Acetylcysteine

V03A - All other therapeutic products ATC S01XA08 Small molecule approved 1963 Oral Parenteral Topical Natural product

JFDA label: Brunac Eye Drops 5%

Mechanism of Action

— Glutathione precursor; — Mycolytic

Indications

Approved

Acetaminophen overdose
Mucolytic

Off-label

Distal intestinal obstruction syndrome (DIOS, previously referred to as meconium ileus equivalent)

Contraindications

Source: Lexicomp

Hypersensitivity to acetylcysteine or any component of the formulation. Effervescent tablet (Cetylev): There are no contraindications listed in the manufacturer's labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (5)

Common Chest tightness · edema · Flushing · hypotension (Bebarta 2010; Sandilands 2008) · tachycardia

Immune system disorders (2)

Very Common Autoimmune disease

Common Hypersensitivity reaction

Gastrointestinal disorders (3)

Common Gastrointestinal symptoms · nausea · Vomiting

Skin and subcutaneous tissue disorders (4)

Common pruritus · rash · Rash (with or without fever) · Urticaria

General disorders and administration site conditions (1)

Very Common Anaphylactoid reaction

Respiratory, thoracic and mediastinal disorders (6)

Common bronchitis · Bronchospasm · Pharyngitis · rhinorrhea · rhonchi · throat tightness

Other (1)

Common Frequency not defined

Dosing

Source: Lexicomp

Acetaminophen overdose: Only the 72-hour oral and 21-hour IV regimens are FDA approved. Ideally, in patients with acute acetaminophen ingestion, treatment should begin within 8 hours of ingestion or as soon as possible after ingestion. In patients with a suspected acute ingestion where the time of ingestion is unknown, the concentration is unobtainable or uninterpretable within 8 hours of ingestion, the patient presents >8 hours after ingestion, or there is clinical evidence of toxicity, initiate treatment immediately and re-evaluate the need for acetylcysteine upon receipt of the results (if applicable). In patients who present following RSTI and treatment is deemed appropriate, acetylcysteine should be initiated immediately. Regardless of the treatment regimen selected, serum acetaminophen concentrations, liver function, and clinical status should be evaluated during and prior to the end of the treatment regimen to determine if treatment discontinuation is appropriate. In patients who continue to experience symptoms of hepatotoxicity or elevated liver function tests at the conclusion of a 72-hour oral or 21-hour IV regimen, extending the treatment course may be appropriate; however, when and to which patients additional doses should be administered is unclear. Possible candidates for extended therapy include patients with a suspected massive overdose, concomitant ingestion of other substances, or patients with preexisting liver disease. In patients with persistently elevated acetaminophen concentrations, persistently elevated liver function tests, or an elevated INR, additional acetylcysteine should be administered. Typically, an additional "third dose" or "third bag" (IV: 100 mg/kg [maximum: 10 g] infused over 16 hours) is administered; however, this dose may be inadequate in some patients (Rumack 2012). Consultation with a poison control center or clinical toxicologist is highly recommended to determine optimal patient care. Oral: (Effervescent tablets [Cetylev]; solution for oral administration): Note: Consultation with a poison control center or clinical toxicologist is highly recommended when considering the discontinuation of oral acetylcysteine prior to the conclusion of a full 18-dose course of therapy. 72-hour regimen: Consists of 18 doses; total dose delivered: 1,330 mg/kg Loading dose: 140 mg/kg Maintenance dose: 70 mg/kg every 4 hours; repeat dose if emesis occurs within 1 hour of administration IV (Acetadote): 21-hour regimen: Consists of 3 doses; total dose delivered: 300 mg/kg Loading dose: 150 mg/kg (maximum: 15 g) infused over 1 hour Second dose: 50 mg/kg (maximum: 5 g) infused over 4 hours Third dose: 100 mg/kg (maximum: 10 g) infused over 16 hours Note: The fluid volume should be reduced in patients weighing ≤40 kg according to the following table: Acetadote Dosing / Fluid Volume Guidelines for Patients ≤40 kg Body Weight (kg) Loading Dose 150 mg/kg over 1 hour Second Dose 50 mg/kg over 4 hours Third Dose 100 mg/kg over 16 ho

(For additional information see "Acetylcysteine: Pediatric drug information") Acetaminophen overdose: Infants, Children, and Adolescents: Refer to adult dosing. Adjuvant therapy in respiratory conditions: Note: Patients should receive an aerosolized bronchodilator 10 to 15 minutes prior to acetylcysteine Inhalation, nebulization (face mask, mouth piece, tracheostomy): Acetylcysteine 10% and 20% solution (dilute 20% solution with sodium chloride or sterile water for inhalation); 10% solution may be used undiluted. Infants: 1 to 2 mL of 20% solution or 2 to 4 mL 10% solution until nebulized given 3 to 4 times/day Children: Refer to adult dosing. Inhalation, nebulization (tent, croupette): Children: Refer to adult dosing.

Refer to adult dosing.

Oral, IV: There are no dosage adjustments provided in the manufacturer's labeling.

Warnings & Precautions

Source: Lexicomp

Anaphylactoid reactions

Acute flushing and erythema have been reported; usually occurs within 30 to 60 minutes and may resolve spontaneously. Serious anaphylactoid reactions (some fatal) have also been reported and are more commonly associated with IV administration, but also occur with oral administration (Mroz 1997). When used for acetaminophen overdose, the incidence is reduced when the initial intravenous loading dose is administered over 60 minutes. The acetylcysteine infusion may be interrupted until the treatment of allergic symptoms is initiated; the infusion can then be carefully restarted. Treatment for anaphylactoid reactions should be immediately available. Conversely, patients with high acetaminophen concentrations (>150 mg/L) may be at a reduced risk for anaphylactoid reactions (Pakravan 2008; Sandilands 2009; Waring 2008).

Fluid overload

IV administration can cause fluid overload, potentially resulting in hyponatremia, seizure and death. To avoid fluid overload in patients ≤40 kg and those requiring fluid restriction, decrease volume of diluent proportionally (see table in dosing section). Disease-related concerns:

Asthma/bronchospasm

Use caution in patients with asthma or history of bronchospasm; these patients may be at increased risk of hypersensitivity reactions. Other warnings/precautions:

Acute acetaminophen overdose

Appropriate use: Acetylcysteine is indicated in patients with a serum acetaminophen concentration that indicates they are at "possible" risk or greater for hepatotoxicity when plotted on the Rumack-Matthew nomogram. There are several situations where the nomogram is of limited use. Serum acetaminophen concentrations obtained 24 hours after an acute ingestion or patients who present following an acute ingestion at an unknown time may be candidates for acetylcysteine therapy; consultation with a poison control center or clinical toxicologist is highly recommended.

Repeated supratherapeutic ingestion (RSTI) of acetaminophen

Appropriate use: The Rumack-Matthew nomogram is not designed to be used following RSTIs. In general, an accurate past medical history, including a comprehensive acetaminophen ingestion history, in conjunction with AST concentrations and serum acetaminophen concentrations, may give the clinician insight as to the patient's risk of acetaminophen toxicity. Some experts recommend that acetylcysteine be administered to any patient with "higher than expected" serum acetaminophen concentrations or serum acetaminophen concentration >10 mcg/mL, even in the absence of hepatic injury; others recommend treatment for patients with laboratory evidence and/or signs and symptoms of hepatotoxicity (Hendrickson 2006; Jones 2000). Consultation with a poison control center or a clinical toxicologist is highly recommended. Dosage form specific issues:

Effervescent tablets (Cetylev)

Contains sodium; consider acetylcysteine treatment as a source of sodium in patients who may be sensitive to excess sodium intake (eg, heart failure, hypertension, renal impairment).

Oral administration

Gastrointestinal hemorrhage: Oral administration of acetylcysteine may result in nausea and vomiting, which may exacerbate vomiting associated with acetaminophen overdose. Therefore, patients at risk of gastrointestinal hemorrhage (eg, esophageal varices, peptic ulcer) may experience an even higher risk of gastrointestinal hemorrhage during therapy.

Inhalation

Since increased bronchial secretions may develop after inhalation, percussion, postural drainage, and suctioning should follow. If bronchospasm occurs, administer a bronchodilator; discontinue acetylcysteine if bronchospasm progresses.

Pregnancy & Lactation

Pregnancy

Teratogenic

Adverse events have not been observed in animal reproduction studies. Based on limited reports using acetylcysteine to treat acetaminophen overdose in pregnant women, acetylcysteine has been shown to cross the placenta and may provide protective concentrations in the fetus. Acetylcysteine may be used to treat acetaminophen overdose in during pregnancy (Wilkes 2005). In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Lactation

It is not known if acetylcysteine is excreted in breast milk. According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of infant exposure, the benefits of breast-feeding to the infant, and benefits of treatment to the mother. Based on pharmacokinetics, acetylcysteine should be nearly completely cleared 30 hours after administration; breast-feeding women may consider pumping and discarding breast milk for 30 hours after

Monitoring

Clinical pearl	Acetaminophen overdose: Monitor patient for the development of anaphylaxis or anaphylactoid reactions; monitor serum acetaminophen concentrations, AST, ALT, bilirubin, PT, INR, serum creatinine, BUN, serum glucose, hemoglobin, hematocrit, and electrolytes. Assess patient for nausea, vomiting, and skin rash following oral administration. Reassess LFTs for possible hepatotoxicity every 4 to 6 hours. An early elevation in the INR may be related to acetylcysteine therapy (Schmidt 2002). Acute ingestion: Obtain the first acetaminophen concentration 4 hours postingestion (or as soon as possible thereafter); plot on the Rumack-Matthew nomogram. In patients who have ingested an extended release formulation of acetaminophen or have coingested an agent known to delay gastric emptying, obtain a repeat serum acetaminophen measurement 4 to 6 hours following the first measurement if the original concentration (taken at 4 to 8 hours postingestion) when plotted on the Rumack-Matthew nomogram indicated that treatment was not necessary.

Clinical pearl

Acetaminophen overdose: Monitor patient for the development of anaphylaxis or anaphylactoid reactions; monitor serum acetaminophen concentrations, AST, ALT, bilirubin, PT, INR, serum creatinine, BUN, serum glucose, hemoglobin, hematocrit, and electrolytes. Assess patient for nausea, vomiting, and skin rash following oral administration. Reassess LFTs for possible hepatotoxicity every 4 to 6 hours. An early elevation in the INR may be related to acetylcysteine therapy (Schmidt 2002). Acute ingestion: Obtain the first acetaminophen concentration 4 hours postingestion (or as soon as possible thereafter); plot on the Rumack-Matthew nomogram. In patients who have ingested an extended release formulation of acetaminophen or have coingested an agent known to delay gastric emptying, obtain a repeat serum acetaminophen measurement 4 to 6 hours following the first measurement if the original concentration (taken at 4 to 8 hours postingestion) when plotted on the Rumack-Matthew nomogram indicated that treatment was not necessary.

Chemistry & Properties

Formula	C5H9NO3S
Molecular weight	163.2 g/mol
IUPAC name	(2R)-2-acetamido-3-sulfanylpropanoic acid
CAS	616-91-1
PubChem CID	12035
InChIKey	`PWKSKIMOESPYIA-BYPYZUCNSA-N`
logP	-0.49 (XLogP 0.4)
Polar surface area	66.4 Å²
H-bond acceptors / donors	3 / 3
Drug-likeness (QED)	0.49
Lipinski violations	0

SMILES

CC(=O)N[C@@H](CS)C(=O)O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (3, DDInter)

Interacting drug	Severity	Management
Insulin human (inhalation, rapid acting)	moderate
Activated charcoal	minor
Ifosfamide	minor

Registered Products (5)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
ACC Junior Cough Syrup	Syrup 20 mg/ml	100 ml	The Jordan Drugstore Co	2.440
Brunac Eye Drops	Ophthalmic Solution 5 %	5 ml	Wefaq Drug Store	3.620
Rinofluimucil 1 % &	Solution 10 mg, 5 mg	10 ml	مستودع ادوية مسروجي	3.740
Qatar Acetylcysteine	Injection 200 mg/ml	30 ml	شركة مستودع ادوية جرينلاند	—
Sunnycysteine	Ampoule 2 g/10 ml	5 amp	Mohamad Zreiqat Drug Store	—