Chlorzoxazone and Acetaminophen (Systemic)



INN:

Acetaminophen—Paracetamol

VA CLASSIFICATION
Primary: MS200

Commonly used brand name(s): Parafon Forte.

Another commonly used name is chlorzoxazone with
APAP .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.



Category:


Analgesic–skeletal muscle relaxant—

Indications

Accepted

Spasm, skeletal muscle, accompanied by pain (treatment)—Chlorzoxazone and acetaminophen combination is indicated as an adjunct to other measures, such as rest and physical therapy, for relief of pain and muscle spasm associated with acute, painful musculoskeletal conditions {05}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Chlorzoxazone: 169.57
    Acetaminophen: 151.16

Mechanism of action/Effect:


Chlorzoxazone:

The precise mechanism of action has not been determined. Chlorzoxazone acts in the central nervous system (CNS) rather than directly on skeletal muscle. It acts primarily at the spinal cord level and at subcortical areas of the brain and preferentially depresses polysynaptic reflexes. {05} The muscle relaxing effects may also be related to chlorzoxazone's CNS depressant (sedative) effects. {05}





Acetaminophen:

The mechanism of analgesic action has not been fully determined. Acetaminophen may act by inhibiting prostaglandin synthesis in the CNS and through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of the synthesis of prostaglandins, or to inhibition of the synthesis or actions of other substances, which sensitize pain receptors to mechanical or chemical stimulation.



Other actions/effects:


Acetaminophen:

Also has antipyretic activity.


Absorption:


Chlorzoxazone:

Rapid and complete.



Acetaminophen:

Rapid and almost complete following oral administration; may be decreased if taken following a high-carbohydrate meal.


Distribution:


In breast milk—Acetaminophen:

Peak concentrations of 10 to 15 mcg per mL (66.2 to 99.3 micromoles/L) have been measured 1 to 2 hours following maternal ingestion of a single 650-mg dose.


Protein binding:


Acetaminophen:

Not significant with usual analgesic doses.


Biotransformation:


Chlorzoxazone:

Hepatic {05}.



Acetaminophen:

Approximately 90 to 95% of a dose is metabolized in the liver, primarily by conjugation with glucuronic acid, sulfuric acid, and cysteine. An intermediate metabolite is hepatotoxic.


Half-life:


Chlorzoxazone:

1 {05} to 2.8 hours.



Acetaminophen:

1 to 4 hours; does not change with renal failure but may be prolonged in some forms of hepatic disease, in the elderly, and in the neonate, and may be somewhat shortened in children.


Onset of action:


Chlorzoxazone:

Within 1 hour.


Time to peak concentration:


Chlorzoxazone:

3 to 4 hours.



Acetaminophen:

0.5 to 2 hours.


Peak serum concentration:


Chlorzoxazone:

9 to 20 mcg per mL (53 to 117.9 micromoles/L) following a 600-mg dose.



Acetaminophen:

5 to 20 mcg per mL (33.1 to 132.4 micromoles/L), with doses up to 650 mg.


Time to peak effect:


Acetaminophen:

1 to 3 hours.


Duration of action:


Chlorzoxazone:

3 to 4 hours.



Acetaminophen:

3 to 4 hours.


Elimination:


Chlorzoxazone—
        Renal, as metabolites; <1% of a dose excreted unchanged {05}.



Acetaminophen——
        Renal, primarily as metabolites; 3% of a dose may be excreted unchanged.



In dialysis—
        Hemodialysis—120 mL per minute (for unmetabolized drug); metabolites also cleared rapidly.
        Hemoperfusion—200 mL per minute.
        Peritoneal dialysis—<10 mL per minute.



Precautions to Consider

Cross-sensitivity and/or related problems


Acetaminophen

Patients sensitive to aspirin are usually not sensitive to acetaminophen; however, mild bronchospastic reactions with acetaminophen have been reported in some aspirin-sensitive patients (less than 5% of those tested).


Pregnancy/Reproduction
Fertility—

Acetaminophen

Chronic toxicity studies in animals have shown that high doses of acetaminophen cause testicular atrophy and inhibition of spermatogenesis; the relevance of this finding to use in humans is not known.


Pregnancy—

Chlorzoxazone

Problems in humans have not been documented.



Acetaminophen

Problems in humans have not been documented. However, although controlled studies have not been done, it has been shown that acetaminophen crosses the placenta.


Breast-feeding


Chlorzoxazone:

Although it is not known whether chlorzoxazone is distributed into breast milk {05}, problems in humans have not been documented.



Acetaminophen:

Problems in humans have not been documented; however, acetaminophen is distributed into breast milk. {05} Although peak concentrations of 10 to 15 mcg per mL (66.2 to 99.3 micromoles/L) have been measured in breast milk 1 to 2 hours following maternal ingestion of a single 650-mg dose, neither acetaminophen nor its metabolites were detected in the urine of the nursing infants. The half-life in breast milk is 1.35 to 3.5 hours.


Pediatrics

Studies performed with chlorzoxazone {01} and with acetaminophen, individually, have not demonstrated pediatrics-specific problems that would limit the usefulness of either medication in children. However, use of this combination medication requires that care be taken to ensure that the dosage of each agent is appropriate for the child's age and weight.


Geriatrics



Chlorzoxazone:

No information is available on the relationship of age to the effects of chlorzoxazone in geriatric patients.



Acetaminophen:

Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of acetaminophen in the elderly.


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.


For chlorzoxazone
» CNS depression–producing medications, other (See Appendix II )    (concurrent use with chlorzoxazone may result in increased CNS depressant, respiratory depressant, and hypotensive effects; caution is recommended, and dosage of one or both agents should be reduced {05})


For acetaminophen
» Alcohol, especially chronic abuse of, or
Hepatic enzyme inducers (See Appendix II ) or
Hepatotoxic medications, other (See Appendix II )    (risk of hepatotoxicity with single toxic doses or prolonged use of high doses of acetaminophen may be increased in alcoholics or in patients regularly taking other hepatotoxic medications or hepatic enzyme inducers)

    (chronic use of barbiturates [except occasional use of butalbital] {02} or primidone has been reported to decrease the therapeutic effects of acetaminophen, probably because of increased metabolism resulting from induction of hepatic microsomal enzyme activity; the possibility should be considered that similar effects may occur with other hepatic enzyme inducers)


Anticoagulants, coumarin- or indandione-derivative    (concurrent use with chronic, high-dose administration of acetaminophen may increase the anticoagulant effect, possibly by decreasing hepatic synthesis of procoagulant factors; anticoagulant dosage adjustment based on increased monitoring of prothrombin time may be necessary when chronic, high-dose acetaminophen therapy is initiated or discontinued; however, this does not apply to occasional use, or to chronic use of doses below 2 grams per day, of acetaminophen)


Aspirin or other salicylates or
Nonsteroidal anti-inflammatory drugs (NSAIDs)    (prolonged concurrent high-dose use of a salicylate with acetaminophen is not recommended because evidence suggests that chronic, high-dose administration of the combined analgesics [1.35 grams daily, or cumulative ingestion of 1 kg annually, for 3 years or longer] significantly increases the risk of analgesic nephropathy, renal papillary necrosis, end-stage renal disease, and cancer of the kidney or urinary bladder; also, it is recommended that for short-term use, the combined dose of acetaminophen plus salicylate not exceed that recommended for acetaminophen or a salicylate given alone, i.e., 4 grams of the combined analgesics per day)

    (prolonged concurrent use of other NSAIDs with acetaminophen may also increase the risk of adverse renal effects; it is recommended that patients be under close medical supervision while receiving such combined therapy)

    (diflunisal may increase the plasma concentration of acetaminophen by 50%, leading to increased risk of hepatotoxicity)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Glucose, blood, determinations    (values may be falsely decreased by acetaminophen when measured by the glucose oxidase/peroxidase method but probably not when measured by the hexokinase/glucose-6-phosphate dehydrogenase [G6PD] method)

    (values may be falsely increased when certain instruments are used in glucose analysis if high acetaminophen concentrations are present; consult manufacturer's instruction manual)


5-Hydroxyindoleacetic acid (5-HIAA), serum, determinations    (acetaminophen may cause false-positive results in qualitative screening tests using nitrosonaphthol reagent; the quantitative test is unaffected)


Pancreatic function tests using bentiromide    (acetaminophen will invalidate test results because acetaminophen is also metabolized to an arylamine and will thus increase the apparent quantity of para-aminobenzoic acid [PABA] recovered; it is recommended that acetaminophen be discontinued at least 3 days prior to administration of bentiromide)


Uric acid, serum, determinations    (acetaminophen may produce falsely increased values when the phosphotungstate uric acid test method is used)

With physiology/laboratory test values
Bilirubin concentrations, serum, and
Lactate dehydrogenase values, serum, and
Prothrombin time and
Transaminase values, serum    (may be increased indicating acetaminophen-induced hepatotoxicity in patients, especially alcoholics, those taking other hepatic enzyme inducers, or those with pre-existing hepatic disease, with single toxic doses [>8 to 10 grams] or with prolonged use of lower doses [>3 to 5 grams a day])


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

For chlorzoxazone:
Allergic reactions to chlorzoxazone or to other medications, history of or
Allergies or history of    (increased risk of allergic reactions)


» CNS depression, pre-existing    (may be exacerbated)


» Hepatic function impairment    (chlorzoxazone metabolized in liver and potentially hepatotoxic)


Renal function impairment    (chlorzoxazone metabolites excreted via kidneys)


For acetaminophen:
» Alcoholism, active or
» Hepatic disease or
» Viral hepatitis    (increased risk of hepatotoxicity)


Renal function impairment, severe    (risk of adverse renal effects may be increased with prolonged use of high doses; occasional use is acceptable)


Sensitivity to acetaminophen or aspirin

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hematopoietic function determinations and
Hepatic function determinations    (may be required at periodic intervals during high-dose or long-term acetaminophen therapy, especially in patients with pre-existing hepatic disease)




Side/Adverse Effects

Note: Although several cases of hepatotoxicity have been reported with chlorzoxazone, a definite causal relationship has not been established {05}.

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
For chlorzoxazone
    
Agranulocytosis (sore throat and fever)
    
anemia (unusual tiredness or weakness)
    
angioedema{05} (hive-like swellings, large, on face, eyelids, mouth, lips, and/or tongue)
    
dermatitis, allergic{05} (skin rash, hives, itching, or redness)
    
gastrointestinal bleeding (bloody or black tarry stools)

For acetaminophen
    
Agranulocytosis (unexplained sore throat and fever)
    
anemia (unusual tiredness or weakness)
    
dermatitis, allergic (skin rash, hives, or itching)
    
hepatitis (yellow eyes or skin)
    
renal colic (pain, severe and/or sharp, in lower back and/or side)—with prolonged use of high doses in patients with severe renal function impairment
    
renal failure (sudden decrease in amount of urine)
    
sterile pyuria (cloudy urine)
    
thrombocytopenia (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)


Note: Renal failure is especially likely to occur with prolonged use of high doses in patients with pre-existing severe renal function impairment and may progress to uremia. Also, although a causal association has not been established, a retrospective study has suggested that long-term daily use of acetaminophen may be associated with an increased risk of chronic renal disease (analgesic nephropathy) in individuals without pre-existing renal function impairment. {03} {04}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
For chlorzoxazone
    
Dizziness or lightheadedness
    
drowsiness


Incidence less frequent
For chlorzoxazone
    
Constipation
    
gastrointestinal irritation (abdominal or stomach cramps or pain; diarrhea ; heartburn; nausea or vomiting)
    
headache
    
unusual excitement, nervousness, restlessness, or irritability






Overdose
For specific information on the agents used in the management of chlorzoxazone and acetaminophen overdose, see:    • Acetylcysteine (Systemic) monograph.
   • Charcoal, Activated (Oral-Local) monograph; and/or


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical Effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
For chlorzoxazone
    
Muscle weakness, severe
    
respiratory depression (fast or irregular breathing)


Acute
For acetaminophen
    
Diarrhea
loss of appetite
increased sweating
nausea or vomiting
stomach cramps or pain —often do not occur, but may occur within 6 to 14 hours after ingestion of the overdose and persist for about 24 hours


Chronic
For Acetaminophen
    
Hepatotoxicity (pain, tenderness, and/or swelling in upper abdominal area)—may occur 2 to 4 days after the overdose is ingested
Note: Signs and symptoms of possible hepatotoxicity and abnormalities in liver function tests may not occur until 2 to 4 days after ingestion of the overdose. Maximal changes in liver function tests usually occur 3 to 5 days after ingestion of the overdose.
Overt hepatic disease or failure may occur 4 to 6 days after ingestion of the overdose. Hepatic encephalopathy (with mental changes, confusion, agitation, or stupor), convulsions, respiratory depression, coma, cerebral edema, coagulation defects, gastrointestinal bleeding, disseminated intravascular coagulation, hypoglycemia, metabolic acidosis, renal tubular necrosis leading to renal failure (signs include bloody or cloudy urine and sudden decrease in amount of urine), cardiac arrhythmias, and cardiovascular collapse may occur.





Treatment of overdose
To decrease absorption—May include emptying the stomach via induction of emesis or gastric lavage.

Removing activated charcoal (if used) by gastric lavage may be advisable. Although activated charcoal is recommended in cases of mixed drug overdose, it may interfere with absorption of orally administered acetylcysteine (antidote used to protect against acetaminophen-induced hepatotoxicity) and decrease its efficacy.

Specific Treatment—Use of acetylcysteine. It is recommended that acetylcysteine administration be instituted as soon as possible after ingestion of an overdose has been reported, without waiting for the results of plasma acetaminophen determinations or other laboratory tests. Acetylcysteine is most effective if treatment is started within 10 to 12 hours after ingestion of the overdose; however, it may be of some benefit if treatment is started within 24 hours. See the package insert or Acetylcysteine (Systemic) monograph for specific dosing guidelines for use of this product.

To enhance elimination— Instituting hemodialysis or hemoperfusion to remove acetaminophen from the circulation may be beneficial if acetylcysteine administration cannot be instituted within 24 hours following ingestion of a massive acetaminophen overdose. However, the efficacy of such treatment in preventing acetaminophen-induced hepatotoxicity is not known.

Monitoring—May include determining plasma acetaminophen concentration at least 4 hours following ingestion of the overdose. Determinations performed prior to this time are not reliable for assessing potential hepatotoxicity. Initial plasma concentrations above 150 mcg per mL (993 micromoles/L) at 4 hours, 100 mcg per mL (663 micromoles/L) at 6 hours, 70 mcg per mL (463.4 micromoles/L) at 8 hours, 50 mcg per mL (331 micromoles/L) at 10 hours, 20 mcg per mL (132.4 micromoles/L) at 15 hours, 8 mcg per mL (53 micromoles/L) at 20 hours, or 3.5 mcg per mL (23.2 micromoles/L) at 24 hours postingestion indicate possible hepatotoxicity and the need for completing the full course of acetylcysteine treatment. If the initial determination indicates a plasma concentration below those listed at the times indicated, cessation of acetylcysteine therapy can be considered. However, some clinicians advise that more than one determination should be performed in order to ascertain peak absorption and half-life of acetaminophen prior to considering discontinuation of acetylcysteine.

Performing liver function tests (serum aspartate aminotransferase [AST or SGOT], serum alanine aminotransferase [ALT or SGPT], prothrombin time, and bilirubin) 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.

Monitoring renal and cardiac function and administering appropriate therapy as required.

Supportive care—May include administering oxygen and artificial respiration if required for respiratory depression induced by chlorzoxazone, and plasma volume expanders or vasopressors if required for hypotension. Cholinergic medications and analeptic medications are of no value in chlorzoxazone overdosage and should not be used.

Maintaining fluid and electolyte 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 3.0). Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Chlorzoxazone and Acetaminophen (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to acetaminophen, aspirin, or chlorzoxazone

Pregnancy—Acetaminophen crosses the placenta





Breast-feeding—Acetaminophen is distributed into breast milk
Other medications, especially alcohol or other CNS depression–producing medications
Other medical problems, especially alcoholism (active), hepatic function impairment or other hepatic disease, and viral hepatitis

Proper use of this medication
» Importance of not taking more medication than the amount prescribed; acetaminophen may cause liver damage with long-term use or greater-than-recommended doses

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician if long-term therapy is prescribed

» Risk of overdose if other medications containing acetaminophen are used

» Avoiding alcohol or other CNS depressants during therapy unless prescribed or otherwise approved by physician

» Risk of hepatotoxicity may be increased if acetaminophen used with alcohol

Not taking aspirin or other anti-inflammatory analgesics concurrently for more than a few days, unless directed by physician

» Caution if drowsiness, dizziness, or lightheadedness occurs

Possible interference with some laboratory tests; preferably discussing use of the medication with physician in charge 3 to 4 days ahead of time; if this is not possible, informing physician in charge if acetaminophen taken within the past 3 or 4 days

Diabetics: Possible false results with blood glucose tests; checking with physician, nurse, or pharmacist if changes in test results noted

» Suspected overdose: Getting emergency help at once even if no symptoms apparent; symptoms of severe acetaminophen overdosage may be delayed, but treatment must be begun as soon as possible; treatment started 24 hours or more after the overdose may be ineffective in preventing liver damage or fatality


Side/adverse effects
Medication may color the urine orange or reddish purple

Signs of potential side effects, especially agranulocytosis, anemia, angioedema, allergic dermatitis, gastrointestinal bleeding, hepatitis, renal colic, renal failure, sterile pyuria, and thrombocytopenia


General Dosing Information
Discontinuation of therapy is recommended if symptoms of hepatotoxicity occur.

One retrospective study has suggested that long-term daily use of acetaminophen may be associated with an increased risk of chronic renal disease (analgesic nephropathy). The results of this study are not considered conclusive, and further investigation is required to establish a causal association. {03} However, until more definitive information is available, prolonged daily administration of acetaminophen should probably be limited to patients who are receiving appropriate medical supervision. {04}


Oral Dosage Forms

CHLORZOXAZONE AND ACETAMINOPHEN TABLETS

Usual adult and adolescent dose
Analgesic–skeletal muscle relaxant
Oral, 500 mg of chlorzoxazone and 600 mg of acetaminophen four times a day {05}.


Usual pediatric dose
Administration of this combination medication to a child depends upon whether the appropriate dose of each ingredient, which must be individualized according to the child's age and weight {01}, can be provided. Dosage of chlorzoxazone ranges between 125 and 500 mg, administered three or four times a day. {01} The quantity of acetaminophen in one tablet of the chlorzoxazone and acetaminophen combination (300 mg) may be administered to children six years of age or older, but the quantity present in two tablets (600 mg) is higher than the maximum dose recommended for children younger than twelve years of age.

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

Canada—


250 mg of chlorzoxazone and 300 mg of acetaminophen (OTC) [Parafon Forte (scored) (sodium bisulfite) (tartrazine)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Revised: 08/29/1994



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. Paraflex (McNeil). In: PDR Physicians' desk reference. 45th ed. 1991. Oradell, NJ: Medical Economics Data, 1991: 1338-9.
  1. Data on file, Forest Pharmaceuticals.
  1. Sandler DP, Smith JC, Weinberg CR, et al. Analgesic use and chronic renal disease. N Engl J Med 1989 May 11; 320: 1238-43.
  1. Panel consensus on Acetaminophen monograph ballot 11/3/89.
  1. Parafon Forte (McNeil). In: Krogh CME, editor. Self-Medication Product Information. 4th ed volume 2. Ottawa: Canadian Pharmaceutical Association, 1993: 130-1.
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