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Brief Summary (For full Prescribing Information refer to package insert.) 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: t the dose in milligrams (mg) and milliliters (mL) is not confused; t the dosing is based on weight for patients under 50 kg; t infusion pumps are properly programmed; and t 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). 1 INDICATIONS AND USAGE OFIRMEV® (acetaminophen) injection is indicated for t the management of mild to moderate pain t the management of moderate to severe pain with adjunctive opioid analgesics t 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 who weigh 50 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 1 and 2 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. 2.2 Recommended Dosage: Adults and Adolescents Adults and adolescents weighing 50 kg and over: the recommended dosage of OFIRMEV is 1000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of OFIRMEV of 1000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 4000 mg per day (includes all routes of administration and all acetaminophen-containing products including combination products). Adults and adolescents weighing under 50 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 (includes all routes of administration and all acetaminophen-containing products including combination products). Table 1: Dosing for Adults and Adolescents 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. Table 2: Dosing for Children 2.4 Instructions for Intravenous Administration For adult and adolescent patients weighing ≥ 50 kg requiring 1000 mg doses of OFIRMEV, administer the dose by inserting a vented intravenous set through the septum of the 100 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 1000 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 (650 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 100 mL vial of OFIRMEV is not intended for use in patients weighing less than 50 kg. OFIRMEV is a single-use vial and the unused portion must be discarded. Place small volume pediatric doses up to 60 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 100 mL glass vial contains 1000 mg acetaminophen (10 mg/mL). 4 CONTRAINDICATIONS Acetaminophen is contraindicated: t in patients with known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation. t in patients with severe hepatic impairment or severe active liver disease. 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 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. 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). 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 rst 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: t the dose in milligrams (mg) and milliliters (mL) is not confused; t the dosing is based on weight for patients under 50 kg; t infusion pumps are properly programmed; and t the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. Age group Adults and adolescents (13 years and older) weighing ≥ 50 kg Adults and adolescents (13 years and older) weighing < 50 kg Dose given every 4 hours Dose given every 6 hours Maximum single dose Maximum total daily dose of acetaminophen (by all routes) 650 mg 1000 mg 1000 mg 4000 mg in 24 hours 12.5 mg/kg 15 mg/kg 15 mg/kg (up to 750 mg) 75 mg/kg in 24 hours (up to 3750 mg) Age group Children 2 to 12 years of age Dose given every 4 hours Dose given every 6 hours Maximum single dose Maximum total daily dose of acetaminophen (by all routes) 12.5 mg/kg 15 mg/kg 15 mg/kg (up to 750 mg) 75 mg/kg in 24 hours (up to 3750 mg) 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 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 Cadence Pharmaceuticals Inc. at 1-877-647-2239 or FDA at 1-800-FDA- 1088 or www.fda.gov/medwatch. 7 DRUG INTERACTIONS 7.1 Eects 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 eects have not been established. Eects 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 4000 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. As no studies have been performed evaluating the short-term use of OFIRMEV in patients on oral anticoagulants, more frequent assessment of INR may be appropriate in such circumstances. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no studies of intravenous acetaminophen in pregnant women. OFIRMEV should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers Caution should be exercised when OFIRMEV is administered to a nursing woman. 8.4 Pediatric Use Pediatric Use: The eectiveness 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 eectiveness 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. 8.5 Geriatric Use No overall dierences in safety or eectiveness were observed between geriatric subjects and younger subjects. 8.6 Patients with 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. A reduced total daily dose of acetaminophen may be warranted. 8.7 Patients with Renal Impairment In cases of severe renal impairment (creatinine clearance ≤ 30 mL/min), longer dosing intervals and a reduced total daily dose of acetaminophen may be warranted. Manufactured for: Cadence Pharmaceuticals, Inc. San Diego, CA 92130 Revised 1/2014 U.S. PATENT NUMBERS: 6,028,222; 6,992,218 OFIRMEV ® and CADENCE ® are trademarks of Cadence Pharmaceuticals, Inc. © 2014 Cadence Pharmaceuticals, Inc. All rights reserved. OFV12821013BS