OFIRMEV a non-opioid, non-nsaid, intravenous analgesic for the management of pain

Transcription

1 FOR PHARMACY PROFESSIONALS In pharmacokinetic studies Rapid time to reach Cmax with IV acetaminophen OFIRMEV from the start OFIRMEV g demonstrated early and high Cmax at minutes Consider administering OFIRMEV pre-op, then scheduling qh Less pain. Less opioids. From the start. Consider beginning your multimodal analgesic regimen with OFIRMEV Mean plasma concentrations of OFIRMEV g and oral acetaminophen g Time to reach Cmax (Tmax) 3 minutes faster than oral acetaminophen Mean plasma concentration (μg/ml) 3 CONTINUE WITH OFIRMEV IF: OFIRMEV g (N=38) Oral acetaminophen g (N=38) Schedule OFIRMEV qh for first hours...7 Open-label, single-center, randomized, -period crossover pharmacokinetic study involving healthy adult males (N=38). Subjects received a total of 8 doses each of OFIRMEV g qh, OFIRMEV g qh, oral acetaminophen g qh, and oral acetaminophen g qh divided among treatment periods (results for the first -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 -minute infusion. Parenteral analgesia is clinically warranted Compromised GI absorption or inability to take oral analgesics % bioavailability desired CONTRAINDICATIONS Acetaminophen is contraindicated in patients with: known hypersensitivity to acetaminophen or to any of the excipients in the intravenous (IV) formulation. severe hepatic impairment or severe active liver disease. TRANSITION TO ORAL ANALGESIA WHEN: WARNINGS AND PRECAUTIONS Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death. Do not exceed the maximum recommended daily dose of acetaminophen. The maximum recommended daily dose of acetaminophen includes all routes of acetaminophen administration and all acetaminophen-containing products administered, including combination products. Dosing errors could result in accidental overdose and death. Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance 3 ml/min). Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Hypersensitivity and anaphylaxis associated with the use of acetaminophen have been reported. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. The antipyretic effects of OFIRMEV may mask fever. Patient can take and absorb oral analgesics Cmax occurs at the end of the -minute IV infusion of OFIRMEV Overall exposure (AUC) after a single dose was similar to oral acetaminophen No significant accumulation with repeated dosing OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Consider beginning your IV analgesic regimen with OFIRMEV Do not exceed the maximum recommended daily limits of acetaminophen by all routes. The maximum total daily dose of OFIRMEV for adults kg is mg. Rapid onset of action No first-pass hepatic exposure Early and high Cmax % bioavailability Significant pain relief 9 Reduced opioid consumption9, Improved patient satisfaction8, Established safety profile and well tolerated in clinical trials,8-, Utilization considerations: Initiate early (pre-op or intra-op) Schedule qh for the first h or as long as clinically warranted Do not exceed the maximum recommended daily limits of acetaminophen by all routes. The maximum total daily dose of OFIRMEV for adults kg is mg. ADVERSE REACTIONS Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity, and anaphylaxis. Common adverse reactions in adults include nausea, vomiting, headache, and insomnia. Common adverse reactions in pediatric patients include nausea, vomiting, constipation, pruritus, agitation, and atelectasis. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. OFIRMEV should be given to a pregnant woman only if clearly needed. Breast Feeding: While studies with OFIRMEV have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration. Pediatrics: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients < years of age. OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Please see additional Important Risk Information, including complete boxed warning, in accompanying Full Prescribing Information. References:. Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged [abstract A3]. Presented at: th Annual Pain Medicine Meeting; November -8, ; Miami, FL.. Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology 99; 83: 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 ; : Crews JC. Multimodal pain management strategies for office-based and ambulatory procedures. JAMA. ;88:9 3.. Data on File, Cadence Pharmaceuticals, a Mallinckrodt company.. OFIRMEV [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; Singla NK, Parulan C,. Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. Plasma and cerebrospinal fluid pharmacokinetic parameters after single dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. ;(7): Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology ;: Sinatra RS, Jahr JS, Reynolds LW, et al. Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis. Pain Pract. ; : Wininger SJ, Miller H, Minkowitz HS, Royal MA, Ang RY, Breitmeyer JB, Singla NK. A randomized, double-blind, placebo-controlled, multi-center, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther ; 3(): Pyxis Anesthesia System [product brochure], San Diego, CA: Carefusion;.. Arici S, Gurbet A, Turker G, et al. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri 9; :-. 9 Mallinckrodt, the M brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. Mallinckrodt. OFV 8/ OFIRMEV.com OFIRMEV a non-opioid, non-nsaid, intravenous analgesic for the management of pain An overview of Unmet needs in postoperative pain management Society recommendation of multimodal analgesia techniques for pain relief OFIRMEV pharmacokinetic and clinical information Utilization considerations for perioperative pain management OFIRMEV dosing information OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (ml) is not confused; the dosing is based on weight for patients under kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product. Please see additional Important Risk Information, including complete boxed warning, in accompanying Full Prescribing Information.

2 Despite pain management, many patients still experience postoperative pain In a survey, approximately 8% of patients reported post-op pain, with a total of % reporting pain as moderate to extreme Post-op pain severity: 99 vs, % adult patients reporting pain 7 3 Moderate to extreme 38 3 None to slight 99 (n=) (n=3) Pain management goals are multifaceted Follow American Society of Anesthesiologists guidelines 3 Facilitate safe and effective acute pain management in the perioperative setting Maintain patient s functional abilities Employ a multimodal approach for acute pain management Use non-opioid analgesics alone in mild to moderate pain, or with adjunctive opioids in moderate to severe pain 3, Begin pain management prior to surgery 3 Multimodal analgesia may decrease opioid dose requirements 3 OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever.

3 Multimodal analgesia in practice American Society of Anesthesiologists (ASA) guidelines 3 The ASA Task Force recommends the use of multimodal analgesia whenever possible in the perioperative setting Patients should receive an around-the-clock regimen of acetaminophen, NSAIDs, or COX- inhibitors unless contraindicated Dosing regimens should be administered to optimize efficacy while minimizing the risk of adverse events Multimodal analgesia can help manage different levels of pain across the perioperative setting 3, Step 3: Severe Pain Step + Step and Higher doses of opioids Step : Moderate Pain Step and Low doses of opioids Step : Mild Pain Acetaminophen, NSAIDs, or COX- selective inhibitors and Local/regional anesthesia Non-opioids, such as acetaminophen, NSAIDs, or COX- selective inhibitors, are the foundational analgesic agents given perioperatively for the management of pain; opioids are added for moderate to severe pain 3, OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Acetaminophen is contraindicated in patients with: known hypersensitivity to acetaminophen or to any of the excipients in the intravenous (IV) formulation. severe hepatic impairment or severe active liver disease. Please see accompanying Full Prescribing Information, including complete boxed warning. 3

4 FOR PHARMACY PROFESSIONALS In pharmacokinetic studies Rapid time to reach Cmax with IV acetaminophen OFIRMEV from the start OFIRMEV g demonstrated early and high Cmax at minutes Consider administering OFIRMEV pre-op, then scheduling qh Less pain. Less opioids. From the start. Consider beginning your multimodal analgesic regimen with OFIRMEV Mean plasma concentrations of OFIRMEV g and oral acetaminophen g Time to reach Cmax (Tmax) 3 minutes faster than oral acetaminophen Mean plasma concentration (μg/ml) 3 CONTINUE WITH OFIRMEV IF: OFIRMEV g (N=38) Oral acetaminophen g (N=38) Schedule OFIRMEV qh for first hours...7 Open-label, single-center, randomized, -period crossover pharmacokinetic study involving healthy adult males (N=38). Subjects received a total of 8 doses each of OFIRMEV g qh, OFIRMEV g qh, oral acetaminophen g qh, and oral acetaminophen g qh divided among treatment periods (results for the first -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 -minute infusion. Parenteral analgesia is clinically warranted Compromised GI absorption or inability to take oral analgesics % bioavailability desired CONTRAINDICATIONS Acetaminophen is contraindicated in patients with: known hypersensitivity to acetaminophen or to any of the excipients in the intravenous (IV) formulation. severe hepatic impairment or severe active liver disease. TRANSITION TO ORAL ANALGESIA WHEN: WARNINGS AND PRECAUTIONS Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death. Do not exceed the maximum recommended daily dose of acetaminophen. The maximum recommended daily dose of acetaminophen includes all routes of acetaminophen administration and all acetaminophen-containing products administered, including combination products. Dosing errors could result in accidental overdose and death. Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance 3 ml/min). Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Hypersensitivity and anaphylaxis associated with the use of acetaminophen have been reported. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. The antipyretic effects of OFIRMEV may mask fever. Patient can take and absorb oral analgesics Cmax occurs at the end of the -minute IV infusion of OFIRMEV Overall exposure (AUC) after a single dose was similar to oral acetaminophen No significant accumulation with repeated dosing OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Consider beginning your IV analgesic regimen with OFIRMEV Do not exceed the maximum recommended daily limits of acetaminophen by all routes. The maximum total daily dose of OFIRMEV for adults kg is mg. Rapid onset of action No first-pass hepatic exposure Early and high Cmax % bioavailability Significant pain relief 9 Reduced opioid consumption9, Improved patient satisfaction8, Established safety profile and well tolerated in clinical trials,8-, Utilization considerations: Initiate early (pre-op or intra-op) Schedule qh for the first h or as long as clinically warranted Do not exceed the maximum recommended daily limits of acetaminophen by all routes. The maximum total daily dose of OFIRMEV for adults kg is mg. ADVERSE REACTIONS Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity, and anaphylaxis. Common adverse reactions in adults include nausea, vomiting, headache, and insomnia. Common adverse reactions in pediatric patients include nausea, vomiting, constipation, pruritus, agitation, and atelectasis. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. OFIRMEV should be given to a pregnant woman only if clearly needed. Breast Feeding: While studies with OFIRMEV have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration. Pediatrics: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients < years of age. OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Please see additional Important Risk Information, including complete boxed warning, in accompanying Full Prescribing Information. References:. Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged [abstract A3]. Presented at: th Annual Pain Medicine Meeting; November -8, ; Miami, FL.. Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology 99; 83: 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 ; : Crews JC. Multimodal pain management strategies for office-based and ambulatory procedures. JAMA. ;88:9 3.. Data on File, Cadence Pharmaceuticals, a Mallinckrodt company.. OFIRMEV [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; Singla NK, Parulan C,. Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. Plasma and cerebrospinal fluid pharmacokinetic parameters after single dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. ;(7): Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology ;: Sinatra RS, Jahr JS, Reynolds LW, et al. Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis. Pain Pract. ; : Wininger SJ, Miller H, Minkowitz HS, Royal MA, Ang RY, Breitmeyer JB, Singla NK. A randomized, double-blind, placebo-controlled, multi-center, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther ; 3(): Pyxis Anesthesia System [product brochure], San Diego, CA: Carefusion;.. Arici S, Gurbet A, Turker G, et al. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri 9; :-. 9 Mallinckrodt, the M brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. Mallinckrodt. OFV 8/ OFIRMEV.com OFIRMEV a non-opioid, non-nsaid, intravenous analgesic for the management of pain An overview of Unmet needs in postoperative pain management Society recommendation of multimodal analgesia techniques for pain relief OFIRMEV pharmacokinetic and clinical information Utilization considerations for perioperative pain management OFIRMEV dosing information OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (ml) is not confused; the dosing is based on weight for patients under kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product. Please see additional Important Risk Information, including complete boxed warning, in accompanying Full Prescribing Information.

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

6 In an orthopaedic surgery study Significant pain relief and reduced opioid consumption OFIRMEV g + PCA* morphine demonstrated significant pain relief vs placebo + PCA morphine 8 Mean pain relief scores, single dose (Total hip or knee replacement surgery) Pain relief Significant improvement over placebo + PCA morphine 3 OFIRMEV g + PCA morphine (n=9) Placebo + PCA morphine (n=) *Patient-controlled analgesia. SPID=sum of pain intensity differences, based on VAS score, at to h. P<. at every time point Sinatra et al. (Pain Study ) Randomized, double-blind, placebocontrolled, single- and repeated-dose -h study (n=). Patients received OFIRMEV g + PCA morphine or placebo + PCA morphine the morning following total hip or knee replacement surgery. Primary endpoint: pain relief measured on a -point verbal scale over h. Morphine rescue was administered as needed. P<. at every time point. Significantly reduced pain intensity over h 9 OFIRMEV showed a greater reduction in pain intensity over h (SPID) compared to placebo (P<.) 9 OFIRMEV g + PCA morphine significantly reduced morphine consumption vs placebo + PCA morphine 8 Reduction in morphine consumption (Total hip or knee replacement surgery) OFIRMEV g + PCA morphine (n=9) Placebo + PCA morphine (n=) 33 % Morphine (mg) 3 Over h P<. % 7.8 mg 9.7 mg 7. mg 38.3 mg Over h P<. Sinatra et al. (Pain Study ) Randomized, double-blind, placebocontrolled, single- and repeated-dose -h study (n=). Patients received OFIRMEV g + PCA morphine or placebo + PCA morphine the morning following total hip or knee replacement surgery. Primary endpoint: pain relief measured on a -point verbal scale over h. Morphine rescue was administered as needed. The clinical benefit of reduced opioid consumption was not evaluated or demonstrated OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever.

7 In an abdominal laparoscopy study Reductions in pain intensity OFIRMEV g + rescue significantly reduced pain intensity vs placebo + rescue over h Sum of pain intensity differences over h Mean SPID (VAS mm). 9. OFIRMEV g qh + rescue (n=9) Placebo + rescue (n=8) P=.8 Wininger et al. (Pain Study ) Randomized, double-blind, placebo-controlled, multicenter, parallel-group study. The morning following abdominal laparoscopic surgery, patients received OFIRMEV g or placebo qh or OFIRMEV mg or placebo qh. IV or oral rescue medication was available to all patients. Primary endpoint: SPID (sum of pain intensity differences, based on VAS score, from baseline, at to h). OFIRMEV g pain intensity scores at each dosing interval over h, Mean pain intensity scores at -h intervals Mean pain intensity (VAS mm) 3 OFIRMEV g qh + rescue (n=9) P<. Placebo + rescue (n=) P=. P=. P=NS 8 8 Wininger et al. (Pain Study ) Randomized, double-blind, placebo-controlled, multicenter, parallel-group study. The morning following abdominal laparoscopic surgery, patients received OFIRMEV g or placebo qh or OFIRMEV mg or placebo qh. IV or oral rescue medication was available to all patients. Primary endpoint: SPID (sum of pain intensity differences, based on VAS score, from baseline, at to h). OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Acetaminophen is contraindicated in patients with: known hypersensitivity to acetaminophen or to any of the excipients in the intravenous (IV) formulation. severe hepatic impairment or severe active liver disease. 7

8 Recommended dosing of OFIRMEV Dosing of OFIRMEV for adults, adolescents, and children years old Age group Dose given every hours Dose given every hours Maximum single dose Maximum total daily dose of acetaminophen (by all routes) Adults and adolescents (3 years and older) weighing kg mg mg mg mg in hours Adults and adolescents (3 years old and older) weighing < kg. mg/kg mg/kg mg/kg (up to 7 mg) 7 mg/kg in hours (up to 37 mg) Children to years of age Minimum dosing interval is qh For instructions regarding qh dosing, please see Full Prescribing Information No dose adjustment is required when transitioning to oral acetaminophen in adults and adolescents OFIRMEV should be administered only as a -minute infusion. Administer only as directed OFIRMEV should be stored at C to C (8 F to 77 F) [See USP Controlled Room Temperature] For single use only. The product should be used within hours after opening OFIRMEV vial fits in the Pyxis Anesthesia System* and other commonly used anesthesia/or carts Vial dimensions:.9 x.3 OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (ml) is not confused; the dosing is based on weight for patients under kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product. * Pyxis Anesthesia System is a registered trademark of CareFusion 8

9 FOR PHARMACY PROFESSIONALS In pharmacokinetic studies Rapid time to reach Cmax with IV acetaminophen OFIRMEV from the start OFIRMEV g demonstrated early and high Cmax at minutes Consider administering OFIRMEV pre-op, then scheduling qh Less pain. Less opioids. From the start. Consider beginning your multimodal analgesic regimen with OFIRMEV Mean plasma concentrations of OFIRMEV g and oral acetaminophen g Time to reach Cmax (Tmax) 3 minutes faster than oral acetaminophen Mean plasma concentration (μg/ml) 3 CONTINUE WITH OFIRMEV IF: OFIRMEV g (N=38) Oral acetaminophen g (N=38) Schedule OFIRMEV qh for first hours...7 Open-label, single-center, randomized, -period crossover pharmacokinetic study involving healthy adult males (N=38). Subjects received a total of 8 doses each of OFIRMEV g qh, OFIRMEV g qh, oral acetaminophen g qh, and oral acetaminophen g qh divided among treatment periods (results for the first -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 -minute infusion. Parenteral analgesia is clinically warranted Compromised GI absorption or inability to take oral analgesics % bioavailability desired CONTRAINDICATIONS Acetaminophen is contraindicated in patients with: known hypersensitivity to acetaminophen or to any of the excipients in the intravenous (IV) formulation. severe hepatic impairment or severe active liver disease. TRANSITION TO ORAL ANALGESIA WHEN: WARNINGS AND PRECAUTIONS Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death. Do not exceed the maximum recommended daily dose of acetaminophen. The maximum recommended daily dose of acetaminophen includes all routes of acetaminophen administration and all acetaminophen-containing products administered, including combination products. Dosing errors could result in accidental overdose and death. Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance 3 ml/min). Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Hypersensitivity and anaphylaxis associated with the use of acetaminophen have been reported. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. The antipyretic effects of OFIRMEV may mask fever. Patient can take and absorb oral analgesics Cmax occurs at the end of the -minute IV infusion of OFIRMEV Overall exposure (AUC) after a single dose was similar to oral acetaminophen No significant accumulation with repeated dosing OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Consider beginning your IV analgesic regimen with OFIRMEV Do not exceed the maximum recommended daily limits of acetaminophen by all routes. The maximum total daily dose of OFIRMEV for adults kg is mg. Rapid onset of action No first-pass hepatic exposure Early and high Cmax % bioavailability Significant pain relief 9 Reduced opioid consumption9, Improved patient satisfaction8, Established safety profile and well tolerated in clinical trials,8-, Utilization considerations: Initiate early (pre-op or intra-op) Schedule qh for the first h or as long as clinically warranted Do not exceed the maximum recommended daily limits of acetaminophen by all routes. The maximum total daily dose of OFIRMEV for adults kg is mg. ADVERSE REACTIONS Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity, and anaphylaxis. Common adverse reactions in adults include nausea, vomiting, headache, and insomnia. Common adverse reactions in pediatric patients include nausea, vomiting, constipation, pruritus, agitation, and atelectasis. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. OFIRMEV should be given to a pregnant woman only if clearly needed. Breast Feeding: While studies with OFIRMEV have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration. Pediatrics: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients < years of age. OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Please see additional Important Risk Information, including complete boxed warning, in accompanying Full Prescribing Information. References:. Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged [abstract A3]. Presented at: th Annual Pain Medicine Meeting; November -8, ; Miami, FL.. Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology 99; 83: 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 ; : Crews JC. Multimodal pain management strategies for office-based and ambulatory procedures. JAMA. ;88:9 3.. Data on File, Cadence Pharmaceuticals, a Mallinckrodt company.. OFIRMEV [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; Singla NK, Parulan C,. Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. Plasma and cerebrospinal fluid pharmacokinetic parameters after single dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. ;(7): Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology ;: Sinatra RS, Jahr JS, Reynolds LW, et al. Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis. Pain Pract. ; : Wininger SJ, Miller H, Minkowitz HS, Royal MA, Ang RY, Breitmeyer JB, Singla NK. A randomized, double-blind, placebo-controlled, multi-center, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther ; 3(): Pyxis Anesthesia System [product brochure], San Diego, CA: Carefusion;.. Arici S, Gurbet A, Turker G, et al. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri 9; :-. 9 Mallinckrodt, the M brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. Mallinckrodt. OFV 8/ OFIRMEV.com OFIRMEV a non-opioid, non-nsaid, intravenous analgesic for the management of pain An overview of Unmet needs in postoperative pain management Society recommendation of multimodal analgesia techniques for pain relief OFIRMEV pharmacokinetic and clinical information Utilization considerations for perioperative pain management OFIRMEV dosing information OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (ml) is not confused; the dosing is based on weight for patients under kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product. Please see additional Important Risk Information, including complete boxed warning, in accompanying Full Prescribing Information.

10 FOR PHARMACY PROFESSIONALS In pharmacokinetic studies Rapid time to reach Cmax with IV acetaminophen OFIRMEV from the start OFIRMEV g demonstrated early and high Cmax at minutes Consider administering OFIRMEV pre-op, then scheduling qh Less pain. Less opioids. From the start. Consider beginning your multimodal analgesic regimen with OFIRMEV Mean plasma concentrations of OFIRMEV g and oral acetaminophen g Time to reach Cmax (Tmax) 3 minutes faster than oral acetaminophen Mean plasma concentration (μg/ml) 3 CONTINUE WITH OFIRMEV IF: OFIRMEV g (N=38) Oral acetaminophen g (N=38) Schedule OFIRMEV qh for first hours...7 Open-label, single-center, randomized, -period crossover pharmacokinetic study involving healthy adult males (N=38). Subjects received a total of 8 doses each of OFIRMEV g qh, OFIRMEV g qh, oral acetaminophen g qh, and oral acetaminophen g qh divided among treatment periods (results for the first -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 -minute infusion. Parenteral analgesia is clinically warranted Compromised GI absorption or inability to take oral analgesics % bioavailability desired CONTRAINDICATIONS Acetaminophen is contraindicated in patients with: known hypersensitivity to acetaminophen or to any of the excipients in the intravenous (IV) formulation. severe hepatic impairment or severe active liver disease. TRANSITION TO ORAL ANALGESIA WHEN: WARNINGS AND PRECAUTIONS Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death. Do not exceed the maximum recommended daily dose of acetaminophen. The maximum recommended daily dose of acetaminophen includes all routes of acetaminophen administration and all acetaminophen-containing products administered, including combination products. Dosing errors could result in accidental overdose and death. Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance 3 ml/min). Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Hypersensitivity and anaphylaxis associated with the use of acetaminophen have been reported. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. The antipyretic effects of OFIRMEV may mask fever. Patient can take and absorb oral analgesics Cmax occurs at the end of the -minute IV infusion of OFIRMEV Overall exposure (AUC) after a single dose was similar to oral acetaminophen No significant accumulation with repeated dosing OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Consider beginning your IV analgesic regimen with OFIRMEV Do not exceed the maximum recommended daily limits of acetaminophen by all routes. The maximum total daily dose of OFIRMEV for adults kg is mg. Rapid onset of action No first-pass hepatic exposure Early and high Cmax % bioavailability Significant pain relief 9 Reduced opioid consumption9, Improved patient satisfaction8, Established safety profile and well tolerated in clinical trials,8-, Utilization considerations: Initiate early (pre-op or intra-op) Schedule qh for the first h or as long as clinically warranted Do not exceed the maximum recommended daily limits of acetaminophen by all routes. The maximum total daily dose of OFIRMEV for adults kg is mg. ADVERSE REACTIONS Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity, and anaphylaxis. Common adverse reactions in adults include nausea, vomiting, headache, and insomnia. Common adverse reactions in pediatric patients include nausea, vomiting, constipation, pruritus, agitation, and atelectasis. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. OFIRMEV should be given to a pregnant woman only if clearly needed. Breast Feeding: While studies with OFIRMEV have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration. Pediatrics: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients < years of age. OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. Please see additional Important Risk Information, including complete boxed warning, in accompanying Full Prescribing Information. References:. Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged [abstract A3]. Presented at: th Annual Pain Medicine Meeting; November -8, ; Miami, FL.. Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology 99; 83: 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 ; : Crews JC. Multimodal pain management strategies for office-based and ambulatory procedures. JAMA. ;88:9 3.. Data on File, Cadence Pharmaceuticals, a Mallinckrodt company.. OFIRMEV [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; Singla NK, Parulan C,. Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. Plasma and cerebrospinal fluid pharmacokinetic parameters after single dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. ;(7): Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology ;: Sinatra RS, Jahr JS, Reynolds LW, et al. Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis. Pain Pract. ; : Wininger SJ, Miller H, Minkowitz HS, Royal MA, Ang RY, Breitmeyer JB, Singla NK. A randomized, double-blind, placebo-controlled, multi-center, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther ; 3(): Pyxis Anesthesia System [product brochure], San Diego, CA: Carefusion;.. Arici S, Gurbet A, Turker G, et al. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri 9; :-. 9 Mallinckrodt, the M brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. Mallinckrodt. OFV 8/ OFIRMEV.com OFIRMEV a non-opioid, non-nsaid, intravenous analgesic for the management of pain An overview of Unmet needs in postoperative pain management Society recommendation of multimodal analgesia techniques for pain relief OFIRMEV pharmacokinetic and clinical information Utilization considerations for perioperative pain management OFIRMEV dosing information OFIRMEV (acetaminophen) injection is indicated for the management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever. WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (ml) is not confused; the dosing is based on weight for patients under kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product. Please see additional Important Risk Information, including complete boxed warning, in accompanying Full Prescribing Information.

11 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: 9 WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY See full prescribing information for complete boxed warning Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product (.) OFIRMEV (acetaminophen) injection is indicated for the Management of mild to moderate pain () Management of moderate to severe pain with adjunctive opioid analgesics () Reduction of fever () DOSAGE AND ADMINISTRATION OFIRMEV may be given as a single or repeated dose. (.) OFIRMEV should be administered only as a -minute intravenous infusion. (.) Adults and Adolescents Weighing kg and Over: mg every hours or mg every hours to a maximum of mg per day. Minimum dosing interval of hours. (.) Adults and Adolescents Weighing Under kg: mg/kg every hours or. mg/kg every hours to a maxi mum of 7 mg/kg per day. Minimum dosing interval of hours. (.) Children: Children to years of age: mg/kg every hours or. mg/kg every hours to a maximum of 7 mg/kg per day. Minimum dosing interval of hours. (.3) DOSAGE FORMS AND STRENGTHS Injection for intravenous infusion. Each ml glass vial contains mg acetaminophen ( mg/ml). (3) CONTRAINDICATIONS Acetaminophen is contraindicated: In patients with known hypersensitivity to acetaminophen or to any of the excipients in the IV formulation. () In patients with severe hepatic impairment or severe active liver disease. () WARNINGS AND PRECAUTIONS Administration of acetaminophen in doses higher than recommended (by all routes of administration and from all FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY DOSAGE AND ADMINISTRATION. General Dosing Information. Recommended Dosage: Adults and Adolescents.3 Recommended Dosage: Children. Instructions for Intravenous Administration 3 DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Hepatic Injury. Serious Skin Reactions.3 Risk of Medication Errors. Allergy and Hypersensitivity ADVERSE REACTIONS. Clinical Trial Experience 7 DRUG INTERACTIONS 7. Effects of other Substances on Acetaminophen 7. Anticoagulants 8 USE IN SPECIFIC POPULATIONS 8. Pregnancy acetaminophen-containing products including combination products) may result in hepatic injury, including the risk of liver failure and death. (.) Do not exceed the maximum recommended daily dose of acetaminophen (by all routes of administration and all acetaminophen-containing products including combination products). (.) Take care when prescribing, preparing, and administering OFIRMEV injection to avoid dosing errors which could result in accidental overdose and death. (.3) 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 at the first appearance of skin rash and if symptoms associated with allergy or hypersensitivity occur. Do not use in patients with aceta minophen allergy. (.,.) 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. (.) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt Hospital Products Inc. at or FDA at -8-FDA-88 or DRUG INTERACTIONS Substances that induce or regulate hepatic cytochrome enzyme CYPE may alter the metabolism of acetaminophen and increase its hepatotoxic potential. (7.) Chronic oral acetaminophen use at a dose of 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.) USE IN SPECIFIC POPULATIONS Pregnancy: Category C. There are no studies of intravenous acetaminophen in pregnant women. Use only if clearly needed. (8.) 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 years of age. The safety and effectiveness of OFIRMEV in pediatric patients older than years is supported by evidence from adequate and well controlled studies in adults with additional safety and pharmacokinetic data for this age group. (8.) Geriatric Use: No overall differences in safety or effectiveness were observed between geriatric and younger subjects. (8.) 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. (,., 8.) Renal Impairment: In cases of severe renal impairment, longer dosing intervals and a reduced total daily dose of acetaminophen may be warranted. (., 8.7) Revised: / 8. Labor and Delivery 8.3 Nursing Mothers 8. Pediatric Use 8. Geriatric Use 8. Patients with Hepatic Impairment 8.7 Patients with Renal Impairment OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mechanism of Action. Pharmacodynamics.3 Pharmacokinetics 3 NONCLINICAL TOXICOLOGY 3. Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES. Adult Acute Pain. Adult Fever.3 Pediatric Acute Pain and Fever HOW SUPPLIED/STORAGE AND HANDLING *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION WARNING: Risk of Medication Errors and Hepatotoxicity Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (ml) is not confused; the dosing is based on weight for patients under kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limits, and often involve more than one acetaminophencontaining product [see Warnings and Precautions (.)]. 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. DOSAGE AND ADMINISTRATION. 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 who weigh kg and above. Calculated maximum daily dose of acetaminophen is based on all routes of administration (i.e., intravenous, oral, and rectal) and all products containing acetaminophen. Exceeding the maximum mg/kg daily dose of acetaminophen as described in Tables and may result in hepatic injury, including the risk of liver failure and death. To avoid the risk of overdose, ensure that the total amount of acetaminophen from all routes and from all sources does not exceed the maximum recommended dose.. Recommended Dosage: Adults and Adolescents Adults and adolescents weighing kg and over: the recommended dosage of OFIRMEV is mg every hours or mg every hours, with a maximum single dose of OFIRMEV of mg, a minimum dosing interval of hours, and a maximum daily dose of acetaminophen of mg per day (includes all routes of administration and all acetaminophen-containing products including combination products). Adults and adolescents weighing under kg: the recommended dosage of OFIRMEV is mg/kg every hours or. mg/kg every hours, with a maximum single dose of OFIRMEV of mg/kg, a minimum dosing interval of hours, and a maximum daily dose of acetaminophen of 7 mg/kg per day (includes all routes of administration and all acetaminophencontaining products including combination products). Table. Dosing for Adults and Adolescents Age group Dose given every hours Dose given every hours Maximum single dose Maximum total daily dose of acetaminophen (by all routes) Adults and adolescents (3 years and older) weighing kg mg mg mg mg in hours Adults and adolescents (3 years and older) weighing < kg. mg/kg mg/kg mg/kg (up to 7 mg) 7 mg/kg in hours (up to 37 mg).3 Recommended Dosage: Children Children to years of age: the recommended dosage of OFIRMEV is mg/kg every hours or. mg/kg every hours, with a maximum single dose of OFIRMEV of mg/kg, a minimum dosing interval of hours, and a maximum daily dose of acetaminophen of 7 mg/kg per day. Table. Dosing for Children Age group Children to years of age Dose given every hours Dose given every hours Maximum single dose. mg/kg mg/kg mg/kg (up to 7 mg) Maximum total daily dose of acetaminophen (by all routes) 7 mg/kg in hours (up to 37 mg). Instructions for Intravenous Administration For adult and adolescent patients weighing kg requiring mg doses of OFIRMEV, administer the dose by inserting a vented intravenous set through the septum of the 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 -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 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 ( mg or weight-based) 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 ml vial of OFIRMEV is not intended for use in patients weighing less than kg. OFIRMEV is a single-use vial and the unused portion must be discarded. Place small volume pediatric doses up to ml in volume in a syringe and administer over 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 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 ml glass vial contains mg acetaminophen ( mg/ml). 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 (.)]. WARNINGS AND PRECAUTIONS. Hepatic Injury Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death [see Overdosage ()]. Do not exceed the maximum recommended daily dose of acetaminophen [see Dosage and Administration ()]. The maximum recommended daily dose of acetaminophen includes all routes of acetaminophen administration and all acetaminophen-containing products administered, including combination products. 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., 8.7)].. Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity..3 Risk of Medication Errors Take care when prescribing, preparing, and administering OFIRMEV (acetaminophen) Injection in order to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (ml) is not confused; the dosing is based on weight for patients under kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits [see Dosage and Administration ()].. 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. ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Hepatic Injury [see Warnings and Precautions (.)] Serious Skin Reactions [see Warnings and Precautions (.)] Allergy and Hypersensitivity [see Warnings and Precautions (.)]. 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 adult patients have received OFIRMEV in clinical trials, including 37.3% (n=38) who received or more doses, and 7.% (n=73) who received more than doses. Most patients were treated with OFIRMEV mg every hours. A total of 3.% (n=3) received OFIRMEV mg every 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 3. The most common adverse events in adult patients treated with OFIRMEV (incidence % and greater than placebo) were nausea, vomiting, headache, and insomnia. Table 3. Treatment-Emergent Adverse Reactions Occurring in 3% of OFIRMEV-treated Patients and at a greater frequency than Placebo in Placebo-Controlled, Repeated Dose Studies System Organ Class Preferred Term Gastrointestinal Disorders Nausea Vomiting OFIRMEV (N=) n (%) 38 (3) () Placebo (N=379) n (%) 9 (3) () General Disorders and Administration Site Conditions Pyrexia* () () Nervous System Disorders Headache 39 () 33 (9) Psychiatric Disorders Insomnia 3 (7) () * 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=) that occurred with an incidence of at least % and at a frequency greater than placebo (n=). 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 3 pediatric patients (7 neonates, infants, 7 children, and 73 adolescents) have received OFIRMEV in active-controlled (n=) and open-label clinical trials (n=), including 9.7% (n=) who received or more doses and 3.% (n=3) who received more than doses. Pediatric patients received OFIRMEV doses up to mg/kg on an every hours, every hours, or every 8 hours schedule. The maximum exposure was 7.7,.,.8, and 7. days in neonates, infants, children, and adolescents, respectively. The most common adverse events (incidence %) 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=3) that occurred with an incidence of at least %. 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, hypo kalemia, 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