Improved acute pain management starts here 1

Transcription

1 Improved acute pain management starts here 1 Indication OFIRMEV is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Important Safety Information OFIRMEV is contraindicated in patients with severe hepatic impairment, severe active liver disease or with known hypersensitivity to acetaminophen or to any of the excipients in the formulation. Acetaminophen should be used with caution in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia, or severe renal impairment. OFIRMEV is approved for use in patients 2 years of age. Please see full Prescribing Information.

2 Treatment of acute pain remains suboptimal Opioids have historically been the foundation for acute pain management 2 In a 212 research database of 1,665,418 patients, 72% of inpatients treated with IV analgesia received IV opioid monotherapy 2 72% opioid only 28% other n=1,25,744 n=459,674 Opioid analgesics rank among the drugs most frequently associated with adverse events 3,4 Patients continue to report significant post-op pain despite the availability of effective analgesics 5,6 Post-op pain severity: 212 vs 1995 % adult patients reporting pain (n=3) 1995 (n=5) Moderate to extreme None to slight In a 212 survey, approximately 85% of patients reported post-op pain, with a total of 65% reporting pain as moderate to extreme 6 8% of patients who received analgesic medications reported adverse events; the most common adverse events reported were drowsiness (56%), constipation (35%), and nausea (28%) 6 OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 2

3 ACUTE PAIN MANAGEMENT Multimodal analgesia can help optimize pain management with less opioids 4,7 Consider a multimodal approach for balanced pain management Multimodal analgesia combines 2 or more analgesic agents or techniques that act by different mechanisms to provide analgesia with better pain relief and less opioids 4,7 Opioids 8 α 2 -agonists 8 Acetaminophen 9 NMDA antagonists 1 Local anesthetics 8 Opioids 8 α 2 -agonists 8 Local anesthetics 8 NSAIDs 8 COXIBs 8 NMDA=N-methyl-D-aspartate. When used in combination with opioids, non-opioid treatments may reduce the dose of opioids required to effectively manage pain 3 Non-pharmacologic therapies: Acupuncture Ice Manipulation or massage Music therapy Physical therapy + Non-opioid pharmacologic therapies: Acetaminophen Anticonvulsants Antidepressants Muscle relaxants NSAIDs GOAL Reduced opioid use 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 3 ml/min) 3

4 Multimodal analgesia is widely supported The multimodal concept is supported by numerous professional and regulatory organizations 212 American Society of Anesthesiologists (ASA) Guideline Recommendations for Acute Pain Management Whenever possible, anesthesiologists should use multimodal pain management therapy. Unless contraindicated, patients should receive an around the clock regimen of COXIBs, NSAIDs, or acetaminophen American Society for Pain Management Nursing (ASPMN) Guideline Recommendations for Analgesic Pharmacotherapy Nurses should act as strong advocates for pain management plans that incorporate opioid dose-sparing strategies initiated early in the course of treatment, eg, on admission, before surgery, during surgery, and early after surgery. Multimodal analgesic therapy that combines opioids with nonopioids, eg, acetaminophen, NSAIDs, anticonvulsants, and antidepressants, has proven efficacy in the treatment of pain Agency for Healthcare Research and Quality (AHRQ) Handbook for Nurses The objective for postsurgical and procedural pain is to prevent and control pain...a multimodal approach (balanced analgesia), which includes opioids, nonopioids such as NSAIDs, and adjuvant medications such as anticonvulsants, is recommended...when more than one analgesic is used, the same level of pain relief may be achieved with a lower dose of each analgesic Society of Critical Care Medicine (SCCM) Clinical Practice Guidelines We suggest that nonopioid analgesics be considered to decrease the amount of opioids administered (or to eliminate the need for IV opioids altogether)...for non-neuropathic pain, nonopioids such as IV acetaminophen, oral, IV, or rectal cyclooxygenase inhibitors, or IV ketamine can be used in addition to opioids. Using nonopioids may also decrease the overall quantity of opioids administered and the incidence and severity of opioid-related side effects The Joint Commission (TJC) Sentinel Event Alert A multimodal approach combines strategies such as psychosocial support, coordination of care, the promotion of healthful behaviors, nonpharmacologic approaches, and nonopioid pain medications. Upon assessment, the best approach may be to start with a non-narcotic. 3 OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 4

5 Multimodal analgesia in practice American Society of Anesthesiologists (ASA) guidelines 7 The ASA Task Force recommends the use of multimodal analgesia whenever possible in the perioperative setting 7 Patients should receive an around-the-clock regimen of acetaminophen, NSAIDs, or COX-2 inhibitors unless contraindicated 7 Dosing regimens should be administered to optimize efficacy while minimizing the risk of adverse events 7 MULTIMODAL ANALGESIA Multimodal analgesia can help manage different levels of pain across the perioperative setting 7,14 Step 3: Severe Pain Step 1 + Step 2 and Higher doses of opioids Step 2: Moderate Pain Step 1 and Low doses of opioids Step 1: Mild Pain Acetaminophen, NSAIDs, or COX-2 selective inhibitors and Local/regional anesthesia Non-opioids, such as acetaminophen, NSAIDs, or COX-2 selective inhibitors, are the foundational analgesic agents given perioperatively for the management of pain; opioids are added for moderate to severe pain 7,14 OFIRMEV is contraindicated in: Patients with severe hepatic impairment or severe active liver disease 5

6 In pharmacokinetic studies Rapid onset of action with IV acetaminophen OFIRMEV 1 g demonstrated early and high C max at 15 minutes 15,16 Mean plasma concentrations of OFIRMEV 1 g and oral acetaminophen 1 g Mean plasma concentration (μg/ml) Time to reach C max (T max ) 3 minutes faster than oral acetaminophen Time (h) 4 OFIRMEV 1 g (N=38) Oral acetaminophen 1 g (N=38) 6 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 q6h, OFIRMEV 1 g q4h, oral acetaminophen 1 g q6h, and oral acetaminophen 1 g q4h divided among 4 treatment periods (results for the first 6-h dosing period shown at left). Primary endpoint: the comparative exposure of OFIRMEV and oral acetaminophen (rapid-release liquid formulation). OFIRMEV was administered as a 15-minute infusion. C max occurs at the end of the 15-minute IV infusion of OFIRMEV 16 Overall exposure (AUC) after a single dose was similar to oral acetaminophen 15,16 No significant accumulation with repeated dosing 15,16 Begin your IV analgesic regimen with OFIRMEV Rapid onset of action Early and high C max No first-pass hepatic exposure 16 1% bioavailability 16 Do not exceed the maximum recommended daily dose of 4 g of acetaminophen by all routes OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 6

7 In pharmacokinetic studies Greater peak levels with IV acetaminophen OFIRMEV 1 g was associated with greater peak plasma levels 17 Mean plasma concentration (μg/ml) Mean plasma concentrations Time (h) *Rectal acetaminophen data reflect standardization of the 13-mg dose to 1 g (linear kinetics). OFIRMEV 1 g (n=6) Oral acetaminophen 1 g (n=6) Rectal acetaminophen 1 g* (n=6) Peak plasma concentrations were 76% higher than oral acetaminophen (P=.4) and 256% higher than rectal acetaminophen (P<.1) 17 Efficacy was not assessed in this study 5 6 Singla et al Three-way, crossover, single-center, single-dose pharmacokinetic study of 6 healthy adult males. Each received 3 singledose treatments of IV, oral, and rectal acetaminophen, separated by a washout period of 24 h. Treatment dosage was 1 g IV and oral acetaminophen, and 13 mg rectal. IV acetaminophen was administered over 15 minutes commencing at h. CSF and blood draws were performed prior to study medication administration and at 8 additional time points for 6 h in each treatment period. PHARMACOKINETICS OFIRMEV 1 g was associated with greater cerebrospinal fluid (CSF) levels 17 Mean CSF concentrations 6 5 OFIRMEV 1 g (n=6) Oral acetaminophen 1 g (n=6) Rectal acetaminophen 1 g* (n=6) Mean CSF concentration (μg/ml) Time (h) Singla et al Three-way, crossover, single-center, single-dose pharmacokinetic study of 6 healthy adult males. Each received 3 singledose treatments of IV, oral, and rectal acetaminophen, separated by a washout period of 24 h. Treatment dosage was 1 g IV and oral acetaminophen, and 13 mg rectal. IV acetaminophen was administered over 15 minutes commencing at h. CSF and blood draws were performed prior to study medication administration and at 8 additional time points for 6 h in each treatment period. *Rectal acetaminophen data reflect standardization of the 13-mg dose to 1 g (linear kinetics). Peak CSF concentrations were 6% higher than oral acetaminophen (P<.1) and 87% higher than rectal acetaminophen (P<.1). No significant difference was seen between oral and rectal groups. 17 Efficacy was not assessed in this study 7

8 Altered gastric emptying may result in changes in the rate of absorption of orally administered drugs Several factors may diminish gastric function following surgery Contributing Factors Opioids Compromised Gastric Function Significant delay in gastric emptying Surgery Pyloric narrowing or closure Anesthesia Subsequent intestinal absorption of nutrients/ medication inhibited Stress Fasting Significant delays in gastric emptying occur with the administration of IV opioid analgesics 18 Absorption of oral acetaminophen is diminished due to compromised gastric function 18,19 OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 8

9 Effect of opioids on gastric emptying and oral absorption in surgical patients Opiate-related pyloric narrowing or closure led to decreased concentration levels of oral acetaminophen 19 Peak plasma levels of oral acetaminophen on Day 1 Peak plasma concentrations (μg/ml) Cardiac surgery patients who received opioids (nasogastric tube) (n=16) 16.5 Healthy volunteers (n=6) Berger et al Prospective pharmacokinetic study conducted in patients who underwent cardiac surgery (n=16) and healthy volunteers who served as controls (n=6) to assess intestinal absorption as a function of placement of tube insertion. As a marker to assess absorption, 1 g of acetaminophen in liquid formulation was administered on post-op days 1 and 3 through a nasogastric (n=11) or postpyloric tube (n=5). GASTRIC EMPTYING/ GI ABSORPTION Oral acetaminophen absorption was decreased following nasogastric administration due to opioid use 19 Morphine markedly delayed the absorption of oral acetaminophen 18 Mean pre-op and post-op plasma concentrations Mean plasma concentration (μg/ml) Oral acetaminophen without morphine (12 h pre-op) (n=7) 3 45 Time (minutes) Oral acetaminophen with morphine (Post-op) (n=8) Petring et al Randomized, double-blind, pharmacokinetic study involving 15 patients undergoing orthopaedic surgery with spinal anesthesia. Upon first complaint of post-op pain, patients were randomized to receive a single dose of intramuscular morphine 1 mg (n=8) or a single dose of intramuscular ketorolac 3 mg (n=7). Oral acetaminophen solution 2 mg/kg was administered twice in each patient as a marker, at least 12 h before scheduled surgery (pre-op) and 3 minutes after administration of morphine (post-op). Post-op plasma concentrations of oral acetaminophen (when used as a marker for gastric absorption) were significantly lower than pre-op values (P<.1) in patients who received opioids following surgery 18 Post-op C max and T max of oral acetaminophen could not be determined following morphine administration due to a marked delay in absorption 18 9

10 In orthopaedic surgery Significant pain relief OFIRMEV 1 g + PCA* morphine demonstrated significant pain relief vs placebo + PCA morphine 1 Mean pain relief scores, single dose (Total hip or knee replacement surgery) 1.8 OFIRMEV 1 g + PCA morphine (n=49) Placebo + PCA morphine (n=52) P<.5 at every time point Pain relief 1.2 Significant improvement over placebo + PCA morphine Time (h) Sinatra et al (Pain Study 1) Randomized, double-blind, placebo-controlled, single- and repeated-dose 24-h study (n=11). Patients received OFIRMEV 1 g + PCA morphine or placebo + PCA morphine the morning following total hip or knee replacement surgery. Primary endpoint: pain relief measured on a 5-point verbal scale over 6 h. Morphine rescue was administered as needed. P<.5 at every time point. *Patient-controlled analgesia. SPID24=sum of pain intensity differences, based on VAS score, at to 24 h. Significantly reduced pain intensity over 24 h 22 OFIRMEV showed a greater reduction in pain intensity over 24 h (SPID24) compared to placebo (P<.1) 22 OFIRMEV is contraindicated in: Patients with severe hepatic impairment or severe active liver disease OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 1

11 In orthopaedic surgery Reduced opioid consumption OFIRMEV 1 g + PCA morphine significantly reduced morphine consumption vs placebo + PCA morphine 1 Reduction in morphine consumption (Total hip or knee replacement surgery) 6 5 OFIRMEV 1 g + PCA morphine (n=49) Placebo + PCA morphine (n=52) 33 % Morphine (mg) Over 6 h P<.1 46 % 17.8 mg 9.7 mg 57.4 mg 38.3 mg Sinatra et al (Pain Study 1) Randomized, double-blind, placebo-controlled, single- and repeated-dose 24-h study (n=11). Patients received OFIRMEV 1 g + PCA morphine or placebo + PCA Over 24 h P<.1 morphine the morning following total hip or knee replacement surgery. Primary endpoint: pain relief measured on a 5-point verbal scale over 6 h. Morphine rescue was administered as needed. EFFICACY ORTHOPAEDIC SURGERY The clinical benefit of reduced opioid consumption was not evaluated or demonstrated Significant improvement in (median) time to first rescue medication 1 3 h vs.8 h for OFIRMEV 1 g vs placebo (P=.1) 1 Patient satisfaction with study treatment was also significantly higher for OFIRMEV 1 g vs placebo 1,15 4.8% vs 23.1% of patients reporting good or excellent satisfaction over PCA morphine alone (P=.4) 15 Patients were asked to evaluate the study treatments overall, using a 4-point categorical scale Most common adverse reactions in adult patients Nausea, vomiting, headache, insomnia 11

12 In acute renal colic Rapid reduction of pain intensity IV acetaminophen 1 g reduced pain intensity at 15 and 3 minutes in the emergency department setting 23 Pain intensity scores, single dose 8 Median pain intensity (VAS 1 mm) OFIRMEV 1 g (n=46) P=.5 vs placebo 3 15 Time (minutes) 3 IV morphine.1 mg/kg (n=49) P=.45 vs placebo 15 Placebo (n=51) 3 Bektas et al Randomized, prospective, double-blind, placebo-controlled, single-center, single-dose trial with 3 parallel groups. Patients received a single dose of IV acetaminophen 1 g, IV morphine.1 mg/kg, or placebo upon presenting to the emergency department with suspected renal colic. IV fentanyl was available to patients with inadequate pain relief at 3 minutes. Primary endpoint: change in pain intensity, based on VAS score, from baseline, at 15 and 3 minutes. Significant reductions in pain intensity vs placebo for IV acetaminophen 1 g and IV morphine 23 Significant mean differences in pain intensity reductions were observed for IV acetaminophen (P=.5) and IV morphine (P=.45) when compared with placebo 23 This study was not designed as a head-to-head, noninferiority trial Do not exceed the maximum recommended daily dose of 4 g of acetaminophen by all routes OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 12

13 In acute renal colic Use of rescue analgesia Fewer patients receiving IV acetaminophen 1 g vs placebo required rescue analgesia following 3-minute study period 23 Use of rescue analgesics at 3 minutes 8 68 % Patients (%) % 49 % OFIRMEV 1 g (n=46) P=NS vs placebo IV morphine.1 mg/kg (n=49) P=NS vs placebo Placebo (n=51) Bektas et al Randomized, prospective, double-blind, placebo-controlled, single-center, single-dose trial with 3 parallel groups. Patients received a single dose of IV acetaminophen 1 g, IV morphine.1 mg/kg, or placebo upon presenting to the emergency department with suspected renal colic. IV fentanyl was available to patients with inadequate pain relief at 3 minutes. Primary endpoint: change in pain intensity, based on VAS score, from baseline, at 15 and 3 minutes. Rescue analgesics at 3 minutes were required by 46% of patients receiving IV acetaminophen, 49% of patients receiving IV morphine, and 68% of patients receiving placebo (P=NS) 23 The clinical benefit of reduced opioid consumption was not evaluated or demonstrated Most common adverse reactions in adult patients Nausea, vomiting, headache, insomnia EFFICACY EMERGENCY DEPT 13

14 In abdominal laparoscopy Reductions in pain intensity OFIRMEV 1 g significantly reduced pain intensity vs placebo over 24 h 24 Sum of pain intensity differences over 24 h Mean SPID24 (VAS 1 mm) OFIRMEV 1 g (n=92) Placebo (n=18) P=.68 Wininger et al (Pain Study 2) Randomized, double-blind, placebo-controlled, multicenter, parallel-group study. The morning following abdominal laparoscopic surgery, patients received OFIRMEV 1 g or placebo q6h or OFIRMEV 65 mg or placebo q4h. IV or oral rescue medication was available to all patients. Primary endpoint: SPID24 (sum of pain intensity differences, based on VAS score, from baseline, at to 24 h). OFIRMEV 1 g pain intensity scores at each dosing interval over 24 h 15,24 Mean pain intensity scores at 6-h intervals Mean pain intensity (VAS 1 mm) OFIRMEV 1 g q6h + rescue (n=92) P<.1 Placebo + rescue (n=42) P=.12 P=.24 P=NS Time (h) Wininger et al (Pain Study 2) Randomized, double-blind, placebo-controlled, multicenter, parallel-group study. The morning following abdominal laparoscopic surgery, patients received OFIRMEV 1 g or placebo q6h or OFIRMEV 65 mg or placebo q4h. IV or oral rescue medication was available to all patients. Primary endpoint: SPID24 (sum of pain intensity differences, based on VAS score, from baseline, at to 24 h). OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 14

15 In abdominal laparoscopy Improved patient satisfaction Patients evaluations of study treatments were significantly higher for OFIRMEV 1 g vs placebo 24 Patient-reported satisfaction with study treatment at 24 h 7.3 % 86.9% P=.4* Placebo (n=18) OFIRMEV 1 g (n=92) Excellent + good Excellent + good Wininger et al (Pain Study 2) Randomized, double-blind, placebo-controlled, multicenter, parallel-group study. The morning following abdominal laparoscopic surgery, patients received OFIRMEV 1 g or placebo q6h or OFIRMEV 65 mg or placebo q4h. IV or oral rescue medication was available to all patients. Primary endpoint: SPID24 (sum of pain intensity differences, based on VAS score, from baseline, at to 24 h). *Overall P value derived from a statistical analysis of a 4-point categorical scale. Patients were asked to evaluate the study treatments overall, using a 4-point categorical scale Study encompassed laparoscopic OB/GYN and general surgical procedures 24 : Hysterectomy Cholecystectomy Hernia repair Prostatectomy 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 3 ml/min) EFFICACY GENERAL SURGERY 15

16 In abdominal hysterectomy Administer IV acetaminophen pre-op to improve post-op pain control Pre-op administration of IV acetaminophen 1 g demonstrated greater reductions in pain intensity vs placebo over 24 h 25 Mean pain intensity scores IV acetaminophen 1 g given 3 min prior to induction (n=28) IV acetaminophen 1 g prior to skin closure (n=27) Mean pain intensity (VAS 1 cm) Placebo (n=27) * * * * * Time (h) *P<.5 * Arici et al Randomized, placebo controlled, parallel-group, single-site study. Patients scheduled for total abdominal hysterectomy received IV acetaminophen 1 g 3 minutes prior to induction (pre-op), IV acetaminophen 1 g prior to skin closure (intra-op), or placebo. PCA morphine was available to all patients. Pain relief, based on VAS, at rest and with movement, sedation, and total morphine consumption were measured at 15 and 3 minutes, 1, 2, 4, 8, 12, and 24 h. Post-op pain intensity scores were significantly lower at all time points for the IV acetaminophen groups (pre-op and intra-op) compared to placebo (P<.5) 25 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 3 ml/min) Do not exceed the maximum recommended daily dose of 4 g of acetaminophen by all routes OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 16

17 In abdominal hysterectomy Administer IV acetaminophen pre-op to significantly reduce opioid use Pre-op administration of IV acetaminophen 1 g resulted in significantly less total opioid consumption over 24 h 25 Morphine consumption over 24 h Morphine (mg) Prior to induction (n=28) P<.5 P<.5 Prior to closure (n=27) Type of administration Placebo (n=27) Arici et al Randomized, placebo controlled, parallel-group, single-site study. Patients scheduled for total abdominal hysterectomy received IV acetaminophen 1 g 3 minutes prior to induction (pre-op), IV acetaminophen 1 g prior to skin closure (intra-op), or placebo. PCA morphine was available to all patients. Pain relief, based on VAS, at rest and with movement, sedation, and total morphine consumption were measured at 15 and 3 minutes, 1, 2, 4, 8, 12, and 24 h. Post-op morphine consumption was significantly lower among the IV acetaminophen groups (pre-op and intra-op) compared to placebo (P<.5) 25 When administered pre-op, IV acetaminophen 1 g demonstrated a significantly greater reduction in morphine consumption compared to the same dose administered intra-op (P<.5) 25 The clinical benefit of reduced opioid consumption was not evaluated or demonstrated OFIRMEV is contraindicated in: Patients with severe hepatic impairment or severe active liver disease EFFICACY PREEMPTIVE ANALGESIA 17

18 OFIRMEV established safety profile and well tolerated in clinical trials Most common adverse reactions 16 Adult patients: nausea, vomiting, headache, and insomnia Pediatric patients: nausea, vomiting, constipation, pruritus, agitation, and atelectasis OFIRMEV was not associated with the following side effects in clinical trials: Respiratory depression, postoperative ileus, sedation, cognitive impairment in older patients, upper gastrointestinal bleeding, surgical site bleeding, renal toxicity, platelet inhibition, or cardiovascular thrombotic events Liver enzyme elevations were comparable to placebo 15 Peak ALT/AST values postbaseline: % of patients in all repeated-dose, placebo-controlled, all-adult studies IV acetaminophen (n=42) Placebo (n=379) ALT >3 ULN 1.1% (n=4) 1.7% (n=6) >5 ULN.3% (n=1).6% (n=2) AST >3 ULN 1.% (n=4) 1.1% (n=4) >5 ULN.5% (n=2).8% (n=3) Data from a pooled analysis of 5 repeated-dose clinical studies involving adult patients. OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 18

19 Indications and usage of OFIRMEV OFIRMEV is indicated for the: Management of mild to moderate pain Management of moderate to severe pain with adjunctive opioid analgesics Reduction of fever OFIRMEV is approved for use in patients 2 years of age OFIRMEV is contraindicated in: Patients with known hypersensitivity to acetaminophen or to any of the excipients in the IV formulation Patients with 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 severe hepatotoxicity and death Do not exceed the maximum recommended daily dose of acetaminophen Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, in cases of alcoholism, chronic malnutrition, severe hypovolemia, or severe renal impairment (creatinine clearance 3 ml/min) Discontinue OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use in patients with acetaminophen allergy. Drug interactions Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential Chronic oral acetaminophen use at a dose of 4 mg/day has been shown to cause an increase in international normalized ratio (INR) in some patients who have been stabilized on sodium warfarin as an anticoagulant SAFETY PROFILE 19

20 Recommended dosing of OFIRMEV Dosing of OFIRMEV for adults, adolescents, and children 2 years old 16 Age Group Dosing interval Maximum single dose Maximum total daily dose of acetaminophen (by any route) Adults and adolescents q6h 1 mg ( 13 years old) (1 ml)* 5 kg 4 mg in 24 hours Adults and adolescents ( 13 years old) <5 kg Children 2 to 12 years old q6h Weight-based dose: 15 mg/kg (up to 75 mg) 75 mg/kg in 24 hours (up to 375 mg) *Each ml contains 1 mg of OFIRMEV. Minimum dosing interval is q4h 16 For instructions regarding q4h dosing, please see full Prescribing Information No dose adjustment is required when transitioning to oral acetaminophen in adults and adolescents 16 OFIRMEV should be administered only as a 15-minute infusion. Administer only as directed. 16 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 3 ml/min) OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Please see full Prescribing Information. 2

21 OFIRMEV from the start Administer OFIRMEV pre-op, then schedule q6h CONTINUE WITH OFIRMEV IF: Schedule OFIRMEV q6h for first 24 hours Parenteral analgesia is clinically warranted Compromised GI absorption or inability to take oral analgesics 1% bioavailability desired TRANSITION TO ORAL ANALGESIA WHEN: Patient can take and absorb oral analgesics Do not exceed the maximum recommended daily dose of 4 g of acetaminophen by all routes Administration of acetaminophen by any route in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death References: 1. Sinatra RS, Jahr JS, Reynolds LW, et al. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology. 25;12: Data from hospital research database maintained by Premier Healthcare Alliance. Jan 13, The Joint Commission. Safe use of opioids in the hospital. Sentinel Event Alert. 212;49: Sinatra R. Review article: causes and consequences of inadequate management of acute pain. Pain Med. 21;11: Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology. 1995;83: Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged [abstract A63]. Presented at: 11th Annual Pain Medicine Meeting; November 15 18, 212; Miami, FL. 7. 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. 212;116: Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 21;63: Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician. 29;12: Wu C, Raja S. Treatment of acute postoperative pain. Lancet. 211;377: Jarzyna D, Jungquist CR, Pasero C, et al. American Society for Pain Management Nursing guidelines on monitoring for opioid-induced sedation and respiratory depression. Pain Manag Nurs. 211;12: Hughes RD, ed. Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Rockville, MD: Agency for Healthcare Research and Quality; Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 213;41: Crews JC. Multimodal pain management strategies for office-based and ambulatory procedures. JAMA. 22;288: Data on file. Cadence Pharmaceuticals, Inc. 16. OFIRMEV (acetaminophen) injection prescribing information. Cadence Pharmaceuticals, Inc. 17. Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after singledose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 212;12: Petring OU, Dawson PJ, Blake DW, et al. Normal postoperative gastric emptying after orthopaedic surgery with spinal anaesthesia and I.M. ketorolac as the first postoperative analgesic. Br J Anaesth. 1995;74: Berger MM, Berger-Gryllaki M, Wiesel PH, et al. Intestinal absorption in patients after cardiac surgery. Crit Care Med. 2;28: Behm B, Stollman N. Postoperative ileus: etiologies and interventions. Clin Gastroenterol Hepatol. 23;1: Petring OU, Blake DW. Gastric emptying in adults: an overview related to anaesthesia. Anaesth Intensive Care. 1993;21: Sinatra RS, Jahr JS, Reynolds LW, et al. Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis. Pain Pract. 212;12: Bektas F, Eken C, Karadeniz O, et al. Intravenous paracetamol or morphine for the treatment of renal colic: a randomized, placebo-controlled trial. Ann Emerg Med. 29;54: 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. 21;32: Arici S, Gurbet A, Türker G, et al. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri. 29;21: dosing/ references

22 Less pain. Less opioids. From the start. Begin your multimodal analgesic regimen with OFIRMEV Significant pain relief 1 Reduced opioid consumption 1,25 Improved patient satisfaction 1,24 Established safety profile and well tolerated in clinical trials 1,16,22-25 Utilization considerations: Initiate early (pre-op or intra-op) Schedule q6h for the first 24 h or as long as clinically warranted Do not exceed the maximum recommended daily dose of 4 g of acetaminophen by all routes Indication OFIRMEV is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever. Important Safety Information OFIRMEV is contraindicated in patients with severe hepatic impairment, severe active liver disease or with known hypersensitivity to acetaminophen or to any of the excipients in the formulation. Acetaminophen should be used with caution in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia, or severe renal impairment. Do not exceed the maximum recommended daily dose of acetaminophen. Administration of acetaminophen by any route in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death. OFIRMEV should be administered only as a 15-minute infusion. Discontinue OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use in patients with acetaminophen allergy. The most common adverse reactions in patients treated with OFIRMEV were nausea, vomiting, headache, and insomnia in adult patients and nausea, vomiting, constipation, pruritus, agitation, and atelectasis in pediatric patients. OFIRMEV is approved for use in patients 2 years of age. The antipyretic effects of OFIRMEV may mask fever in patients treated with postsurgical pain. To report SUSPECTED ADVERSE REACTIONS, contact Cadence Pharmaceuticals, Inc. at or FDA at 1-8-FDA-188 or Please see accompanying full Prescribing Information. Cadence, OFIRMEV, and the OFIRMEV dot design are trademarks of Cadence Pharmaceuticals, Inc. 213 Cadence Pharmaceuticals, Inc. All rights reserved. OFV

23 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OFIRMEV safely and effectively. See full prescribing information for OFIRMEV. OFIRMEV (acetaminophen) Injection Initial U.S. Approval: 1951 INDICATIONS AND USAGE OFIRMEV (acetaminophen) injection is indicated for the Management of mild to moderate pain (1) Management of moderate to severe pain with adjunctive opioid analgesics (1) Reduction of fever (1) DOSAGE AND ADMINISTRATION OFIRMEV may be given as a single or repeated dose. (2.1) OFIRMEV should be administered only as a 15-minute intravenous infusion. (2.4) Adults and Adolescents Weighing 5 kg and Over: 1 mg every 6 hours or 65 mg every 4 hours to a maximum of 4 mg per day. Minimum dosing interval of 4 hours. (2.2) Adults and Adolescents Weighing Under 5 kg: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours to a maximum of 75 mg/kg per day. Minimum dosing interval of 4 hours. (2.2) Children: Children 2 to 12 years old: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours to a maximum of 75 mg/kg per day. Minimum dosing interval of 4 hours. (2.3) DOSAGE FORMS AND STRENGTHS Injection for intravenous infusion. Each 1 ml glass vial contains 1 mg acetaminophen (1 mg/ml). (3) CONTRAINDICATIONS Acetaminophen is contraindicated: In patients with known hypersensitivity to acetaminophen or to any of the excipients in the IV formulation. (4) In patients with severe hepatic impairment or severe active liver disease. (4) WARNINGS AND PRECAUTIONS Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death. (5.1) Do not exceed the maximum recommended daily dose of acetaminophen. (5.1) FULL PRESCRIBING INFORMATION: CONTENTS* 1. INDICATIONS AND USAGE 2. DOSAGE AND ADMINISTRATION 2.1 General Dosing Information 2.2 Recommended Dosage: Adults and Adolescents 2.3 Recommended Dosage: Children 2.4 Instructions for Intravenous Administration 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1 Hepatic Injury 5.2 Allergy and Hypersensitivity 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience 7. DRUG INTERACTIONS 7.1 Effects of other Substances on Acetaminophen 7.2 Anticoagulants 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients with Hepatic Impairment 8.7 Patients with Renal Impairment 1. OVERDOSAGE 11. DESCRIPTION Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, in cases of alcoholism, chronic malnutrition, severe hypovolemia, or severe renal impairment (creatinine clearance 3 ml/min). (5.1) Discontinue OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use in patients with acetaminophen allergy. (5.2) ADVERSE REACTIONS The most common adverse reactions in patients treated with OFIRMEV were nausea, vomiting, headache, and insomnia in adult patients and nausea, vomiting, constipation, pruritus, agitation, and atelectasis in pediatric patients. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Cadence Pharmaceuticals Inc. at or FDA at 1-8-FDA-188 or DRUG INTERACTIONS Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential. (7.1) Chronic oral acetaminophen use at a dose of 4 mg/day has been shown to cause an increase in international normalized ratio (INR) in some patients who have been stabilized on sodium warfarin as an anticoagulant. (7.2) USE IN SPECIFIC POPULATIONS Pregnancy: Category C. There are no studies of intravenous acetaminophen in pregnant women. Use only if clearly needed. (8.1) Nursing Mothers: Caution should be exercised when administered to a nursing woman. (8.3) Pediatric Use: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients less than 2 years of age. The safety and effectiveness of OFIRMEV in pediatric patients older than 2 years is supported by evidence from adequate and well controlled studies in adults with additional safety and pharmacokinetic data for this age group. (8.4) Geriatric Use: No overall differences in safety or effectiveness were observed between geriatric and younger subjects. (8.5) Hepatic Impairment: OFIRMEV is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease. (4, 5.1, 8.6) Renal Impairment: In cases of severe renal impairment, longer dosing intervals and a reduced total daily dose of acetaminophen may be warranted. (5.1, 8.7) Revised: 11/ CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14. CLINICAL STUDIES 14.1 Adult Acute Pain 14.2 Adult Fever 14.3 Pediatric Acute Pain and Fever 16. HOW SUPPLIED/STORAGE AND HANDLING *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain the management of moderate to severe pain with adjunctive opioid analgesics the reduction of fever. 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Information OFIRMEV may be given as a single or repeated dose for the treatment of acute pain or fever. No dose adjustment is required when converting between oral acetaminophen and OFIRMEV dosing in adults and adolescents. The maximum daily dose of acetaminophen is based on all routes of administration (i.e. intravenous, oral, and rectal) and all products containing acetaminophen. 2.2 Recommended Dosage: Adults and Adolescents Adults and adolescents weighing 5 kg and over: the recommended dosage of OFIRMEV is 1 mg every 6 hours or 65 mg every 4 hours, with a maximum single dose of OFIRMEV of 1 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 4 mg per day. Adults and adolescents weighing under 5 kg: the recommended dosage of OFIRMEV is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of OFIRMEV of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 75 mg/kg per day. Table 1: Dosing for Adults and Adolescents Age group Dose given Dose given Maximum Maximum total every 4 hours every 6 hours single dose daily dose of acetaminophen (by any routes) Adults and adolescents (13 years and older) weighing Adults and adolescents (13 years and older) weighing 65 mg 1 mg 1 mg 4 mg in 24 hours 12.5 mg/kg 15 mg/kg 15 mg/kg 75 mg/kg in 24 hours (up to 75 mg) (up to 375 mg) 2.3 Recommended Dosage: Children Children 2 to 12 years of age: the recommended dosage of OFIRMEV is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of OFIRMEV of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 75 mg/kg per day. 2.4 Instructions for Intravenous Administration For adult and adolescent patients weighing 5 kg requiring 1 mg doses of OFIRMEV, administer the dose by inserting a vented intravenous set through the septum of the 1 ml vial. OFIRMEV may be administered without further dilution. Examine the vial contents before dose preparation or administering. DO NOT USE if particulate matter or discoloration is observed. Administer the contents of the vial intravenously over 15-minutes. Use aseptic technique when preparing OFIRMEV for intravenous infusion. Do not add other medications to the OFIRMEV vial or infusion device. For doses less than 1 mg, the appropriate dose must be withdrawn from the vial and placed into a separate container prior to administration. Using aseptic technique, withdraw the appropriate dose (65 mg or weightbased) from an intact sealed OFIRMEV vial and place the measured dose in a separate empty, sterile container (e.g. glass bottle, plastic intravenous container, or syringe) for intravenous infusion to avoid the inadvertent delivery and administration of the total volume of the commercially available container. The entire 1 ml vial of OFIRMEV is not intended for use in patients weighing less than 5 kg. OFIRMEV is a single-use vial and the unused portion must be discarded. Place small volume pediatric doses up to 6 ml in volume in a syringe and administer over 15 minutes using a syringe pump. Monitor the end of the infusion in order to prevent the possibility of an air embolism, especially in cases where the OFIRMEV infusion is the primary infusion. Once the vacuum seal of the glass vial has been penetrated, or the contents transferred to another container, administer the dose of OFIRMEV within 6 hours. Do not add other medications to the OFIRMEV solution. Diazepam and chlorpromazine hydrochloride are physically incompatible with OFIRMEV, therefore do not administer simultaneously. 3 DOSAGE FORMS AND STRENGTHS OFIRMEV is a sterile, clear, colorless, non pyrogenic, preservative free, isotonic formulation of acetaminophen intended for intravenous infusion. Each 1 ml glass vial contains 1 mg acetaminophen (1 mg/ml). 4 CONTRAINDICATIONS Acetaminophen is contraindicated: in patients with known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation. in patients with severe hepatic impairment or severe active liver disease [see WARNINGS AND PRECAUTIONS (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Injury Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death [see OVERDOSAGE (1)]. Do not exceed the maximum recommended daily dose of acetaminophen [see DOSAGE AND ADMINISTRATION (2)]. 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 3 ml/min) [see USE IN SPECIFIC POPULATIONS (8.6, 8.7)]. 5.2 Allergy and Hypersensitivity There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. There were infrequent reports of life-threatening anaphylaxis requiring emergent medical attention. Discontinue OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use OFIRMEV in patients with acetaminophen allergy. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Hepatic Injury [see WARNINGS AND PRECAUTIONS (5.1)] Allergy and Hypersensitivity [see WARNINGS AND PRECAUTIONS (5.2)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Adult Population A total of 12 adult patients have received OFIRMEV in clinical trials, including 37.3% (n=38) who received 5 or more doses, and 17.% (n=173) who received more than 1 doses. Most patients were treated with OFIRMEV 1 mg every 6 hours. A total of 13.1% (n=134) received OFIRMEV 65 mg every 4 hours. All adverse reactions that occurred in adult patients treated with either OFIRMEV or placebo in repeated dose, placebo-controlled clinical trials at an incidence 3% and at a greater frequency than placebo are listed in Table 2. The most common adverse events in adult patients treated with OFIRMEV (incidence 5% and greater than placebo) were nausea, vomiting, headache, and insomnia. Table 2. Treatment-Emergent Adverse Reactions Occurring % in OFIRMEV and at a greater frequency than Placebo in Placebo-Controlled, Repeated Dose Studies System Organ Class Preferred Term Gastrointestinal Disorders Nausea Vomiting OFIRMEV (N=42) n (%) 138 (34) 62 (15) Placebo (N= ) n (%) 119 (31) 42 (11) General Disorders and Administration Site Conditions Pyrexia* 22 (5) 52 (14) Nervous System Disorders Headache 39 (1) 33 (9) Psychiatric Disorders Insomnia 3 (7) 21 (5) * Pyrexia adverse reaction frequency data is included in order to alert healthcare practitioners that the antipyretic effects of OFIRMEV may mask fever. Other Adverse Reactions Observed During Clinical Studies of OFIRMEV in Adults The following additional treatment-emergent adverse reactions were reported by adult subjects treated with OFIRMEV in all clinical trials (n=12) that occurred with an incidence of at least 1% and at a frequency greater than placebo (n=525). Blood and lymphatic system disorders: anemia General disorders and administration site conditions: fatigue, infusion site pain, edema peripheral Investigations: aspartate aminotransferase increased, breath sounds abnormal Metabolism and nutrition disorders: hypokalemia Musculoskeletal and connective tissue disorders: muscle spasms, trismus Psychiatric disorders: anxiety Respiratory, thoracic and mediastinal disorders: dyspnea Vascular disorders: hypertension, hypotension Pediatric population A total of 355 pediatric patients (47 neonates, 64 infants, 171 children, and 73 adolescents) have received OFIRMEV in active-controlled (n=25) and open-label clinical trials (n=225), including 59.7% (n=212) who received 5 or more doses and 43.1% (n=153) who received more than 1 doses. Pediatric patients received OFIRMEV doses up to 15 mg/kg on an every 4 hours, every 6 hours, or every 8 hours schedule. The maximum exposure was 7.7, 6.4, 6.8, and 7.1 days in neonates, infants, children, and adolescents, respectively. The most common adverse events (incidence 5%) in pediatric patients treated with OFIRMEV were nausea, vomiting, constipation, pruritus, agitation, and atelectasis. Other Adverse Reactions Observed During Clinical Studies of OFIRMEV in Pediatrics The following additional treatment-emergent adverse reactions were reported by pediatric subjects treated with OFIRMEV (n=355) that occurred with an incidence of at least 1%. Blood and lymphatic system disorders: anemia Cardiac disorders: tachycardia Gastrointestinal disorders: abdominal pain, diarrhea General disorders and administration site conditions: injection site pain, edema peripheral, pyrexia Investigations: hepatic enzyme increase Metabolism and nutrition disorders: hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia, hypervolemia Musculoskeletal and connective tissue disorders: muscle spasm, pain in extremity Nervous system disorders: headache Psychiatric disorders: insomnia Renal and urinary disorders: oliguria Respiratory, thoracic and mediastinal disorders: pulmonary edema, hypoxia, pleural effusion, stridor, wheezing Skin and subcutaneous tissue disorders: periorbital edema, rash Vascular disorders: hypertension, hypotension 7 DRUG INTERACTIONS 7.1 Effects of other Substances on Acetaminophen Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential. The clinical consequences of these effects have not been established. Effects of ethanol are complex, because excessive alcohol usage can induce hepatic cytochromes, but ethanol also acts as a competitive inhibitor of the metabolism of acetaminophen. 7.2 Anticoagulants Chronic oral acetaminophen use at a dose of 4 mg/day has been shown to cause an increase 12199_OFIRMEV.indd 1 6/8/11 5:25 PM