are three available studies that look at the use of IV ibuprofen for fever, with a total of 241 patients. [10,12,15] One trial wasin hospitalized patients that developed a fever of >101°F from any cause, [12] one was in patients with malaria, [10] and the thirdwas in burn patients with burns to over 10 percent of their body surface area. [15] All three trials were placebo-controlled, butunlike the trials for analgesia, they used lower doses of IV ibuprofen for fever relief. Both trials were able to demonstrate a smallbut statistically significant decreases in temperature as compared to placebo, expressed as area under the temperature curve vs.time (AUC-T°). However, in the two most robust of the studies, [12,15] the statistical significance was only observed between 1 to5 hours post-surgery. Beyond that time, most patients, regardless of treatment group, were afebrile, making the clinicalsignificance of this effect unclear.SafetyOf the six IV ibuprofen studies, only two reported any statistically significant increases in adverse effects as compared toplacebo. One study in the treatment of post-operative pain showed an increased incidence of nausea as compared withplacebo. [17] This result is confounded by the fact that all patients were also receiving morphine, which itself has a high incidenceof nausea. Another study in patients with malaria showed that patients receiving IV ibuprofen had a significant delay in theclearance of the parasite. [10] The authors hypothesized that this was due to the drugs impediment of certain cytokines involvedin the natural immune response to the pathogen. Ultimately, this effect did not have a deleterious impact on patient recovery.Apart from these two outcomes, the six IV ibuprofen trials did not observe any other differences in adverse effects between thedrug and placebo. This result can be misleading, however, as none of these studies were adequately powered to detectdifferences in adverse effects. In addition, patients that would be expected to have adverse effects based on current risk factorswere excluded from these studies (e.g. patients at risk of bleeding, patients with renal impairment, etc.).All NSAIDs are required to carry a black box warning about their gastrointestinal risks including bleeding, ulceration andperforation. Of all the NSAIDs, ketorolac is associated with the highest risk of upper GI bleed. [11] A case-control study foundthat NSAIDs overall were associated with an adjusted relative risk of 4.4, but ketorolac alone was associated with an adjustedrelative risk of 24.7. [11] Ibuprofen was associated with an adjusted relative risk of 3.1—less than the average risk associated withNSAID use overall. This study included NSAIDs given by any route, not specifically IV formulations. Its also important to notethat this study only compared "commonly used doses" of NSAIDs. Most patients in this study that took ibuprofen received <1200mg/day. Based on IV ibuprofen’s prescribing information, patients could expect to receive up to 3200 mg of ibuprofen per day. [3]Future comparison trials of high dose ibuprofen to ketorolac may reveal this difference in relative risk to be much smaller thanseen in this study. Additionally, postmarketing observational data has further defined those at risk of a GI bleed from ketorolac.[7] A study of approximately 10,000 patients who received ketorolac IV/IM revealed that there is a dose-dependent risk ofclinically significant GI bleeding especially in the elderly (age ≥65) and in patients with a history of peptic ulcer disease. [7]
  9. 9. Caldolor™ All NSAIDs are also capable of inducing acute kidney injury. Ketorolac specifically has been associated with the highest risk. A retrospective cohort of over 10,000 hospitalized patients showed that those receiving ketorolac for more than 5 consecutive days were significantly more likely to have developed an acute kidney injury during therapy. [5] This finding is the basis for ketorolacs 5-day limit. Cost Using ******* contract prices, the costs for generic ketorolac tromethamine injection, USP and Caldolor™ on a per dose and per day basis are listed below in Table 9. Table 9: Costs of therapy based on ******* contract prices Agent Cost per dose Cost per day a Ketorolac $0.05 $0.20 Caldolor™ $7.90 $31.60a Based on labeled dosing instructions for analgesia. Both medications are dosed every 6 hours (4 doses per day). SUMMARY The antipyretic and analgesic effects of ibuprofen are well-established in the literature and through decades of clinical experience, so it was disappointing to see that none of the Caldolor™ trials were against an active comparator (e.g. ketorolac). Its expected that a sufficient dose of ibuprofen by any route would produce pain-relief or reduce fever. Overall, no conclusions can be drawn as to which drug is the superior analgesic. Based solely on evidence provided by clinical trials, both drugs appear to be effective analgesics for post-operative pain. However, the decades of study and experience with ketorolac and the relative paucity of evidence provided by the IV ibuprofen trials makes ketorolac the more reliable agent at this time. There have been no clinical trials of ketorolac for the treatment of fever to date, so its impossible to compare with IV ibuprofen. However, the marginal fever relief demonstrated in the IV ibuprofen studies suggests that the clinical significance of its antipyretic effects is minimal. Other modalities for fever relief exist and are more cost-effective. With regards to safety, ibuprofen is generally considered to be a safer NSAID than ketorolac. However, at doses that provide equivalent analgesia, ibuprofen’s benefits may be somewhat diminished. It is important to note that the relative lack of adverse effects in the six IV ibuprofen studies does not necessarily indicate that the drug is safe, since none of the studies were adequately powered to detect those differences and certain at-risk patients were excluded. Ultimately, since most NSAIDs contain the same warnings and precautions, it’s likely that a patient not suitable for treatment with ketorolac would be best served by avoiding NSAIDs all together. RECOMMENDATIONS Maintain IV ibuprofen as a non-formulary agent. REVIEWER DISCLOSURE STATEMENT The Reviewer of this product for formulary consideration has no real or potential conflict of interest related to the product(s) or the manufacturer(s) of the product(s).
  10. 10. Caldolor™REFERENCES 1. Alexander R, El-Moalem HE, Gan TJ. Comparison of the morphine-sparing effects of diclofenac sodium and ketorolac tromethamine after major orthopedic surgery. Journal of Clinical Anesthesia. 2002;14(3):187-192. Available at: http://linkinghub.elsevier.com/retrieve/pii/S0952818001003828. 2. American Society of Anesthesiologists. 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):248-73. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22227789. Accessed April 13, 2012. 3. Caldolor™ (ibuprofen) Injection [Package Insert]. Nashville, TN: Cumberland Pharmaceuticals Inc.; 2009. 4. Chen J-yuan, Ko T-lin, Wen Y-ray, et al. Opioid-sparing effects of ketorolac and its correlation with the recovery of postoperative bowel function in colorectal surgery patients: a prospective randomized double-blinded study. 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