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Acetadote (Acetylcysteine Injection) - Summary

 
 



ACETADOTE SUMMARY

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.

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.

Acetaminophen Assays Interpretation and Methodology — Acute Ingestion

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

  1. When results of the plasma acetaminophen assay are available, refer to the nomogram in Figure 1 to determine if plasma concentration is in the potentially toxic range. Values above the line connecting 200 mcg/mL at 4 hours with 50 mcg/mL at 12 hours (probable line) are associated with a probability of hepatic toxicity if an antidote is not administered.
  2. If the predetoxification plasma level is above the line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours (possible line), continue with maintenance doses of acetylcysteine. It is better to err on the safe side and thus this line, defining possible toxicity, is plotted 25% below the line defining probable toxicity.
  3. If the predetoxification plasma level is below the line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours (possible line), there is minimal risk of hepatic toxicity, and acetylcysteine treatment may be discontinued.

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 evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141:380-385).

Acetaminophen Assays Interpretation and Methodology — Repeated Supratherapeutic Ingestion

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.


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NEWS HIGHLIGHTS

Published Studies Related to Acetadote (Acetylcysteine Injection)

Potentially detrimental effects of N-acetylcysteine on renal function in knee arthroplasty. [2009.07]
Ischaemia/reperfusion induces systemic inflammation and oxidative stress and thereby remote organ injury in the kidney. In a double-blind, placebo-controlled clinical trial of 30 patients undergoing knee arthroplasty with tourniquet, this study evaluated the effect of N-acetylcysteine (NAC) infusion on renal function by measuring urine alpha-1-microglobulin, N-acetyl-beta-D-glucosaminidase (NAG), glutathione-S-transferase-alpha and -phi and serum creatinine and cystatin C concentrations up to 24 h post-operatively...

Nephrotoxic effects of iodixanol and iopromide in patients with abnormal renal function receiving N-acetylcysteine and hydration before coronary angiography and intervention: a randomized trial. [2009.01]
BACKGROUND: The use of contrast agents during coronary intervention can result in nephropathy, particularly in patients with renal dysfunction. We aimed to determine whether the use of iso-osmolar iodixanol is less nephrotoxic than that of low-osmolar iopromide when patients are adequately prehydrated and have received N-acetylcysteine... CONCLUSION: There remains a high incidence of CIN despite prehydration and routine use of N-acetylcysteine in patients with pre-existing renal dysfunction undergoing coronary interventional procedures. Although our study is underpowered, iodixanol was not associated with a statistically significant lower incidence of CIN when compared with iopromide.

Is treatment with N-acetylcysteine to prevent contrast-induced nephropathy when using bicarbonate hydration out of date? [2008.12]
AIMS: Chronic renal failure (CRF) is a major risk factor for contrast-induced nephropathy (CIN) and could be prevented by bicarbonate hydration. The effect of N-acetylcysteine (NAC) in preventing CIN in patients treated by bicarbonate hydration has never been investigated... CONCLUSION: In CRF patients undergoing cardiac angiography, the use of bicarbonate hydration is associated with a very low incidence of CIN. In these conditions, on the basis of our results, we cannot draw any meaningful conclusion on the effect of NAC on the prevention of CIN.

Improved estimation of glomerular filtration rate by serum cystatin C in preventing contrast induced nephropathy by N-acetylcysteine or zinc--preliminary results. [2008.04]
BACKGROUND: Prevention of contrast media (CM) induced nephropathy (CIN) by prophylaxis (e.g. N-acetylcysteine; NAC) is controversially discussed. Up to now, assessment of kidney function has been based on measurements of serum creatinine, although this biomarker has several limitations. We investigated NAC and zinc (Zn) for the prevention of CIN by monitoring creatinine and cystatin C... CONCLUSIONS: Cystatin C seems to reflect CM-induced changes in kidney function better than creatinine. NAC and Zn have no effect in preventing CIN by the standard definition, but based on cystatin C we can confirm a preventive effect of NAC. It appears mandatory to assess kidney function by cystatin C in CIN intervention trials, because relying on creatinine can be misleading.

I.v. N-acetylcysteine and emergency CT: use of serum creatinine and cystatin C as markers of radiocontrast nephrotoxicity. [2007.09]
CONCLUSION: On the basis of serum creatinine concentration only, i.v. administration of NAC appears protective against the nephrotoxicity of contrast medium. No effect is found when serum cystatin C concentration is used to assess renal function. The effect of NAC on serum creatinine level remains unclear and may not be related to a renoprotective action.

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Clinical Trials Related to Acetadote (Acetylcysteine Injection)

Safety and Efficacy Study of a New Formulation of Acetylcysteine Injection [Recruiting]
The primary purpose of this study is determine if a new formulation of Acetadote is at least as effective as the current formulation in the prevention and treatment of acetaminophen overdose related liver injury.

Methylprednisolone N Acetylcysteine in Hepatic Resections [Recruiting]
This is a prospective double-blind randomized phase II clinical trial, with two groups of intervention (one with administration of N-acetylcysteine and the other with administration of methylprednisolone), and one group of placebo. The purpose of this study is to investigate the role of N-acetylcysteine and Methylprednisolone in the modulation of warm ischemia of the liver during hepatic resection. In fact to avoid massive blood loss in liver surgery, continuous or intermittent vascular clamping of the hepatic hilum ('Pringle maneuver') is generally used with good results. However, as a consequence, ischemia and subsequent reperfusion result in complex metabolic, immunological, and microvascular changes, which together might contribute to hepatocellular damage and dysfunction. This phenomenon, known as ischemia-reperfusion (IR) injury of the liver, is a complex multi-path process leading to the activation of some inflammatory pathways. Any patient candidate to liver resection will be enrolled in the study based on the aforementioned criteria. The primary objective of the study is to assess the real efficacy of Methylprednisolone and N-acetylcysteine in reducing the secondary damage from ischemia reperfusion injury in liver resection and in reducing inflammatory response. Secondary objective of the study is whether the reduction of ischemia-reperfusion injury results in: lower incidence of postoperative liver failure, improvement of postoperative liver function, and reduction of blood components transfusions. The randomization will be done the day before the operation. The drugs will be prepared in a blind fashion by the hospital pharmacy. The hospital pharmacy will provide to each patient a drip to make bolus of about an hour before the start of the liver resection and a syringe pump for an infusion of approximately 6 hours. If the patient is enrolled and randomized in the placebo arm, he/she will receive 250 ml of glucose 5% plus the infusion of 100 ml of glucose 5% If the patient is randomized in the Methylprednisolone arm, he/she will receive a dose of 500 mg in 250 ml of glucose 5% plus 100 mg of glucose 5%. If the patient is randomized in the N-acetylcysteine arm, he/she will receive a dose of 150 mg/kg in 250 ml of glucose 5% plus N-acetylcysteine 50 mg/kg in 100 ml glucose 5%. Systematic sampling of liver function tests will be done the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7.

Mechanisms for the Effect of Acetylcysteine on Renal Function After Exposure to Radiographic Contrast Material [Recruiting]
Millions of people receive radiographic contrast material for investigations like CT and coronary angiography. While considered safe in healthy patients, it can cause acute renal impairment. This is termed radiocontrast-induced nephropathy (RCIN) and is generally defined as an increase in serum creatinine over baseline of more than 25% or 0. 5 mg/dL (44. 2 ╬╝mol/l) within 48 hrs. RCIN occurs in less than 2% of patients with normal renal function but is more common in patients with pre-existing renal damage.

The pathophysiology of RCIN is unclear. Possible mechanisms involve 1) reduced renal blood flow leading to acute tubular necrosis and 2) direct renal tubular injury by oxygen free radicals. Current prevention strategies focus on increasing renal blood flow and reducing oxidative stress. Patients at risk of RCIN currently receive fluids, a low dose of contrast, and variable and unproven doses of acetylcysteine.

The evidence for acetylcysteine administration is unclear. A RCIN consensus working group reported in the American Journal of Cardiology in September 2006 that "N-acetylcysteine is not consistently effective in reducing the risk for contrast-induced nephropathy". The perception of a benefit from acetylcysteine administration that is unproven has disadvantages as some clinicians report giving larger amounts of radio-contrast to patients who have received acetylcysteine since they believe that it prevents RCIN. There is a need to determine how acetylcysteine might prevent RCIN and to identify the appropriate dose and route of administration.

Since acetylcysteine is a vasodilator as well as an antioxidant, it may work in two distinct ways, by preventing reduction in renal blood flow (RBF) or contrast-induced oxidative damage. Previous studies have used changes in serum creatinine. In addition to being an insensitive marker of altered renal function, if contrast causes renal vasoconstriction and acetylcysteine vasodilatation, changes in serum creatinine will not be the ideal marker of effect. Finally the optimum dose and route of acetylcysteine administration is unclear, as illustrated by studies using a variety of doses and routes.

We propose to study the mechanism of effects of acetylcysteine on healthy and diseased kidneys, both unstressed and stressed by radiocontrast administration. We hypothesise that acetylcysteine may exert a renoprotective effect in RCIN by a renal vasodilatation and/or antioxidant mechanism.

N-Acetyl Cysteine Plus Behavioral Therapy for Nicotine Dependent Pathological Gamblers [Recruiting]
The objective of this application is to examine whether, given its mechanism of action, the dietary supplement, N-acetyl cysteine (NAC) will reduce both tobacco use and pathological gamblers (PG) symptoms in nicotine dependent pathological gamblers.

N-acetylcysteine in Intra-amniotic Infection/Inflammation [Recruiting]
The aim of the study is to determine if N-acetylcysteine (a potent free radical scavenger) prevents the occurrence of adverse neonatal outcomes in preterm deliveries complicated by infection associated with preterm labor or preterm premature rupture of membranes (PPROM). The working hypothesis is that in pregnancies complicated by intra-amniotic infection or inflammation, N-acetylcysteine protects the fetus by preventing the development, or decreasing the intensity and/or progression of the fetal inflammatory syndrome.

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Reports of Suspected Acetadote (Acetylcysteine Injection) Side Effects

Infusion Related Reaction (3)Transaminases Increased (2)LIP Swelling (1)Maternal Drugs Affecting Foetus (1)Headache (1)Haematocrit Decreased (1)Overdose (1)Haemolytic Uraemic Syndrome (1)Renal Failure Acute (1)Dyspnoea (1)more >>


Page last updated: 2009-10-20

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