FDA label c5662877-ba4e-4f2b-a64e-3ecab2358a53

WARNING: Risk of Medication Errors and Hepatotoxicity Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (mL) is not confused; the dosing is based on weight for patients under 50 kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limits, and often involve more than one acetaminophen-containing product [see Warnings and Precautions (5.1) ] . 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. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Administration of acetaminophen in doses higher than recommended (by all routes of administration and from all acetaminophen-containing products including combination products) may result in hepatic injury, including the risk of liver failure and death. ( 5.1 ) 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 ≤ 30 mL/min). ( 5.1 ) 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 acetaminophen allergy. ( 5.2 , 5.4 ) Take care when prescribing, preparing, and administering OFIRMEV injection to avoid dosing errors which could result in accidental overdose and death. ( 5.3 ) 5.1 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 (10) ] . Do not exceed the maximum recommended daily dose of acetaminophen [see Dosage and Administration (2) ] . 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 ≤ 30 mL/min) [see Use in Specific Populations (8.6 , 8.7) ] . 5.2 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. 5.3 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 50 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 (2) ] . 5.4 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) ] Serious Skin Reactions [see Warnings and Precautions (5.2) ] Allergy and Hypersensitivity [see Warnings and Precautions (5.4) ] The most common adverse reactions in patients treated with OFIRMEV were nausea, vomiting, headache, and insomnia in adult patients; nausea, vomiting, constipation, and pruritus in pediatric patients. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt Hospital Products Inc. at 1-800-844-2830 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 1020 adult patients have received OFIRMEV in clinical trials, including 37.3% (n=380) who received 5 or more doses, and 17.0% (n=173) who received more than 10 doses. Most patients were treated with OFIRMEV 1000 mg every 6 hours. A total of 13.1% (n=134) received OFIRMEV 650 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 4. The most common adverse events in adult patients treated with OFIRMEV (incidence ≥ 5% and greater than placebo) were nausea, vomiting, headache, and insomnia. Table 4. Treatment-Emergent Adverse Reactions Occurring in ≥ 3% of OFIRMEV-treated Adult Patients and at a Greater Frequency than Placebo in Placebo-Controlled, Repeated Dose Studies System Organ Class – Preferred Term OFIRMEV (N=402) n (%) Placebo (N=379) n (%) Gastrointestinal Disorders Nausea 138 (34) 119 (31) Vomiting 62 (15) 42 (11) General Disorders and Administration Site Conditions Pyrexia Pyrexia adverse reaction frequency data is included in order to alert healthcare practitioners that the antipyretic effects of OFIRMEV may mask fever. 22 (5) 52 (14) Nervous System Disorders Headache 39 (10) 33 (9) Psychiatric Disorders Insomnia 30 (7) 21 (5) 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=1020) 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 483 pediatric patients (72 neonates, 167 infants, 171 children, and 73 adolescents) have received OFIRMEV in active-controlled (n=250) and open-label clinical trials (n=225), including 43.9% (n=212) who received 5 or more doses and 31.2% (n=153) who received more than 10 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, and pruritus. 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=483) that occurred with an incidence of at least 1%. Blood and lymphatic system disorders : anemia Gastrointestinal disorders : diarrhea General disorders and administration site conditions : pyrexia, injection site pain Metabolism and nutrition disorders : hypokalemia, hypomagnesemia, hypoalbuminemia, hypophosphatemia Musculoskeletal and connective tissue disorders : muscle spasm Nervous system disorders : headache Psychiatric disorders : agitation Renal and urinary disorders : oliguria Respiratory, thoracic and mediastinal disorders : atelectasis, pleural effusion, pulmonary edema, stridor, wheezing Vascular disorders : hypotension, hypertension

<table width="75%"><caption>Table 4. Treatment-Emergent Adverse Reactions Occurring in &#x2265; 3% of OFIRMEV-treated Adult Patients and at a Greater Frequency than Placebo in Placebo-Controlled, Repeated Dose Studies</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="bottom"/><col width="25%" align="center" valign="bottom"/><thead><tr><th styleCode="Lrule Rrule">System Organ Class &#x2013; Preferred Term</th><th styleCode="Rrule">OFIRMEV (N=402) n (%)</th><th styleCode="Rrule">Placebo (N=379) n (%)</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">138 (34)</td><td styleCode="Rrule">119 (31)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">62 (15)</td><td styleCode="Rrule">42 (11)</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia<footnote>Pyrexia adverse reaction frequency data is included in order to alert healthcare practitioners that the antipyretic effects of OFIRMEV may mask fever.</footnote></td><td styleCode="Rrule">22 (5)</td><td styleCode="Rrule">52 (14)</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">39 (10)</td><td styleCode="Rrule">33 (9)</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric Disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">30 (7)</td><td styleCode="Rrule">21 (5)</td></tr></tbody></table>