Professional Drug Information > Parvolex

Acetylcysteine (Systemic)

JAN:
N-Acetyl- L-Cysteine ^{09} .

VA CLASSIFICATION
Oral
Primary: RE400
Secondary: AD900

Parenteral
Primary: AD900


Commonly used brand name(s): Mucomyst; Mucosil; Parvolex.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidote (to acetaminophen overdose).—

Indications

Accepted

Toxicity, acetaminophen (treatment)—Acetylcysteine is indicated in the treatment of acetaminophen overdose to protect against hepatotoxicity ^{{11} {12} {13}}.

Acceptance not established
There are insufficient data to show that acetylcysteine in combination with nitroglycerin is safe and effective for the management of unstable angina pectoris.^{19}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    163.19 ^{09}

Mechanism of action/Effect:

Acetylcysteine may protect against acetaminophen overdose-induced hepatotoxicity by maintaining or restoring hepatic concentrations of glutathione. Glutathione is required to inactivate an intermediate metabolite of acetaminophen that is thought to be hepatotoxic. In acetaminophen overdose, excessive quantities of this metabolite are formed because the primary metabolic (glucuronide and sulfate conjugation) pathways become saturated. Acetylcysteine may act by reducing the metabolite to the parent compound and/or by providing sulfhydryl for conjugation of the metabolite. Experimental evidence also suggests that a sulfhydryl-containing compound such as acetylcysteine may also directly inactivate the metabolite.

Biotransformation:

Deacetylated by the liver to cysteine and subsequently metabolized ^{{01} {11}}.


Precautions to Consider

Carcinogenicity

Studies have not been done to determine the carcinogenic potential of acetylcysteine ^{{01} {11}}.

Mutagenicity

In the Ames test, both with and without metabolic activation, acetylcysteine was not shown to be mutagenic ^{{01} {11}}.

Pregnancy/Reproduction
Fertility—
Reproductive studies performed in rats given oral doses of up to 1000 mg per kg of body weight (mg/kg) of acetylcysteine per day showed a slight reduction in fertility with doses of 500 or 1000 mg/kg per day (2.6 and 5.2 times the human dose, respectively). Studies in rabbits given up to 500 mg/kg per day (2.6 times the human dose) revealed no evidence of impaired fertility. ^{11}

Pregnancy—
Adequate and well-controlled studies in humans have not been done ^{11}. However, several reports have indicated that use of acetylcysteine to treat acetaminophen overdose in pregnant women is safe and effective, and may prevent hepatotoxicity in the fetus as well as in the mother ^{14}.

Studies in rabbits given oral doses of 500 mg/kg per day on Day 6 through Day 16 of gestation and in rabbits given 10% acetylcysteine plus 0.5% isoproterenol by inhalation for 30 or 35 minutes twice a day on Day 16 through Day 18 of gestation showed no evidence of teratogenicity or harm to the fetus. Also, studies in rats administered acetylcysteine and isoproterenol by inhalation showed no evidence of teratogenicity or harm to the fetus. ^{11}

FDA Pregnancy Category B ^{11}.

Breast-feeding

It is not known whether acetylcysteine is distributed into breast milk ^{11}. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of acetylcysteine have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.


Geriatrics


No information is available on the relationship of age to the effects of acetylcysteine in geriatric patients being treated for acetaminophen overdose.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Asthma, history of    (risk of bronchospastic reactions—with intravenous administration)


Conditions predisposing to gastrointestinal hemorrhage, such as:
Esophageal varices
Peptic ulceration    (acetylcysteine-induced vomiting may increase the risk of hemorrhage)


Sensitivity to acetylcysteine


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Bronchospastic allergic reaction (shortness of breath, troubled breathing, tightness in chest, or wheezing)
    
dermatitis, allergic (skin rash or hives)
    
facial edema
Note: Bronchospasm may also occur in conjunction with a generalized anaphylactoid reaction. These allergic reactions and facial edema have been reported only with intravenous administration. ^{12}





Those indicating need for medical attention only if they continue or are bothersome
    
Drowsiness
    
fever
    
nausea or vomiting




General Dosing Information
Because an injectable dosage form of acetylcysteine is not commercially available in the U.S., some emergency care practitioners have advocated that the oral solution be diluted and given by intravenous infusion when necessary. Oral administration is preferred because of the risk of bronchospastic or anaphylactoid reactions associated with intravenous administration of acetylcysteine. Also, the fact must be kept in mind that the oral solution available in the U.S., although sterile, is not required to be pyrogen-free. ^{10}

Administration of acetylcysteine is only part of an overall regimen for the treatment of acetaminophen overdose. Other measures include emptying the stomach via induction of emesis or gastric lavage; monitoring plasma acetaminophen concentration, liver function, renal function, and fluid and electrolyte balance; and supportive treatment as described below. ^{{11} {12} {13}} Administration of activated charcoal as part of the treatment regimen may be needed ^{{11} {12} {13} {15}}. Although its use has been recommended primarily in cases of mixed overdose ^{{11} {12} {13}}, one study has shown that administration of activated charcoal plus acetylcysteine may be more effective than acetylcysteine alone in preventing hepatotoxicity after an acetaminophen overdose ^{15}.

Acetylcysteine therapy should be initiated within 24 hours after ingestion of an acetaminophen overdose ^{{11} {12} {13}}. If initiation of treatment will not be delayed beyond 10 to 12 hours after ingestion of the overdose, acetylcysteine therapy may be withheld until the results of plasma acetaminophen determinations are available ^{13}. Otherwise, an initial dose of acetylcysteine should be administered immediately, without waiting for the results of acetaminophen determinations or other laboratory tests ^{13}.

The plasma acetaminophen concentration should be determined not less than 4 hours following ingestion of the overdose. Concentrations determined prior to this time are not reliable for assessing potential hepatotoxicity. ^{{11} {12} {13}} The following table shows plasma concentrations of acetaminophen that are potentially hepatotoxic if they are measured at the listed times after ingestion of a possible overdose ^{{11} {12} {13}}. If the initial determination shows a higher concentration, a full course of acetylcysteine should be administered. If a lower plasma concentration is reported, initiation or continuation of acetylcysteine treatment is not necessary. ^{13}

Time after Ingestion of Overdose (hr)	Acetaminophen Concentration
	mcg/mL	micromoles/L
4	150	993
6	100	662
8	70	463.4
10	50	331
15	20	132.4
20	8	53
24	3.5	23.2

Liver function tests (serum aspartate aminotransferase [AST; SGOT], serum alanine aminotransferase [ALT; SGPT], prothrombin time, and bilirubin) should be performed at 24-hour intervals for at least 96 hours postingestion if the plasma acetaminophen concentration indicates potential hepatotoxicity. If no abnormalities are detected within 96 hours, further determinations are not needed.

Renal and cardiac function should be monitored and appropriate therapy instituted if necessary.

Supportive treatment includes maintaining fluid and electrolyte balance, correcting hypoglycemia, and administering vitamin K ₁ (if prothrombin time ratio exceeds 1.5) and fresh frozen plasma or clotting factor concentrate (if prothrombin time ratio exceeds 3). ^{11}

Administration of diuretics and forced diuresis are not recommended ^{{11} {12} {13}}.

Additional therapy to treat mixed overdose with other agents (i.e., naloxone for an opioid analgesic) may be needed, especially if symptoms of central nervous system (CNS) depression occur within a few hours after ingestion of the overdose.

Discontinuation of acetylcysteine therapy should be considered if generalized urticaria or other symptoms of an allergic reaction occur and cannot be controlled by other means ^{11}.
For oral dosage form only
Acetylcysteine solution must be diluted prior to administration ^{{11} {12} {13}} because of its unpleasant odor and its irritating or sclerosing properties ^{16}. Dilution may also reduce the risk of vomiting. Also, the medication may be tolerated better if the diluted solution is administered well chilled (over ice, if necessary) and sipped from a covered container through a drinking straw. ^{17} If necessary, an antiemetic may be used concurrently or acetylcysteine can be given via nasogastric tube ^{18}.



Oral Dosage Forms

Note: The dosage form administered orally is the same solution that is administered via inhalation as a mucolytic (see Acetylcysteine [Local] ).

ACETYLCYSTEINE SOLUTION USP

Usual adult and adolescent dose
Antidote (to acetaminophen overdose)
Oral, 140 mg per kg of body weight initially, followed by 70 mg per kg of body weight every four hours for seventeen additional doses ^{{11} {12} {13}}.


Note: Any dose vomited within one hour of administration must be repeated ^{{11} {12} {13}}. If necessary, an antiemetic may be given concurrently and/or acetylcysteine, diluted with water, may be given via nasogastric tube ^{18}.


Usual pediatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


10% (100 mg per mL) (Rx) [Mucomyst] [Mucosil]^{02}{03}{11}


20% (200 mg per mL) (Rx) [Mucomyst] [Mucosil]^{02}{03}{11}

Canada—


20% (200 mg per mL) (Rx) [Mucomyst^{12}]^{12}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Keep container tightly closed. Protect from freezing.

Preparation of dosage form:
For patients weighing up to 20 kg (usually children younger than 6 years of age)—Dilute each mL of acetylcysteine solution with 3 mL of cola or other soft drinks ^{{02} {03} {11} {12}}.

For patients weighing 20 kg or more—Dilute the required quantity of acetylcysteine solution with enough cola or other soft drinks to make a 5% solution. The following quantities of acetylcysteine (20% solution) and diluent are needed to prepare a 5% solution containing the required initial dose and subsequent doses for patients weighing up to 110 kg:

Body weight (kg)	Acetylcysteine		mL of diluent	mL of 5% solution
	Grams	mL of 20% solution
Loading dose
100–110	15	75	225	300
90–100	14	70	210	280
80–90	13	65	195	260
70–80	11	55	165	220
60–70	10	50	150	200
50–60	8	40	120	160
40–50	7	35	105	140
30–40	6	30	90	120
20–30	4	20	60	80
Maintenance dose
100–110	7.5	37	113	150
90–100	7.0	35	105	140
80–90	6.5	33	97	130
70–80	5.5	28	82	110
60–70	5.0	25	75	100
50–60	4.0	20	60	80
40–50	3.5	18	52	70
30–40	3.0	15	45	60
20–30	2.0	10	30	40

Stability:
Because the solution contains no preservative, partially used vials should be refrigerated; opened vials should be discarded after 96 hours ^{{11} {13}}.

Diluted solutions should be freshly prepared and used within one hour ^{{11} {13}}.

Incompatibilities:
Acetylcysteine reacts with certain metals, especially iron, nickel, and copper, and with rubber. Contact with these substances should be avoided. ^{{11} {12}}

Auxiliary labeling:
   • Store in refrigerator after opening.
   • Discard opened vial after 96 hours.



Parenteral Dosage Forms

ACETYLCYSTEINE INJECTION

Usual adult and adolescent dose
Antidote (to acetaminophen overdose)
Intravenous, 300 mg per kg of body weight administered over twenty and one-fourth hours, divided as follows:

• Initial loading dose—150 mg per kg of body weight in up to 200 mL of 5% dextrose injection, administered over fifteen minutes.


• Second infusion—50 mg per kg of body weight in 500 mL of 5% dextrose injection, administered over four hours.


• Third infusion—100 mg per kg of body weight in 1000 mL of 5% dextrose injection, administered over the next sixteen hours.



Usual pediatric dose
See Usual adult and adolescent dose.

Note: The volumes and rates of infusion administered to children must be adjusted according to the medical circumstances and any restrictions in the volumes of parenteral fluids administered, as applicable to the individual patient.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


20% (200 mg per mL) (Rx) [Mucomyst] [Parvolex^{04}{12}]

Preparation of dosage form:


Initial loading dose (to be administered over fifteen minutes)—
Add the required quantity of acetylcysteine injection to the following quantities of 5% dextrose injection:


• For patients weighing 10 to 15 kg—40 mL.


• For patients weighing 15 to 20 kg—50 mL.


• For patients weighing 20 to 30 kg—75 mL.


• For patients weighing 30 to 40 kg—100 mL.


• For patients weighing 40 kg and over—200 mL.




Second infusion (to be administered over four hours):
Add the required quantity of acetylcysteine injection to 500 mL of 5% dextrose injection.



Third infusion (to be administered over sixteen hours):
Add the required quantity of acetylcysteine injection to 1 liter of 5% dextrose injection.

Note: The following quantities of acetylcysteine injection and 5% dextrose injection are needed for preparing initial and subsequent infusion solutions for administration to patients of various weights:

Body weight (kg)	20% Acetylcysteine (mL)
	First infusion/ 5% dextrose injection (mL)	Second infusion *	Third infusion †
100–110	82.5/200	27.5	55
90–100	75/200	25	50
80–90	67.5/200	22.5	45
70–80	60/200	20	40
60–70	52.5/200	17.5	35
50–60	45/200	15	30
40–50	37.5/200	12.5	25
30–40	30/100	10	20
25–30	22.5/75	7.5	15
20–25	18.75/75	6.25	12.5
15–20	15/50	5	10
10–15	11.25/40	3.75	7.5

^* Add to 500 mL of 5% dextrose injection.
^†  Add to 1000 mL of 5% dextrose injection.



Incompatibilities:
Acetylcysteine reacts with certain metals, especially iron, nickel, and copper, and with rubber. Contact with these substances should be avoided. ^{12}

Revised: 01/24/2001

References

Note:  All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

1. Reviewers" consensus on Acetylcysteine (Inhalation-Local) monograph, 1988.
   

2. Mucomyst (Bristol). In: PDR Physicians" desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 752.
   

3. Red book 1988. (January Update).
   

4. Airbron (A&H); Mucomyst (Bristol); Parvolex (A&H). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 22nd ed. Ottawa: Canadian Pharmaceutical Association, 1987: 17, 541, 655.
   

5. Airbron (Duncan, Flockhart); Parvolex (A&H). In: ABPI Data Sheet Compendium 1985-1986.
   

6. Br Med J 1983; 287: 876-7.
   

7. Clin Pharm 1984; 3: 587.
   

8. Br Med J 1984; 289: 217-9.
   

9. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 19.
   

10. Reviewers" consensus on monograph revision of 5/89.
    

11. Acetylcysteine package insert (Cetus Oncology—US), Rev 8/92, Rec 5/93.
    

12. Mucomyst (Bristol). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 756-7.
    

13. Protocol for management of acetaminophen overdose (McNeil Consumer Products—US), Rev 8/91, Rec 3/94.
    

14. Panel comment, 5/94.
    

15. Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ. A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose. Ann Emerg Med 1994; 23: 519-23.
    

16. Panel comment, 1983.
    

17. Reviewers" consensus on monograph revision of 4/94.
    

18. Reviewer comment, 4/94.
    

19. Reviewers' responses to Acetylcysteine Ballot of 12/07/2000.
    

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