Acetaminophen (Page 2 of 5)

2.5 Instructions for Intravenous Administration

For adult and adolescent patients weighing ≥ 50 kg requiring 1000 mg doses of acetaminophen injection, administer the dose by inserting a non-vented intravenous set through the administration spike port of the 100 mL bag. Acetaminophen injection may be administered without further dilution. Examine the container contents before dose preparation or administering. DO NOT USE if particulate matter or discoloration is observed. Administer the contents of the container intravenously over 15 minutes. Use aseptic technique when preparing acetaminophen injection for intravenous infusion. Do not add other medications to the acetaminophen injection infusion device.

For doses less than 1000 mg, the appropriate dose must be withdrawn from the container and placed into a separate container prior to administration.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 acetaminophen injection container 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 container of acetaminophen injection is not intended for use in patients weighing less than 50 kg. Acetaminophen injection is supplied in a single-dose container 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 acetaminophen injection infusion is the primary infusion.

Once the container seal has been penetrated, or the contents transferred to another container, administer the dose of acetaminophen injection within 6 hours.

Refrain from applying excessive pressure causing distortion to the bag, such as wringing or twisting, since such handling could result in breakage of the bag.

Do not add other medications to the acetaminophen injection solution. Diazepam and chlorpromazine hydrochloride are physically incompatible with acetaminophen injection, therefore do not administer simultaneously.

3 DOSAGE FORMS AND STRENGTHS

Acetaminophen injection is a sterile, clear, colorless to slightly yellow colored, non-pyrogenic, preservative free, isotonic formulation of acetaminophen intended for intravenous infusion. Each 100 mL bag contains 1000 mg acetaminophen (10 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 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 acetaminophen 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 acetaminophen immediately if symptoms associated with allergy or hypersensitivity occur. Do not use acetaminophen 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)]

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 patient have received acetaminophen 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 acetaminophen 1000 mg every 6 hours. A total of 13.1% (n=134) received acetaminophen 650 mg every 4 hours.

All adverse reactions that occurred in adult patients treated with either acetaminophen 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 acetaminophen (incidence ≥ 5% and greater than placebo) were nausea, vomiting, headache, and insomnia.

Table 4. Treatment-Emergent Adverse Reactions Occurring in ≥ 3% of Acetaminophen-treated Adult Patients and at a Greater Frequency than Placebo in Placebo-Controlled, Repeated Dose Studies

System Organ Class – Preferred Term

Acetaminophen

(N=402)

n (%)

Placebo

(N=379)

n (%)

Gastrointestinal Disorders

Nausea
Vomiting

138 (34)

62 (15)

119 (31)

42 (11)

General Disorders and Administration Site Conditions

Pyrexia*

22 (5)

52 (14)

Nervous System Disorders

Headache

39 (10)

33 (9)

Psychiatric Disorders

Insomnia

30 (7)

21 (5)

*Pyrexia adverse reaction frequency data is included in order to alert healthcare practitioners that the antipyretic effects of acetaminophen may mask fever.

Other Adverse Reactions Observed During Clinical Studies of Acetaminophen in Adults

The following additional treatment-emergent adverse reactions were reported by adult subjects treated with acetaminophen 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 acetaminophen 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 acetaminophen 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 acetaminophen were nausea, vomiting, constipation, and pruritus.

Other Adverse Reactions Observed During Clinical Studies of Acetaminophen in Pediatrics

The following additional treatment-emergent adverse reactions were reported by pediatric subjects treated with acetaminophen (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

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