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Acetadote

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These highlights do not include all the information needed to use Acetadote safely and effectively. See full prescribing information for Acetadote.ACETADOTE (acetylcysteine) InjectionInitial U.S. Approval: 2004

Acetadote, administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen, is indicated to prevent or lessen hepatic injury [see Dosage and Administration (2) and Acetaminophen Assays – Interpretation and Methodology (1.1, 1.2)].

On admission for suspected acetaminophen overdose, a serum blood sample should be drawn at least 4 hours after ingestion to determine the acetaminophen level and will serve as a basis for determining the need for treatment with acetylcysteine. If the patient presents after 4 hours post-ingestion, the serum acetaminophen sample should be determined immediately.

Acetadote should be administered within 8 hours from acetaminophen ingestion for maximal protection against hepatic injury for patients whose serum acetaminophen levels fall above the “possible” toxicity line on the Rumack-Matthew nomogram (line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours); [see Acetaminophen Assays – Interpretation and Methodology (1.1, 1.2)]. If the time of ingestion is unknown, or the serum acetaminophen level is not available, cannot be interpreted, or is not available within the 8 hour time interval from acetaminophen ingestion, Acetadote should be administered immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen, regardless of the quantity reported to have been ingested.

The aspartate aminotransferase (AST, SGOT), alanine aminotranferase (ALT, SGPT), bilirubin, prothrombin time, creatinine, blood urea nitrogen (BUN), blood glucose, and electrolytes also should be determined in order to monitor hepatic and renal function and electrolyte and fluid balance.

NOTE: The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between 0 – 8 hours. Efficacy diminishes progressively after 8 hours and treatment initiation between 15 and 24 hours post-ingestion of acetaminophen yields limited efficacy. However, it does not appear to worsen the condition of patients and it should not be withheld, since the reported time of ingestion may not be correct.

The acute ingestion of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic toxicity. However, the reported history of the quantity of a drug ingested as an overdose is often inaccurate and is not a reliable guide to therapy of the overdose. Therefore, plasma or serum acetaminophen concentrations, determined as early as possible, but no sooner than four hours following an acute overdose, are essential in assessing the potential risk of hepatotoxicity. If an assay for acetaminophen cannot be obtained, it is necessary to assume that the overdose is potentially toxic.

Interpretation of Acetaminophen Assays

Estimating Potential for Hepatotoxicity: The following depiction of the Rumack-Matthew nomogram has been developed to estimate the probability that plasma levels in relation to intervals post-ingestion will result in hepatotoxicity.

Figure 1. Rumack-Matthew Nomogram: Plasma or Serum Acetaminophen Concentration vs. Time Post Acetaminophen Ingestion (Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876 and Rumack BH, Peterson RC, Kock GG, Amara IA. Acetaminophen overdose. 662 cases with eva luation of oral acetylcysteine treatment. Arch Intern Med. 1981;141:380-385).

Repeated Supratherapeutic Ingestion (RSI) is defined as ingestion of acetaminophen at doses higher than those recommended for extended periods of time. The nomogram does not apply to patients with RSI. Treatment is based on the acetaminophen and elevated AST/ALT levels indicative of potential toxicity due to acetaminophen. For specific treatment information regarding the clinical management of repeated supratherapeutic acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.

Figure 2. Acetadote Treatment Flow Chart

*Acetaminophen levels drawn less than 4 hours post-ingestion may be misleading.

# With an extended-release preparation, an acetaminophen level drawn less than 8 hours post-ingestion may be misleading. Draw a second level at 4 to 6 hours after the initial level. If either falls above the toxicity line, acetylcysteine treatment should be initiated.

***Acetylcysteine may be withheld until acetaminophen assay results are available as long as initiation of treatment is not delayed beyond 8 hours post-ingestion. If more than 8 hours post-ingestion, start acetylcysteine treatment immediately.

The total dose of Acetadote is 300 mg/kg administered over 21 hours. Please refer to the guidelines below for dose preparation based upon patient weight.

Patients > 40 kg (Table 1):

The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction:

Patients >20 - <40 kg (Table 2):

Patients < 20 kg (Table 3):

Single dose vial, preservative-free, discard unused portion. If vial was previously opened, do not use for I.V. administration.

Stability studies indicate that the diluted solution is stable for 24 hours at controlled room temperature.

Note: The color of Acetadote may turn from essentially colorless to a slight pink or purple once the stopper is punctured. The color change does not affect the quality of the product.

Table 1. Three-Bag Method Dosage Guide by Weight, patients≥ 40 kg
Body Weight		LOADING Dose 150 mg/kg in	SECOND Dose 50 mg/kg in	THIRD Dose 100 mg/kg in
		200 mL diluent over 60 min	500mL diluent over 4 hours	1000mL diluent over 16 hours
(kg)	(lb)	Acetadote (mL)	Acetadote (mL)	Acetadote (mL)
100	220	75	25	50
90	198	67.5	22.5	45
80	176	60	20	40
70	154	52.5	17.5	35
60	132	45	15	30
50	110	37.5	12.5	25
40	88	30	10	20

Table 2. Three-Bag Method Dosage Guide by Weight, patients >20 - < 40 kg
Body Weight		LOADING Dose 150 mg/kg over 60 minutes		SECOND Dose 50 mg/kg over 4 hours		THIRD Dose 100 mg/kg over 16 hours
(kg)	(lb)	Acetadote (mL)	Diluent^◊ (mL)	Acetadote (mL)	Diluent (mL)	Acetadote (mL)	Diluent (mL)
30	66	22.5	100	7.5	250	15	500
25	55	18.75	100	6.25	250	12.5	500

Table 3. Three-Bag Method Dosage Guide by Weight, patients≤ 20 kg
^◊Acetadote is hyperosmolar (2600 mOsm/L) and is compatible with 5% Dextrose (D5W), ½ Normal Saline (0.45% Sodium Chloride Injection, ½ NS), and Water for Injection (WFI).
Body Weight		LOADING Dose 150 mg/kg over 60 minutes		SECOND Dose 50 mg/kg over 4 hours		THIRD Dose 100 mg/kg over 16 hours
(kg)	(lb)	Acetadote (mL)	Diluent^◊ (mL)	Acetadote (mL)	Diluent (mL)	Acetadote (mL)	Diluent (mL)
20	44	15	60	5	140	10	280
15	33	11.25	45	3.75	105	7.5	210
10	22	7.5	30	2.5	70	5	140

No data are available to determine if a dose adjustment in patients with moderate or severe renal impairment is required.

Although there was a threefold increase in acetylcysteine plasma concentrations in patients with hepatic cirrhosis, no data are available to determine if a dose adjustment in these patients is required. The published medical literature does not indicate that the dose of acetylcysteine in patients with hepatic impairment should be reduced.

Acetadote (acetylcysteine) Injection is available as a 20% solution (200mg/mL) in 30 mL single dose glass vials. Acetadote is sterile and can be used for I.V. administration.

Acetadote is contraindicated in patients with previous anaphylactoid reactions to acetylcysteine.

Serious anaphylactoid reactions, including death in a patient with asthma, have been reported in patients administered acetylcysteine intravenously.

Acute flushing and erythema of the skin may occur in patients receiving acetylcysteine intravenously. These reactions usually occur 30 to 60 minutes after initiating the infusion and often resolve spontaneously despite continued infusion of acetylcysteine. Anaphylactoid reactions (defined as the occurrence of an acute hypersensitivity reaction during acetylcysteine administration including rash, hypotension, wheezing, and/or shortness of breath) have been observed in patients receiving I.V. acetylcysteine for acetaminophen overdose and occurred soon after initiation of the infusion [see Adverse Reactions (6.1)]. If a reaction to acetylcysteine involves more than simply flushing and erythema of the skin, it should be treated as an anaphylactoid reaction. This usually entails administering antihistaminic drugs and in severe cases may require administration of epinephrine. In addition, the acetylcysteine infusion may be interrupted until treatment of the anaphylactoid symptoms has been initiated and then carefully restarted. If the anaphylactoid reaction returns upon reinitiation of treatment or increases in severity, intravenous acetylcysteine should be discontinued and alternative patient management should be considered.

Acetadote should be used with caution in patients with asthma, or where there is a history of bronchospasm.

The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. To avoid fluid overload, the volume of diluent should be reduced as needed [see Dosage and Administration (2)]. If volume is not adjusted fluid overload can occur, potentially resulting in hyponatremia, seizure and death.

For specific treatment information regarding the clinical management of acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the literature the most frequently reported adverse reactions attributed to I.V. acetylcysteine administration were rash, urticaria and pruritus. The frequency of adverse reactions has been reported to be between 0.2% and 20.8%, and they most commonly occur during the initial loading dose of acetylcysteine.

Loading Dose/Infusion Rate Study

The incidence of drug-related adverse reactions occurring within the first 2 hours following acetylcysteine administration reported in a randomized study in patients with acetaminophen poisoning is presented in Table 4 by preferred term. In this study patients were randomized to a 15-minute or a 60-minute loading dose regimen.

Within the first 2 hours following I.V. acetylcysteine administration, 17% developed an anaphylactoid reaction (18% in the 15-minute treatment group; 14% in the 60-minute treatment group) in this randomized, open-label, multi-center clinical study conducted in Australia to compare the rates of anaphylactoid reactions between two rates of infusion for the I.V. acetylcysteine loading dose [see Warnings (Section 5) and Clinical Studies - Loading Dose/Infusion Rate Study (Section 14)].

Table 4. Incidence of Drug-Related Adverse Reactions Occurring Within the First 2 Hours Following Study Drug Administration by Preferred Term: Loading Dose/Infusion Rate Study
Unkn=Unknown
Treatment Group	15-min				60-min
Number of Patients	n=109				n=71
Cardiac disorders	5 (5%)				2 (3%)
Severity:	Unkn	Mild	Moderate	Severe	Unkn	Mild	Moderate	Severe
Tachycardia NOS		4 (4%)	1 (1%)			2 (3%)
Gastrointestinal disorders	16 (15%)				7 (10%)
Severity:	Unkn	Mild	Moderate	Severe	Unkn	Mild	Moderate	Severe
Nausea	1 (1%)		6 (6%)			1 (1%)	1 (1%)
Vomiting NOS		2 (2%)	11 (10%)			2 (3%)	4 (6%)
Immune System Disorders	20 (18%)				10 (14%)
Severity:	Unkn	Mild	Moderate	Severe	Unkn	Mild	Moderate	Severe
Anaphylactoid reaction	2 (2%)	6 (6%)	11 (10%)	1 (1%)		4 (6%)	5 (7%)	1 (1%)
Respiratory, thoracic and mediastinal disorders	2 (2%)				2 (3%)
Severity:	Unkn	Mild	Moderate	Severe	Unkn	Mild	Moderate	Severe
Pharyngitis			1 (1%)
Rhinorrhoea		1 (1%)
Rhonchi						1 (1%)
Throat tightness						1 (1%)
Skin & subcutaneous tissue disorders	6 (6%)				5 (7%)
Severity:	Unkn	Mild	Moderate	Severe	Unkn	Mild	Moderate	Severe
Pruritus		1 (1%)				2 (3%)
Rash NOS		3 (3%)	2 (2%)			3 (4%)
Vascular disorders	2 (2%)				3 (4%)
Severity:	Unkn	Mild	Moderate	Severe	Unkn	Mild	Moderate	Severe
Flushing		1 (1%)	1 (1%)			2 (3%)	1 (1%)

Postmarketing Safety Study

A large multi-center study was performed in Canada where data were collected from patients who were treated with I.V. NAC for acetaminophen overdose between 1980 and 2005. This study eva luated 4709 adult cases and 1905 pediatric cases. The incidence of anaphylactoid reactions in adult (overall incidence 7.9%) and pediatric (overall incidence 9.5%) patients is presented in Tables 5 and 6.

Table 5. Distribution of reported reactions in adult patients receiving I.V. NAC
	Incidence (%)
Reaction	% of Patients (n=4709)
Urticaria/Facial Flushing	6.1%
Pruritus	4.3%
Respiratory Symptoms*	1.9%
Edema	1.6%
Hypotension	0.1%
Anaphylaxis	0.1%

Table 6. Distribution of reported reactions in pediatric patients receiving I.V. NAC
*Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm.
	Incidence (%)
Reaction	% of Patients (n=1905)
Urticaria/Facial Flushing	7.6%
Pruritus	4.1%
Respiratory Symptoms*	2.2%
Edema	1.2%
Anaphylaxis	0.2%
Hypotension	0.1%

No drug-drug interaction studies have been conducted.

Pregnancy Category B

There are no adequate and well-controlled studies of Acetadote in pregnant women. However, limited case reports of pregnant women exposed to acetylcysteine during various trimesters did not report any adverse maternal, fetal or neonatal outcomes.

There are published reports on four pregnant women with acetaminophen toxicity, who were treated with oral or intravenous acetylcysteine at the time of delivery. Acetylcysteine crossed the placenta and was measurable following delivery in serum and cord blood of three viable infants and in cardiac blood of a fourth infant at autopsy (22 weeks gestational age who died 3 hours after birth). No adverse sequelae developed in the three viable infants. All mothers recovered and none of the infants had evidence of acetaminophen poisoning.

Reproductive and developmental toxicity studies performed in rats at oral doses up to 6.7 times the recommended human intravenous dose and in rabbits at doses up to 3.3 times the recommended human intravenous dose revealed no evidence of impaired fertility or embryofetal toxicity [see Reproductive and Developmental Toxicology (13.3)].

It is not known whether Acetadote is present in human milk. Because many drugs are excreted in human milk, caution should be exercised when acetylcysteine is administered to a nursing woman. Based on the pharmacokinetics of acetylcysteine, it should be nearly completely cleared 30 hours after administration. Nursing women may consider resuming nursing 30 hours after administration.

No adverse effects were noted during I.V. infusion with acetylcysteine at a mean rate of 4.2 mg/kg/h for 24 hours to 10 preterm newborns ranging in gestational age from 25 to 31 weeks and in weight from 500 to 1380 grams in one study or in 6 newborns ranging in gestational age from 26 to 30 weeks and in weight from 520 to 1335 grams infused with acetylcysteine at 0.1 to 1.3 mg/kg/h for 6 days. Elimination of acetylcysteine was slower in these infants than in adults; mean elimination half-life was 11 hours. There are no adequate and well-controlled studies in pediatric patients.

The clinical studies do not provide a sufficient number of geriatric subjects to determine whether the elderly respond differently.

Single intravenous doses of acetylcysteine at 1000 mg/kg in mice, 2445 mg/kg in rats, 1500 mg/kg in guinea pigs, 1200 mg/kg in rabbits and 500 mg/kg in dogs were lethal. Symptoms of acute toxicity were ataxia, hypoactivity, labored respiration, cyanosis, loss of righting reflex and convulsions.

Acetylcysteine injection is an intravenous (I.V.) medication for the treatment of acetaminophen overdose. Acetylcysteine is the nonproprietary name for the N-acetyl derivative of the naturally occurring amino acid, L-cysteine (N-acetyl-L-cysteine, NAC). The compound is a white crystalline powder, which melts in the range of 104° to 110°C and has a very slight odor. The molecular formula of the compound is CHNOS, and its molecular weight is 163.2. Acetylcysteine has the following structural formula:

Acetadote is supplie