Antihistamines, Decongestants, and Analgesics (Systemic)

This monograph includes information on the following:


Note: Products containing phenylpropanolamine were removed from the U.S. and Canadian Markets in November 2000.{27}

1) Brompheniramine, Pseudoephedrine, and Acetaminophen 
2) Chlorpheniramine, Phenylephrine, and Acetaminophen
3) Chlorpheniramine, Pseudoephedrine, and Acetaminophen
4) Chlorpheniramine, Pyrilamine, Phenylephrine, and Acetaminophen 
5) Dexbrompheniramine, Pseudoephedrine, and Acetaminophen 
6) Diphenhydramine, Pseudoephedrine, and Acetaminophen
7) Pheniramine, Phenylephrine, and Acetaminophen *
8) Pheniramine, Phenylephrine, Sodium Salicylate, and Caffeine 
9) Triprolidine, Pseudoephedrine, and Acetaminophen

VA CLASSIFICATION
Primary: RE599


Note: Other combinations containing decongestants are found in Antihistamines and Decongestants (Systemic) , Antihistamines, Decongestants, and Anticholinergics (Systemic) , Cough/Cold Combinations (Systemic) , and Decongestants and Analgesics (Systemic) .



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.

Not commercially available in Canada.



Category:


Antihistaminic (H 1-receptor)-decongestant-analgesic—

Indications

Accepted

Cold symptoms (treatment);
Congestion, nasal (treatment); and
Congestion, sinus (treatment)—Antihistamine, decongestant, and analgesic combinations are indicated for the temporary relief of nasal and sinus congestion and headaches, pains, and general discomfort due to colds, flu, or allergies. The antihistamine in these combinations may provide added relief of nasal congestion, rhinorrhea, and sneezing. It may also serve as an adjunct because of its anticholinergic drying effects. {01}
—The therapeutic effectiveness of oral phenylephrine as a nasal decongestant has been questioned, especially at the usual oral dose.

Note: In November 2000, the Food and Drug Administration (FDA) issued a public health warning regarding phenylpropanolamine (PPA) due to the risk of hemorrhagic stroke. The FDA, supported by the final report of The Hemorrhagic Stroke Project (HSP){28}, requested that manufacturers voluntarily discontinue marketing products that contain PPA and that consumers work with their healthcare providers to select alternative products.{27}



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—


Antihistaminic (H 1-receptor)::


Ethanolamine derivatives—
    Diphenhydramine



Ethylenediamine derivatives—
    Pyrilamine



Propylamine derivatives (alkylamines)—
    Chlorpheniramine; Triprolidine




Decongestant:


Sympathomimetic amines—
    Phenylephrine; Pseudoephedrine




Analgesic:


Salicylates—
    Aspirin; Sodium Salicylate


Molecular weight—
    Acetaminophen: 151.16
    Aspirin: 180.16
    Brompheniramine maleate: 435.32
    Caffeine: 212.21 (monohydrate); 194.19 (anhydrous)
    Chlorpheniramine maleate: 390.87
    Diphenhydramine hydrochloride: 291.82
    Phenylephrine hydrochloride: 203.67
    Pseudoephedrine hydrochloride: 201.70
    Pseudoephedrine sulfate: 428.54
    Pyrilamine maleate: 401.46
    Sodium salicylate: 160.10
    Triprolidine hydrochloride: 332.87

pKa—
    Brompheniramine maleate: 3.59 and 9.12
    Chlorpheniramine maleate: 9.2
    Diphenhydramine hydrochloride: 9
    Pseudoephedrine: 9.4 {16}
    Triprolidine hydrochloride: 3.6 and 9.3

Mechanism of action/Effect:


Antihistaminic (H 1-receptor):

Antihistamines used in the treatment of allergy act by competing with histamine for H 1-receptor sites on effector cells. They thereby prevent, but do not reverse, responses mediated by histamine alone. The anticholinergic actions of most antihistamines provide a drying effect on the nasal mucosa.



Decongestant:

Sympathomimetic amines act on alpha-adrenergic receptors in the mucosa of the respiratory tract to produce vasoconstriction, which temporarily reduces the swelling associated with inflammation of the mucous membranes lining the nasal passages.



Analgesic:

Acetaminophen or

Salicylates: The mechanism of analgesic action has not been fully determined. Acetaminophen and salicylates may act by inhibiting prostaglandin synthesis in the central nervous system (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 that sensitize pain receptors to mechanical or chemical stimulation. Acetaminophen may act predominantly in the CNS, whereas salicylates may act predominantly via peripheral actions.

Caffeine: A mild CNS stimulant. Caffeine-induced constriction of cerebral blood vessels may contribute to relief of headache. Also, preliminary evidence suggests that the addition of caffeine to acetaminophen and/or aspirin may provide a more rapid onset of action and/or enhanced pain relief with lower doses of analgesics.



Other actions/effects:


Sympathomimetic amines:

Pseudoephedrine: Has an indirect vasoconstrictor effect; has relatively weaker pressor and cardiac actions than ephedrine; may also produce mild CNS stimulation, especially in patients sensitive to sympathomimetic drugs.



Aspirin:

Inhibits platelet aggregation. Also has antipyretic, anti-inflammatory, and antirheumatic actions; however, the required plasma concentrations may not be achievable with the quantities present in these combination medications.


Absorption:


Antihistamines:

Well absorbed from the gastrointestinal tract after oral administration.



Sympathomimetic amines:

Most sympathomimetic amines (except phenylephrine) are well absorbed from the gastrointestinal tract after oral administration. Phenylephrine has reduced bioavailability (about 38%) from gastrointestinal tract because of first pass metabolism by monoamine oxidase in the stomach and liver. {16}



Analgesics:

Acetaminophen: Rapid and almost complete; may be decreased if acetaminophen is taken following a high-carbohydrate meal.

Salicylates: Generally rapid and complete but may vary according to specific salicylate used and other factors such as tablet dissolution rate and gastric or intraluminal pH. Food decreases the rate, but not the extent, of absorption.

Caffeine: Well absorbed from the gastrointestinal tract.


Protein binding:

Acetaminophen—Not significant with usual analgesic doses.

Chlorpheniramine—High (72%).

Diphenhydramine—Very high (98 to 99%).

Salicylate (from aspirin)—High (to albumin).

Caffeine—Low.

Biotransformation:


Antihistamines:

Hepatic; some renal.



Sympathomimetic amines:

Phenylephrine: Extensive, in the intestinal wall and in the liver. Sulfate conjugates are formed largely in the intestinal wall. Also, phenylephrine undergoes oxidative deamination by monoamine oxidase. {16}

Pseudoephedrine: Incompletely metabolized in the liver; less than 1% by N-demethylation to the active metabolite norpseudoephedrine {16}.



Analgesics:

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.

Aspirin: Largely hydrolyzed in the gastrointestinal tract, liver, and blood to salicylate, which is further metabolized, primarily in the liver.

Caffeine: Hepatic.


Half-life:


Antihistamines:


Brompheniramine—

25 hours.



Chlorpheniramine—

21 to 27 hours.



Diphenhydramine—

1 to 4 hours.



Triprolidine—

3 to 3.3 hours.




Sympathomimetic amines:


Phenylephrine—

2.1 to 3.4 hours. {16}



Pseudoephedrine—

4.5 to 8 hours.

In children—Mean half-life of pseudoephedrine has been reported to be 4.6 hours.




Analgesics:


Acetaminophen—

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



Aspirin—

15 to 20 minutes (for intact molecule); rapidly hydrolyzed to salicylate.



Caffeine—

3 to 4 hours.



Salicylate (from aspirin)—

Dependent on dose and urinary pH; about 2 to 3 hours with usual analgesic doses.



Onset of action:


Sympathomimetic amines:

Pseudoephedrine: 30 minutes.


Time to peak concentration:


Antihistamines:

Brompheniramine: 2 to 5 hours.

Chlorpheniramine: 2 to 6 hours.

Diphenhydramine: 1 to 4 hours.

Triprolidine: 2 hours.



Sympathomimetic amines:

Phenylephrine: 0.75 to 2 hours (to achieve peak concentrations ranging from 0.9 to 298 nanograms/mL, respectively) {16}.

Pseudoephedrine: 1.97 hours (to achieve a concentration of 422 nanograms/mL) {16}.



Analgesics:

Acetaminophen: 0.5 to 2 hours.

Aspirin: Generally 1 to 2 hours with single doses.


Peak serum concentration:

Acetaminophen—5 to 20 mcg per mL with doses up to 650 mg.

Therapeutic plasma concentration

Analgesic—Salicylate (from aspirin): 25 to 50 mcg per mL (2.5 to 5 mg per 100 mL); these concentrations are generally reached with doses of 325 to 650 mg.

Time to peak effect:


Antihistamines:

Brompheniramine: 3 to 9 hours.

Chlorpheniramine: 6 hours.

Triprolidine: 2 to 3 hours.



Analgesics:


Acetaminophen—

1 to 3 hours.



Duration of action:


Antihistamines:

Ethanolamine derivatives: 6 to 8 hours.

Propylamine derivatives: 4 to 8 hours.

Pyrilamine: 8 hours.



Sympathomimetic amines:

Pseudoephedrine: 3 to 4 hours.



Analgesics:


Acetaminophen—

3 to 4 hours.



Elimination:


Antihistamines—
        Renal. Most of the antihistamines studied are excreted as metabolites within 24 hours.



Sympathomimetic amines—
        Renal.


Phenylephrine—
        2.6% of the administered oral dose is excreted unchanged. Eighty to 86% of unchanged phenylephrine and metabolites is recovered in the urine within 48 hours after oral administration.



Pseudoephedrine—
        43 to 96% is excreted unchanged in urine within 24 hours. Clearance of pseudoephedrine is more rapid in children than in adults. {15}




Analgesics—


Acetaminophen—
        Renal, as metabolites, primarily conjugates; 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.




Aspirin—
        Renal, primarily as free salicylic acid and conjugated metabolites. There are large interindividual variations in elimination kinetics. Also, the rate of excretion of total salicylate and the quantity of free salicylic acid eliminated are increased in alkaline urine and decreased in acidic urine.


In dialysis—


As salicylate—
        Hemodialysis—Clearances of 35 to 100 mL per minute have been reported.
        Peritoneal dialysis—Removed more slowly than with hemodialysis; clearances of 45 to 90 mL per hour have been reported in infants.
        Caffeine: Renal, primarily as metabolites. About 10% of a dose is excreted unchanged.






Precautions to Consider

Cross-sensitivity and/or related problems


Antihistamines

Patients sensitive to other antihistamines may be sensitive to this medication also.



Sympathomimetic amines

Patients sensitive to other sympathomimetic amines (for example, amphetamines, ephedrine, epinephrine, isoproterenol, metaproterenol, norepinephrine, terbutaline) may be sensitive to this medication also.



Acetaminophen

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



Salicylates

Patients sensitive to one salicylate, including methyl salicylate (oil of wintergreen), may be sensitive to other salicylates also. However, patients sensitive to aspirin are not necessarily sensitive to other non-acetylated salicylates, such as sodium salicylate.

Patients sensitive to other nonsteroidal anti-inflammatory drugs (NSAIDs) also may be sensitive to salicylates, especially aspirin.


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 {01}.

Pregnancy—
Although the occasional use of recommended doses of antihistamine, decongestant, and analgesic combinations during pregnancy is not likely to result in adverse effects on the fetus or newborn infant, the following information should be considered {01}.


Sympathomimetic amines


Phenylephrine—

Studies on teratogenic effects have not been done in either animals or humans with phenylephrine {01}.



Pseudoephedrine—

Studies in humans have not been done with pseudoephedrine. However, studies in animals have not shown that pseudoephedrine causes teratogenic effects on the fetus. It was shown that pseudoephedrine caused reduced average weight, length, and rate of skeletal ossification in the animal fetus. {01}




Acetaminophen

Problems in humans have not been documented. Although controlled studies have not been done, it is known that acetaminophen crosses the placenta {01}.



Salicylates


First trimester—

Salicylates readily cross the placenta. Studies in animals have shown that salicylates cause birth defects, including fissure of the spine and skull; facial clefts; eye defects; and malformations of the CNS, viscera, and skeleton (especially the vertebrae and ribs). It has been reported that aspirin use during pregnancy may increase the risk of birth defects in humans; however, controlled studies using usual therapeutic doses of aspirin have not shown proof of teratogenicity. Studies in humans with other salicylates have not been done. {01}



Third trimester—

Pregnant women should be advised not to take aspirin during the last trimester of pregnancy unless such therapy is prescribed and monitored by a physician {01}.

Chronic, high-dose salicylate therapy may result in prolonged gestation, increased risk of postmaturity syndrome (fetal damage or death due to decreased placental function when pregnancy is greatly prolonged), and increased risk of maternal antenatal hemorrhage {01}.

Ingestion of salicylates, especially aspirin, during the last 2 weeks of pregnancy may increase the risk of fetal or neonatal hemorrhage. Also, the possibility must be considered that regular use of aspirin during late pregnancy may result in constriction or premature closure of the fetal ductus arteriosus, possibly leading to persistent pulmonary hypertension and heart failure in the neonate. {01}

Overuse or abuse of aspirin late in pregnancy has been reported to reduce birthweight and to increase the risk of stillbirth or neonatal death, possibly because of prepartum maternal or fetal hemorrhage or premature ductus arteriosus closure; however, studies using therapeutic doses of aspirin have not shown these adverse effects.




Caffeine

Studies in animals have shown that caffeine causes skeletal abnormalities in the digits and phalanges (when given in doses equivalent to the caffeine content of 12 to 24 cups of coffee daily throughout pregnancy or when given in very large single doses, i.e., 50 to 100 mg per kg of body weight [mg/kg]) and retarded skeletal development (when given in lower doses). However, studies in humans have not shown that caffeine causes birth defects. {01}



Labor and delivery—

Salicylates: Chronic, high-dose salicylate therapy late in pregnancy may result in prolonged labor, complicated deliveries, and increased risk of maternal or fetal hemorrhage {01}.

Breast-feeding


Antihistamines:

Small amounts of antihistamines are distributed into breast milk; use is not recommended in nursing mothers because of the risk of antihistamines causing excitement or irritability in infants. Also, antihistamines may inhibit lactation because of their anticholinergic action.



Sympathomimetic amines:

Small amounts of sympathomimetic amines are distributed into breast milk; use is not recommended in nursing mothers because of the high risk for infants from sympathomimetic amines. {02}

Pseudoephedrine: Approximately 0.5% of an oral dose is distributed into breast milk over 24 hours. {16}



Acetaminophen:

Problems in humans have not been documented. Although peak concentrations of 10 to 15 mcg per mL 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.



Salicylates:

Problems in humans with usual analgesic doses have not been documented; however, salicylate is distributed into breast milk; with chronic, high-dose use, intake by the infant may be high enough to cause adverse effects.

In one study, peak salicylate concentrations of 173 to 483 mcg per mL were measured in breast milk 5 to 8 hours after maternal ingestion of a single 650-mg dose of aspirin. The half-life in breast milk was 3.8 to 12.5 hours (average 7.1 hours).



Caffeine:

Caffeine is distributed into breast milk in very small amounts; at recommended doses, concentration in the infant is considered insignificant.


Pediatrics


Antihistamines:

Use of antihistamines is not recommended in newborn or premature infants. This age group may be at a higher risk than other age groups because of an increased susceptibility to anticholinergic effects, such as CNS excitation, and an increased tendency toward convulsions. {14}

In children taking antihistamines, a paradoxical reaction characterized by hyperexcitability may occur.



Sympathomimetic amines:

Very young children may be more sensitive to the effects, especially the vasopressor effects, of sympathomimetic amines. {07}



Acetaminophen and salicylate combinations:

The use of acetaminophen and salicylate combinations in children is controversial. Many clinicians recommend that these medications not be given to children below 12 years of age. However, other clinicians advise that these medications may be given to children, provided that proper dosage can be achieved with the individual product.



Salicylates:

Pediatric patients, especially those with fever and dehydration, may be more susceptible to the toxic effects of salicylates.

Aspirin use may be associated with the development of Reye's syndrome in children with acute febrile illnesses, especially influenza and varicella. It is recommended that salicylate therapy not be initiated in febrile pediatric patients until after the presence of such an illness has been ruled out. Also, it is recommended that chronic salicylate therapy in these patients be discontinued if a fever occurs, and not resumed until it has been determined that an illness that may predispose to Reye's syndrome is not present or has run its course.




Adolescents

Salicylates—Aspirin use may be associated with the development of Reye's syndrome in adolescents with acute febrile illnesses, especially influenza and varicella. It is recommended that salicylate therapy not be initiated in febrile adolescent patients until after the presence of such an illness has been ruled out. Also, it is recommended that chronic salicylate therapy in these patients be discontinued if a fever occurs, and not resumed until it has been determined that an illness that may predispose to Reye's syndrome is not present or has run its course.


Geriatrics


Antihistamines—Confusion, dizziness, sedation, hypotension, hyperexcitability, and anticholinergic side effects, such as dryness of mouth and urinary retention (especially in males), may be more likely to occur in geriatric patients taking antihistamines. If the anticholinergic side effects occur and continue or are severe, medication should probably be discontinued.

Sympathomimetic amines—Confusion, hallucinations, seizures, and CNS depression may be more likely to occur in geriatric patients taking sympathomimetic amines. {03} {07} Geriatric patients may also be more sensitive to the other effects, especially to the vasopressor effects, of sympathomimetic amines.

Salicylates—Geriatric patients may be more susceptible to the toxic effects of salicylates, possibly because of decreased renal function.


Dental

Prolonged use of antihistamines may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

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.

» Alcohol or
» CNS depression–producing medications, other (see Appendix II )    (concurrent use may potentiate the CNS depressant effects of either these medications or antihistamines)


» Anesthetics, hydrocarbon inhalation, such as:
Chloroform
Cyclopropane
Enflurane
Halothane
Isoflurane
Methoxyflurane
Trichloroethylene, or
» Digitalis glycosides    (cardiac arrhythmias may occur when phenylephrine or pseudoephedrine is used prior to anesthesia or concurrently with digitalis glycosides, since these medications may sensitize the myocardium to the effects of the sympathomimetics )


» Anticholinergics or other medications with anticholinergic activity (see Appendix II ) or
Antihistamines, other    (anticholinergic effects may be potentiated when these medications are used concurrently with antihistamines; patients should be advised to report occurrence of gastrointestinal problems promptly, since paralytic ileus may occur with concurrent therapy)


» Antidepressants, tricyclic, or
Maprotiline    (concurrent use with antihistamines may potentiate the CNS depressant effects of these medications or the antihistamine contained in these combinations )

    (concurrent use may potentiate the cardiovascular effects of sympathomimetic amines)


Antihypertensives or
Diuretics used as antihypertensives    (antihypertensive effects may be reduced when these medications are used concurrently with sympathomimetic amines; the patient should be carefully monitored to confirm that the desired effect is being obtained)


» Beta-adrenergic blocking agents, oral    (concurrent use with sympathomimetic amines may result in significant hypertension and excessive bradycardia with possible heart block; concurrent use requires careful monitoring)


» CNS stimulation–producing medications, other (see Appendix II )    (concurrent use with pseudoephedrine may result in additive CNS stimulation to excessive levels, which may cause unwanted effects, such as nervousness, irritability, insomnia, or possibly convulsions or cardiac arrhythmias)


Doxapram    (concurrent use may increase the pressor effects of either doxapram or sympathomimetic amines)


» Monoamine oxidase (MAO) inhibitors, including furazolidone and procarbazine    (concurrent use with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines; concurrent use is not recommended )

    (concurrent use with sympathomimetic amines may prolong and intensify the cardiac stimulant and vasopressor effects [including headache, cardiac arrhythmias, vomiting, sudden and severe hypertensive and hyperpyretic crises] of phenylephrine and pseudoephedrine because of release of catecholamines, which accumulate in intraneuronal storage sites during MAO inhibitor therapy; these medications should not be administered during or within 14 days following the administration of an MAO inhibitor)


Ototoxic medications (see Appendix II )    (concurrent use with antihistamines may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo)


» Rauwolfia alkaloids    (concurrent use may inhibit the indirect-acting sympathomimetic action of pseudoephedrine by depleting catecholamine stores, and may theoretically prolong the action of direct-acting sympathomimetics, such as phenylephrine, by preventing uptake into storage granules)


For acetaminophen-containing combinations (in addition to the interactions listed for other ingredients)
» 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 butalbital] 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 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)


Anti-inflammatory drugs, nonsteroidal (NSAIDs), or
Aspirin or other salicylates    (prolonged concurrent use of acetaminophen with a salicylate is not recommended because 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)

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

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


» Zidovudine    (acetaminophen may competitively inhibit the hepatic glucuronidation and decrease the clearance of zidovudine; zidovudine may also inhibit the hepatic glucuronidation of acetaminophen; concurrent use should be avoided because the toxicity of either or both medications may be potentiated)


For salicylate-containing combinations (in addition to the interactions listed for other ingredients)
Acetaminophen    (prolonged concurrent use of acetaminophen with a salicylate is not recommended because 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)


Acidifiers, urinary, such as:
Ammonium chloride
Ascorbic acid
Potassium or sodium phosphates     (acidification of the urine by these medications decreases excretion of salicylate, leading to increased salicylate plasma concentrations)


Alcohol or
» Anti-inflammatory drugs, nonsteroidal (NSAIDs), other     (risk of gastrointestinal side effects, including ulceration and gastrointestinal blood loss, may be increased when these agents are used concurrently with aspirin or sodium salicylate; also, concurrent use of aspirin or sodium salicylate with other NSAIDs may increase the risk of severe gastrointestinal side effects without providing additional symptomatic relief and is therefore not recommended )

    (aspirin may decrease the bioavailability of many NSAIDs, including diflunisal, fenoprofen, indomethacin, ketoprofen, meclofenamate, piroxicam, and the active sulfide metabolite of sulindac)

    (concurrent use of other NSAIDs with aspirin may also increase the risk of bleeding at sites other than the gastrointestinal tract because of additive inhibition of platelet aggregation)


» Alkalizers, urinary, such as:
Carbonic anhydrase inhibitors
Citrates, or
Antacids, chronic high-dose use, especially calcium- and/or magnesium-containing or sodium bicarbonate    (alkalinization of the urine by these agents increases excretion of salicylate [from aspirin], leading to decreased salicylate plasma concentrations, reduced effectiveness, and shortened duration of analgesic action)

    (carbonic anhydrase inhibitors may also increase the risk of salicylate intoxication in patients receiving large doses of aspirin or sodium salicylate, because metabolic acidosis induced by carbonic anhydrase inhibitors may increase penetration of salicylate into the brain; the increased risk of severe metabolic acidosis and salicylate toxicity must be considered if acetazolamide is used to produce forced alkaline diuresis in the treatment of aspirin overdose)


» Anticoagulants, coumarin- or indandione-derivative, or
» Heparin or
» Thrombolytic agents, such as:
Alteplase (tissue-type plasminogen activator, recombinant)
Anistreplase
Streptokinase
Urokinase     (effects of coumarin- or indandione-derivative anticoagulants may be increased because of displacement by aspirin or sodium salicylate from protein-binding sites)

    (concurrent use with combinations containing aspirin is not recommended because aspirin-induced inhibition of platelet function may lead to prolonged bleeding time and hemorrhage in patients receiving anticoagulant or thrombolytic therapy)

    (the potential occurrence of gastrointestinal ulceration or hemorrhage during salicylate therapy, especially aspirin, may cause increased risk to patients receiving anticoagulant or thrombolytic therapy)


Anticonvulsants, hydantoin {18} {19} {20} {21} {22}    (aspirin may decrease metabolism of hydantoin anticonvulsants, leading to increased serum concentrations and to increased therapeutic and/or toxic effects of the anticonvulsant; adjustment of hydantoin dosage may be necessary)


» Antidiabetic agents, oral, or
Insulin    (hypoglycemic effects of these medications may be increased by large doses of aspirin or sodium salicylate; dosage adjustments may be necessary; potentiation of oral antidiabetic agents may partially be caused by displacement from serum proteins; glipizide and glyburide, because of their nonionic binding characteristics, may not be affected as much as the other oral agents; however, caution in concurrent use is recommended with all of these agents)


Antiemetics, including antihistamines and phenothiazines    (antiemetics may mask the symptoms of aspirin- or sodium salicylate–induced ototoxicity, such as dizziness, vertigo, and tinnitus)


Bismuth subsalicylate    (repeated ingestion of large doses as for traveler's diarrhea may produce substantial plasma salicylate concentrations; concurrent use with large doses of analgesic salicylates may increase the risk of salicylate toxicity)


» Cefamandole or
» Cefoperazone or
» Cefotetan or
» Plicamycin    (these medications may cause hypoprothrombinemia and/or inhibition of platelet aggregation; concurrent use with aspirin may increase the risk of bleeding because of additive inhibition of platelet aggregation and/or the potential occurrence of gastrointestinal ulceration or hemorrhage during therapy with aspirin)


Laxatives, cellulose-containing    (concurrent use may reduce the salicylate effect because of physical binding or other absorptive hindrance; medications should be administered 2 hours apart)


» Methotrexate    (aspirin or sodium salicylate may displace methotrexate from its binding sites and decrease its renal clearance, leading to toxic plasma concentrations of methotrexate; if these medications are used concurrently, methotrexate dosage should be decreased, the patient observed for signs of toxicity, and/or methotrexate plasma concentration monitored; also, it is recommended that salicylate therapy be discontinued 24 to 48 hours prior to, and not resumed for at least 12 hours following, administration of a high-dose methotrexate infusion)


Ototoxic medications, other (see Appendix II) especially
» Vancomycin    (concurrent or sequential administration of these medications with aspirin or sodium salicylate should be avoided because the potential for ototoxicity may be increased, especially with long-term, high-dose use or overdose of salicylates; hearing loss may occur and may progress to deafness even after discontinuation of the medication; these effects may be reversible, but usually are permanent)

    (concurrent use of furosemide with high doses of aspirin or sodium salicylate may lead to salicylate toxicity because of competition for renal excretory sites)


» Platelet aggregation inhibitors, other (see Appendix II )    (concurrent use with combinations containing aspirin is not recommended because of the increased risk of hemorrhage resulting from additive inhibition of platelet aggregation, the potential occurrence of gastrointestinal ulceration or hemorrhage during aspirin therapy, and the hypoprothrombinemic effect of large doses of aspirin)

    (plicamycin may cause hypoprothrombinemia as well as inhibition of platelet aggregation; concurrent use of plicamycin with aspirin may be especially hazardous {01})


» Probenecid or
» Sulfinpyrazone    (concurrent use of aspirin or sodium salicylate is not recommended when these medications are used to treat hyperuricemia or gout, because uricosuric effects of probenecid or sulfinpyrazone may be decreased by doses of aspirin or sodium salicylate that produce serum salicylate concentrations above 50 mcg per mL; also, probenecid may decrease renal clearance and increase plasma concentrations of salicylate, thereby increasing the risk of toxicity)

    (sulfinpyrazone may decrease salicylate [from aspirin or sodium salicylate] excretion and/or displace salicylate from its protein binding sites, possibly leading to increased salicylate concentrations and toxicity)

    (concurrent use of sulfinpyrazone with aspirin may increase the risk of gastrointestinal ulceration or hemorrhage; also, concurrent use of sulfinpyrazone with aspirin may increase the risk of bleeding at sites other than the gastrointestinal tract because of additive inhibition of platelet aggregation)


Salicylic acid (topical)    (concurrent use with salicylates may increase the risk of salicylate toxicity if significant quantities are absorbed)


Vitamin K    (requirements for this vitamin may be increased in patients receiving high doses of aspirin or sodium salicylate)


» Zidovudine    (aspirin may competitively inhibit the hepatic glucuronidation and decrease the clearance of zidovudine leading to potentiation of zidovudine toxicity; the possibility must be considered that aspirin toxicity may also be increased; concurrent use of the 2 medications should be avoided)


For caffeine-containing combinations (in addition to the interactions listed for other ingredients)
CNS stimulation–producing medications, other (see Appendix II )    (concurrent use with caffeine may result in excessive CNS stimulation, leading to unwanted effects such as nervousness, irritability, insomnia, or possibly convulsions or cardiac arrhythmias; close observation is recommended)



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
Skin tests using allergen extracts    (antihistamines contained in these combinations may inhibit the cutaneous histamine response thus producing false-negative results; it is recommended that antihistamine-containing medication be discontinued at least 72 hours before testing begins)


For acetaminophen-containing combinations:
Glucose, blood, determinations    (acetaminophen may cause falsely decreased values 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), urine, determinations    (acetaminophen may cause false-positive results in qualitative screening tests using nitrosonaphthol reagent; the quantitative test is unaffected)


Pancreatic function determinations using bentiromide    (administration of acetaminophen prior to the bentiromide test 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 cause falsely increased values when the phosphotungstate uric acid test method is used)


For salicylate-containing combinations:
Gerhardt test for urine aceto-acetic acid    (interference may occur with aspirin or sodium salicylate because reaction with ferric chloride produces a reddish color that persists after boiling )


5-Hydroxyindoleacetic acid (5-HIAA), urine, determinations    (aspirin may alter results when fluorescent method is used)


Protirelin-induced thyroid-stimulating hormone (TSH) release    (TSH response to protirelin may be decreased by aspirin doses of 2 to 3.6 grams daily; peak TSH concentrations occur at the same time after administration but are reduced)


Renal function test using phenolsulfonphthalein (PSP)    (salicylate [from aspirin] may competitively inhibit renal tubular secretion of PSP, thereby decreasing urinary PSP concentration and invalidating test results)


Vanillylmandelic acid (VMA), urine    (concentrations may be falsely increased or decreased by aspirin or sodium salicylate, depending on method used)

With physiology/laboratory test values

For acetaminophen-containing combinations
Bilirubin, serum, and
Lactate dehydrogenase (LDH), serum, and
Prothrombin time and
Transaminase, serum    (prothrombin time and concentrations of bilirubin, LDH, and transaminase may be increased indicating acetaminophen-induced hepatotoxicity, especially in alcoholics, patients taking hepatic enzyme–inducing agents, or those with pre-existing hepatic disease, when single toxic doses [> 8–10 grams] are taken or with prolonged use of lower doses [> 3–5 grams a day])


For salicylate-containing combinations
Bleeding time    (may be prolonged by aspirin for 4 to 7 days because of suppressed platelet aggregation; as little as 40 mg of aspirin affects platelet function for at least 96 hours following administration; however, clinical bleeding problems have not been reported with small doses [150 mg or less])


Potassium, serum    (concentrations may be decreased by aspirin or sodium salicylate because of increased potassium excretion caused by direct effect on renal tubules )


Uric acid, serum    (concentrations may be increased with doses of aspirin or sodium salicylate producing plasma salicylate concentrations below 100 to 150 mcg per mL or decreased with doses producing plasma salicylate concentrations above 100 to 150 mcg per mL)


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).


Except under special circumstances, this medication should not be used when the following medical problems exist::

For salicylate-containing combinations:
» Bleeding ulcers or
» Hemorrhagic states, other active    (may be exacerbated because of antiplatelet action of aspirin or sodium salicylate and decreased procoagulant factor synthesis [with high doses])


» Hemophilia or other bleeding problems, including coagulation or platelet function disorders    (risk of hemorrhage is increased by aspirin or sodium salicylate)


Risk-benefit should be considered when the following medical problems exist:
Asthma, acute    (although antihistamines may decrease allergen-induced bronchoconstriction, anticholinergic drying effects may cause thickening of secretions and impair expectoration during an acute episode of asthma)


» Bladder neck obstruction or
» Urinary retention, predisposition to    (anticholinergic effects of antihistamines may precipitate or aggravate urinary retention)


» Cardiovascular disease    (pressor effects and increase in heart rate may be exacerbated due to sympathomimetic amine–induced cardiovascular effects)


» Diabetes mellitus    (sympathomimetic amines may increase risk of developing cardiovascular disease )


Glaucoma, angle-closure, or predisposition to    (increased intraocular pressure may precipitate an acute attack of angle-closure glaucoma)


Glaucoma, open angle    (mydriatic effect may cause a slight increase in intraocular pressure; glaucoma therapy may need to be adjusted)


Hepatic function impairment    (increased risk of hepatotoxicity because of decreased metabolism of acetaminophen and/or salicylates; also, in severe hepatic function impairment, inhibition of platelet aggregation by aspirin may increase risk of hemorrhage)


Hypertension    (vasoconstrictive properties of sympathomimetic amines may exacerbate condition )


» Hypertension, severe    (pressor effect of sympathomimetic amines may precipitate a hypertensive crisis)


» Hyperthyroidism    (characterized by tachycardia, which may be increased due to cardiac stimulant properties of sympathomimetic amines)


» Prostatic hypertrophy, symptomatic    (reduction in tone of urinary bladder due to anticholinergic effect of antihistamines may lead to complete urinary retention)


Renal function impairment, severe    (increased risk of adverse renal effects, especially with prolonged use of high doses)


For acetaminophen-containing combinations (in addition to those listed for other ingredients):
» Alcoholism (active) or
» Viral hepatitis    (increased risk of hepatotoxicity)


For salicylate-containing combinations (in addition to those listed for other ingredients):
Anemia    (increased gastrointestinal blood loss may exacerbate condition, especially with aspirin; also, pseudoanemia may result from peripheral vasodilation)


» Asthma, allergies, and nasal polyps, aspirin-sensitivity induced    (increased risk of bronchospastic hypersensitivity reactions with aspirin )


» Gastritis, erosive, or
» Ulcer, peptic    (may be exacerbated because of ulcerogenic effects; risk of gastrointestinal bleeding is increased)


Gout    (aspirin or sodium salicylate may increase serum uric acid concentrations; also, may interfere with efficacy of uricosuric antigout agents)


Hypoprothrombinemia or
Vitamin K deficiency    (increased risk of bleeding because of antiplatelet action of salicylates and decreased procoagulant factor synthesis with high doses)


For caffeine-containing combinations (in addition to those listed for other ingredients):
Cardiac disease, severe    (high doses of caffeine may increase risk of tachycardia or extrasystoles, which may lead to heart failure)




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
For all combinations
Incidence rare
—more frequent with high doses    
Allergic reactions (skin rash; hives; itching)
    
anemia (unusual tiredness or weakness)—with the use of acetaminophen- or salicylate-containing combinations
    
blood dyscrasias (sore throat; fever; unusual bleeding or bruising; unusual tiredness or weakness)
    
psychotic episodes (mood or mental changes)—usually associated with previous history of psychiatric illness
    
tightness in chest


Symptoms of overdose
    
Anticholinergic effects (clumsiness or unsteadiness; severe dryness of mouth, nose, or throat; flushing or redness of face; shortness of breath or troubled breathing)
    
CNS stimulation (hallucinations; seizures; trouble in sleeping)
    
severe drowsiness
    
hypertension (continuing headache; fast heartbeat)

For acetaminophen-containing combinations (in addition to those listed for all combinations)
Incidence rare
    
Azotemia
uremia
renal colic
sterile pyuria —with prolonged use of high doses in patients with severe renal function impairment
    
renal tubular necrosis (bloody or cloudy urine, difficult or painful urination, sudden decrease in amount of urine)—in overdosage
    
hepatitis (yellow eyes or skin)


Symptoms of overdose
    
Diarrhea
increased sweating
loss of appetite
nausea
vomiting
stomach cramps or pain (early symptoms—may occur within 6 to 14 hours after ingestion and persist for about 24 hours)
    
hepatotoxicity —symptoms may occur 2 to 4 days after ingestion (pain or tenderness in upper abdominal area, swelling of abdominal area)

Note: Signs and symptoms of possible liver damage and abnormalities in liver function tests may not occur until 2 to 4 days after ingestion of an overdose. Maximal changes in liver function tests usually occur 3 to 5 days after ingestion.
Overt hepatic disease or failure may occur 4 to 6 days after ingestion. 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, cardiac arrhythmias, and cardiovascular collapse may occur.


For salicylate-containing combinations (in addition to those listed for all combinations)
Incidence more frequent
    
Gastrointestinal irritation (mild stomach pain; nausea with or without vomiting)

Incidence less frequent or rare
    
Anaphylactoid reaction (bluish discoloration or flushing or redness of skin; coughing; difficulty in swallowing; severe dizziness or feeling faint; skin rash; hives [may include giant urticaria]; itching; stuffy nose; swelling of eyelids, face, or lips; tightness in chest, troubled breathing, and/or wheezing, especially in asthmatic patients)
    
anemia (unusual tiredness or weakness)—may occur secondary to gastrointestinal microbleeding
    
bronchospastic allergic reaction (shortness of breath, troubled breathing, tightness in chest, or wheezing)
    
gastrointestinal bleeding or ulceration (bloody or black, tarry stools; severe stomach pain; vomiting of blood or material that looks like coffee grounds)


Symptoms of overdose
    
Salicylism, mild (any loss of hearing; confusion; severe or continuing diarrhea; dizziness or lightheadedness; severe drowsiness; fast or deep breathing; severe or continuing headache; increased sweating; continuing nausea or vomiting; continuing ringing or buzzing in ears; severe or continuing stomach pain; uncontrollable flapping movements of the hands, especially in elderly patients; unusual thirst; vision problems)
    
salicylism, severe (bloody urine; convulsions; fever; hallucinations; shortness of breath or troubled breathing)
Note: In young children, the only signs of an overdose may be changes in behavior, severe drowsiness or tiredness, and/or fast or deep breathing.
Laboratory findings in overdose may indicate encephalographic abnormalities, alterations in acid-base balance (especially respiratory alkalosis and metabolic acidosis), hyperglycemia or hypoglycemia (especially in children), ketonuria, hyponatremia, hypokalemia, and proteinuria.





Those indicating possible analgesic nephropathy with combination analgesic/antipyretic medications and the need for medical attention if they occur during or following long-term high-dose use
Incidence rare
    
Bloody or cloudy urine
    
difficult or decreased urination
    
swelling of face, feet, or lower legs
    
weight gain, unusual



Those indicating need for medical attention only if they continue or are bothersome
For all combinations
Incidence more frequent
    
Drowsiness
    
thickening of mucus

Incidence less frequent
—more frequent with high doses    
Blurred vision
    
confusion
    
difficult or painful urination
    
dizziness
    
dryness of mouth, nose, or throat
    
headache
    
loss of appetite
    
paradoxical reaction (nightmares; unusual excitement, nervousness, restlessness, or irritability)
    
pounding heartbeat
    
ringing or buzzing in ears
    
skin rash
    
stomach upset or pain


For salicylate-containing combinations (in addition to those listed for all combinations)
Incidence more frequent
    
Heartburn or indigestion






Overdose

Treatment of overdose


Recommended treatment of overdose consists of the following:
For acetaminophen-containing combinations

   • Emptying the stomach via induction of emesis or gastric lavage.
   • Administering activated charcoal. However, activated charcoal may interfere with absorption of oral acetylcysteine (antidote used to protect against acetaminophen-induced hepatotoxicity); removal of activated charcoal via gastric lavage may be advisable prior to acetylcysteine administration.
   • For excessive hypertensive effect—An alpha-adrenergic blocker, such as phentolamine, may be administered.
   • The cardiac state should be monitored and serum electrolytes measured.
   • Administering 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. For oral administration, the recommended adult dose of acetylcysteine is 140 mg per kg of body weight (mg/kg) initially, then 70 mg/kg every 4 hours for 17 doses. Each dose should be diluted to a 5% solution with cola or other soft drinks prior to administration because of acetylcysteine's unpleasant odor and its irritating or sclerosing properties. Consult the manufacturer's prescribing information for a table showing quantities of acetylcysteine (20% solution) and diluent needed to prepare a 5% solution containing the required initial dose and subsequent doses for patients weighing up to 109 kg. Any dose vomited within 1 hour of administration must be repeated. If necessary, the antidote may be given (diluted with water) via duodenal intubation.
   • 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 at 4 hours, 100 mcg per mL at 6 hours, 70 mcg per mL at 8 hours, 50 mcg per mL at 10 hours, 20 mcg per mL at 15 hours, 8 mcg per mL at 20 hours, or 3.5 mcg per mL 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 to ascertain peak absorption and half-life of acetaminophen prior to considering discontinuation of acetylcysteine.
   • 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 this treatment in preventing acetaminophen-induced hepatotoxicity is not known.
   • Performing liver function tests (serum aspartate aminotransferase [AST; SGOT], serum alanine aminotransferase [ALT; 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.
   • Instituting supportive treatment, including 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).
For salicylate-containing combinations

   • Emptying the stomach via induction of emesis or gastric lavage.
   • Administering activated charcoal.
   • For excessive hypertensive effect—An alpha-adrenergic blocker, such as phentolamine, may be administered.
   • The cardiac state should be monitored and serum electrolytes measured.
   • Correcting hyperthermia; fluid, electrolyte, and acid-base imbalances; ketosis; and plasma glucose concentration as needed.
   • Monitoring serum salicylate concentration until it is apparent that the concentration is decreasing to the nontoxic range. Salicylate concentrations of 500 mcg per mL 2 hours after ingestion indicate serious toxicity; salicylate concentrations above 800 mcg per mL 2 hours after ingestion indicate possible fatality. In addition, prolonged monitoring may be necessary in massive overdosage because absorption may be delayed.
   • Inducing forced alkaline diuresis to increase salicylate excretion. However, bicarbonate should not be administered orally for this purpose because salicylate absorption may be increased. Also, if acetazolamide is used, the increased risk of severe metabolic acidosis and salicylate toxicity (caused by increased penetration of salicylate into the brain because of metabolic acidosis) must be considered. It is recommended that acetazolamide be given concurrently with an alkaline intravenous solution, e.g., one that contains sodium bicarbonate or sodium lactate.
   • Institution of exchange transfusion, hemodialysis, peritoneal dialysis, or hemoperfusion as needed in severe overdose.
   • Monitoring for pulmonary edema and instituting appropriate therapy if required.
   • Administering blood or vitamin K 1 if necessary to treat hemorrhaging.



Patient Consultation

Note: Products containing phenylpropanolamine were removed from the U.S. and Canadian Markets in November 2000

As an aid to patient consultation, refer to Advice for the Patient, Antihistamines, Decongestants, and Analgesics (Systemic) .

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

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any of the medications in the combination being taken

Pregnancy—Concern for the fetus and/or newborn infant only with high doses and long-term therapy; use of aspirin-containing combinations not recommended during third trimester





Breast-feeding—Antihistamines may cause excitement or irritability in nursing infant; high risk for infants from sympathomimetic amines; also, concern with high doses and chronic use because of high salicylate intake by infant





Use in children—Increased susceptibility to anticholinergic effects of antihistamines and to vasopressor effects of sympathomimetic amines; hyperexcitability (paradoxical reaction) may occur; also, increased susceptibility to toxic effects of salicylates, especially if fever and dehydration present; possible association between aspirin usage and Reye's syndrome




Use in adolescents—
Possible association between aspirin usage and Reye's syndrome






Use in the elderly—Anticholinergic and CNS stimulant effects more likely to occur; increased susceptibility to toxic effects of salicylates
Other medications, especially anticholinergics, medicine for high blood pressure or depression, or CNS depressants or stimulants
Other medical problems, especially alcoholism, cardiovascular disease, diabetes, gastritis or peptic ulcer (with salicylate-containing), hypertension, hyperthyroidism, or prostatic hypertrophy

Proper use of this medication
» Importance of not taking more medication than the amount recommended

Taking with food, water, or milk to minimize gastric irritation

Swallowing extended-release dosage form whole

» Not taking combinations containing aspirin if a strong vinegar-like odor is present

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

» Proper storage

Precautions while using this medication
Caution if skin tests using allergens required; possible interference with test results

Checking with physician if symptoms persist or become worse, or if high fever is present

» Avoiding alcoholic beverages or other CNS depressants while taking these medications; also, alcohol consumption may increase risk of salicylate-induced gastrointestinal toxicity and acetaminophen-induced liver toxicity

» Caution if drowsiness or dizziness occurs

» Possible insomnia; taking the medication a few hours before bedtime

» Caution if taking appetite suppressants

Need to inform physician or dentist of use of medication if any kind of surgery (including dental surgery) or emergency treatment is required

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with dentist if dry mouth continues for more than 2 weeks

» Caution if other medications containing acetaminophen, aspirin, or other salicylates (including diflunisal) are used

» Suspected overdose: Getting emergency help at once

Not taking products containing aspirin for 5 days prior to any kind of surgery, unless otherwise directed by physician

Diabetics: Aspirin present in some combination formulations may cause false urine sugar test results with prolonged use of 8 or more 325-mg (5-grain) doses per day


Side/adverse effects
Signs of potential side effects, especially allergic reactions, anticholinergic effects, blood dyscrasias, jaundice (with acetaminophen-containing), and signs of gastrointestinal irritation or bleeding (with salicylate-containing)


General Dosing Information
This medication may be taken with food, water, or milk to lessen gastric irritation.

ANTIHISTAMINES, DECONGESTANTS, AND ANALGESICS


Oral Dosage Forms

Note: Products containing phenylpropanolamine were removed from the U.S. and Canadian Markets in November 2000{27}

Table 1. Oral Dosage Forms


Note: Content per capsule, tablet, or 5 mL, unless otherwise stated.



Brand or
generic name
[availability]
Antihistamines
Decongestants
Analgesics
Other
content
information
as per
product
label
Usual adult and
adolescent
dose *
(prn)
Usual
pediatric
dose (prn)
Packaging,
storage,
and
auxiliary
labeling
Actifed Cold & Sinus Caplets Tablets (OTC)
[U.S.]
Chlorpheniramine
Maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  2 tabs q 6 hr
(max 8 tabs/day)
Not
recommended
a, d
Actifed Plus Extra Strength Caplets Tablets (OTC)
[Canada]
Triprolidine
HCl 2.5 mg
Pseudoephedrine
HCl 60 mg
Acetaminophen
500 mg
Scored
1 tab q 4–6 hr
(max 4 tabs/day)
  a, d
Alka-Seltzer Plus Cold Medicine Liqui-Gels Capsules (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  a, d
Benadryl Allergy/ Sinus Headache Caplets Tablets (OTC)
[U.S.]
Diphenhydramine
HCl 12.5 mg
Pseudoephedrine HCl 30 mg
Acetaminophen 500 mg
  2 tabs q 6 hr (max 8 tabs/day)
  a, d
Children"s Tylenol Cold Multi-Symptom Oral Solution (OTC)
[U.S.]
Chlorpheniramine
maleate 1 mg
Pseudoephedrine
HCl 15 mg
Acetaminophen
160 mg
Sorbitol
Alcohol free
Intended for
pediatric use
2–5 yrs:
5 mL,
6–11 yrs:
10 mL,
q 4–6 hr
(max 4 doses/day)
a, c, d
Chewable Tablets
(OTC)
[U.S.]
Chlorpheniramine
maleate 0.5 mg
Pseudoephedrine
HCl 7.5 mg
Acetaminophen
80 mg
Phenylalanine
4 mg
Scored
Intended for
pediatric use
2–5 yrs:
2 tabs,
6–11 yrs:
4 tabs,
q 4–6 hr
(max 4 doses/day)
a, d
Comtrex Allergy-Sinus Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
Coated
2 tabs
q 6 hr
(max 8 tabs/day)
  a, d
Comtrex Allergy-Sinus Caplets Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
Coated
2 tabs
q 6 hr
(max 8 tabs/day)
  a, d
Contac Allergy/ Sinus Night Caplets Tablets
(OTC)
[U.S.]
Diphenhydramine
HCl 50 mg
Pseudoephedrine
HCl 60 mg
Acetaminophen
650 mg
In dual
package that
also contains
Contac Allergy/Sinus Day Caplets
1 tab q 6 hr
(max 4 tabs/day
of any
combination of Day or
Night Caplets)
  a, d
Dimetapp Cold & Fever Suspension Oral Suspension
(OTC)
[U.S.]
Brompheniramine
maleate 1 mg
Pseudoephedrine
HCl 15 mg
Acetaminophen
160 mg
  Intended for
pediatric use
6–11 mos:
2.5 mL,
12–23 mos:
5 mL,
q 6–8 hr
(max 4 doses/day);
2–6 yrs:
5 mL,
6–12 yrs:
10 mL,
q 4 hr
a, c, d, e
Dristan Capsules (OTC)
[Canada]
Chlorpheniramine
maleate 2 mg
Phenylephrine
HCl 5 mg
Acetaminophen
325 mg
  2 caps or
tabs q 4 hr
(max 8 caps
or tabs/day)
6–12 yrs:
1 cap or tab
q 4 hr
(max 4 caps
or tabs/day)
a, d
Tablets (OTC)
[Canada]
             
Dristan Cold Multi-Symptom Formula Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Phenylephrine
HCl 5 mg
Acetaminophen
325 mg
  2 tabs
q 4 hr
  a, d
Dristan Extra Strength Caplets Tablets (OTC)
[Canada]
Chlorpheniramine
maleate 2 mg
Phenylephrine
HCl 5 mg
Acetaminophen
500 mg
  2 tabs
q 4–6 hr
(max 8 tabs/day)
  a, d
Dristan Formula P Tablets (OTC)
[Canada]
Pyrilamine
maleate 12.5 mg
Phenylephrine
HCl 5 mg
Aspirin 325 mg
Caffeine
16 mg
Tartrazine-
free
2 tabs
q 4 hr
10–14 yrs:
1 tab q 4 hr
a, d
Drixoral Allergy-Sinus Extended-release
Tablets (OTC)
[U.S.]
Dexbromphenir-
amine maleate
3 mg
Pseudoephedrine
sulfate 60 mg
Acetaminophen
500 mg
  2 tabs
q 12 hr
  b, d
Drixoral Cold and Flu Extended-release
Tablets (OTC)
[U.S.]
Dexbromphenir-
amine maleate
3 mg
Pseudoephedrine
sulfate 60 mg
Acetaminophen
500 mg
  2 tabs
q 12 hr
  b, d
Kolephrin Caplets Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
325 mg
  2 tabs
q 4–6 hr
(max 8 tabs/day)
6–12 yrs:
1 tab
q 4–6 hr
(max 4 tabs/day)
a, d
ND-Gesic Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 1 mg,
Pyrilamine
maleate 8 mg
Phenindemine
tartrate 5 mg
Phenylephrine
HCl 5 mg
Acetaminophen
300 mg
Sugar coated
  a, d
Neo Citran Nutrasweet for Oral Solution
(OTC)
[Canada]
Pheniramine
maleate
20 mg per pouch
Phenylephrine HCl
10 mg per pouch
Acetaminophen
325 mg
per pouch
Vitamin C
50 mg
per pouch
1 pouch
dissolved
in 8 oz of
hot water
q 3–4 hr
  a, d
Neo Citran Extra Strength Colds and Flu for Oral Solution
(OTC)
[Canada]
Pheniramine
maleate
20 mg per pouch
Phenylephrine HCl
10 mg per pouch
Acetaminophen
600 mg
per pouch
Vitamin C
50 mg
per pouch
1 pouch
dissolved
in 8 oz of
hot water
q 3–4 hr
  a, d
Scot-Tussin Original 5-Action Cold Formula Oral Solution (OTC)
[U.S.]
Pheniramine
maleate 13.3 mg
Phenylephrine
HCl 4.2 mg
Sodium
salicylate
83.3 mg
Caffeine citrate
25 mg;
Sodium
citrate
83.3 mg;
Alcohol free;
With or
without
sugar
5 mL
q 3–4 hr
(max 20 mL/day)
6–12 yrs:
2.5 mL
q 3–4 hr
a, c, d
Sinarest Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
325 mg
  2 tabs
q 4–6 hr
(max 8 tabs/day)
6–12 yrs:
1 tab
q 4–6 hr
(max 4 tabs/day)
a
Sine-Off Sinus Medicine Caplets Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  2 tabs
q 6 hr
(max 8 tabs/day)
  a, d
Singlet for Adults Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 4 mg
Pseudoephedrine
HCl 60 mg
Acetaminophen
650 mg
  1 tab
q 6–8 hr
(max 4 tabs/day)
  a, d
Sinutab Extra Strength Caplets Tablets (OTC)
[Canada]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  1–2 tabs
q 4–6 hr
(max 8 tabs/day)
  a, d
Sinutab Regular Caplets Tablets (OTC)
[Canada]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
325 mg
Scored
2 tabs
q 4–6 hr
(max 8 tabs/day)
6–12 yrs:
1 tab
q 4–6 hr
(max 4 tabs/day)
a, d
TheraFlu/Flu and Cold Medicine for Oral Solution
(OTC)
[U.S.]
Chlorpheniramine
maleate
4 mg per packet
Pseudoephedrine
HCl 60 mg
per packet
Acetaminophen
650 mg
per packet
  1 packet
dissolved
in 6-oz
of hot water
q 4 hr
(max 4
doses/day)
  a, d
TheraFlu/Flu and Cold Medicine for Sore Throat for Oral Solution
0 (OTC)
[U.S.]
Chlorpheniramine
maleate
4 mg per packet
Pseudoephedrine
HCl 60 mg
per packet
Acetaminophen
1000 mg
per packet
  1 packet
dissolved
in 6-oz
of hot water
q 6 hr
(max 4
doses/day)
Not
recommended
a, d
Tylenol Allergy Sinus Medication Extra Strength Caplets Tablets (OTC)
[Canada]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
Film-coated;
Tartrazine-
free
2 tabs
q 6 hr
(max 8 tabs/day)
  a, d
Tylenol Allergy Sinus Medication Maximum Strength Caplets Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  2 tabs
q 6 hr
(max 8 tabs/day)
Not
recommended
a, d
Tylenol Allergy Sinus Medication Maximum Strength Gelcaps Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  2 tabs
q 6 hr
(max 8 tabs/day)
Not
recommended
a, d
Tylenol Allergy Sinus Medication Maximum Strength Geltabs Tablets (OTC)
[U.S.]
Chlorpheniramine
maleate 2 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  2 tabs
q 6 hr
(max 8 tabs/day)
Not
recommended
a, d
Tylenol Allergy Sinus Night Time Medicine Maximum Strength Caplets Tablets (OTC)
[U.S.]
Diphenhydramine
HCl 25 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  2 tabs hs
Not
recommended
a, d
Tylenol Cold Medication Children"s Oral Solution (OTC) [Canada]  Chlorpheniramine
maleate 1 mg
Pseudoephedrine HCl 15 mg
Acetaminophen 160 mg
Sorbitol; Alcohol-free
Intended for pediatric use
2–5 yrs: 5 mL, 6–12 yrs: 10 mL, q 4–6 hr (max 4 doses/day)
a, c, d
Chewable Tablets
(OTC)
[Canada]
Chlorpheniramine
maleate 0.5 mg
Pseudoephedrine
HCl 7.5 mg
Acetaminophen
80 mg
Phenylalanine;
Scored
Intended for
pediatric use
2–5 yrs:
2 tabs,
6–12 yrs:
4 tabs,
q 4–6 hr
(max 4 doses/day)
a, d
Tylenol Flu NightTime Medication Extra Strength Gelcaps Tablets (OTC)
[Canada]
Diphenhydramine
HCl 25 mg
Pseudoephedrine
HCl 30 mg
Acetaminophen
500 mg
  1–2 tabs
q 6 hr
(max 8 tabs/day)
  a, d
{29} *  Geriatric patients may be more sensitive to the effects of usual adult dose.
 For appropriate Packaging and storage and Auxiliary labeling information refer to designated letters as follows:

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


• b—Store between 2 and 30 °C (36 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.


• c—Protect from freezing.


• d—Auxiliary labeling: o May cause drowsiness. o Avoid alcoholic beverages.


• e—Auxiliary labeling: o Shake well.





Strength(s) usually available
U.S.—
See above table.



Revised: 05/30/2002



References
  1. Product package labeling.
  1. Histalet package insert (Solvay—U.S.).
  1. Novafed A (Marion Merrell Dow) and Trinalin Repetabs (Key). In: PDR Physicians" desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989.
  1. Horowitz JD, Howes LG, Christophidis N, et al. Hypertensive responses induced by phenylpropanolamine in anorectic and decongestant preparations. Lancet 1980; 1:60-61.
  1. Lake CR, Zaloga G, Clymier R, Quirk RM, et al. A Double Dose of Phenylpropanolamine Causes Transient Hypertension. The Am J of Medicine Sept 1988; 85: 339-43.
  1. Curatolo P, Robertson D. The health consequences of caffeine. Ann Intern Med 1983; 98: 641-53.
  1. Lake CR, et al. Psychiatric side effects attributed to phenylpropanolamine. Pharmacopsychiatry 1988; 21: 171-81.
  1. Schlemmer RF, et al. Caffeine potentiates pheylpropanolamine lethality but not motor behavior (abstract). Fed Proc 1984; 43: 572.
  1. Mueller SM. Neurologic complications of phenylpropanolamine use. Neurology 1983; 33: 650-2.
  1. Bain J. Visual hallucinations in children receiving decongestants. Br Med J 1984 June; 288:1688.
  1. Logie AW. Phenylpropanolamine overdose. Br Med J 1984 Sept; 289: 591.
  1. Fallis RJ: Phenylpropanolamine—Cerebral hemorrhage and vasculitis. Reactions 1985 Apr: 9.
  1. Cuthbert MF, et al. Cough and cold remedies—potential danger to patients on MAO inhibitors. Br Med J 1969; 1: 404-6.
  1. AMA Drug evaluations. 5th ed. Chicago: American Medical Association, April 1983: 1327
  1. Johnson DA, Hricik JG. The pharmacology of alpha-adrenergic decongestants. Pharmacotherapy 1993; 13(6): 110S-15S.
  1. Kanfer I, Dowse R, Vusumuzi V. Pharmacokinetics of oral decongestants. Pharmacotherapy 1993; 13(6): 116S-28S.
  1. Raudixin (Princeton). In: PDR Physicians" desk reference. 46th ed. 1992. Montvale, NJ: Medical Economics Data, 1992: 1803.
  1. Larsen JR, Larsen LS. Clinical features and management of poisoning due to phenytoin. Med Toxicol Adverse Drug Exp 1989; 4(4): 229-45.
  1. Hansten PD, Horn JR. Drug interactions. 5th ed. Philadelphia: Lea & Febiger, 1985: 121-38.
  1. Shinn AF, Shrewsbury RP. EDI, Evaluation of drug interactions. 3rd ed. St Louis: Mosby, 1985: 229-70.
  1. Nation RL, Evans AM, Milne RW. Pharmacokinetic drug interactions with phenytoin (Part I). Clin Pharmacokinet (Jan) 1990; 18(1): 37-60.
  1. Dilantin/Phenytoin ``Right Dose"" Program. Advances in the management of acute seizures in hospitalized patients. Resource Manual. Health Sciences Institute, 1990.
  1. Fireman P. Pathophysiology and pharmacotherapy of common upper respiratory diseases. Pharmacotherapy 1993; 13(6): 101S-109S.
  1. Goodman RP et al: The effect of phenylpropanolamine on cardiovascular and sympathetic nervous system function. Clin Pharmacol Ther 1986; 40: 144-7.
  1. Hendeles L. Selecting a decongestant. Pharmacotherapy 1993; 13(6): 129S-134S.
  1. Pentel P: Toxicity of over-the-counter stimulants. JAMA 1984; 252: 1898-903.
  1. FDA Talk Paper: FDA issues public health warning on phenylpropanolamine. United States Food and Drug Administration, U.S. Department of Health and Human Services, Rockville, MD 11/2000.
  1. Horwitz, RI, Brass LM, Kernan WN, et al. Phenylpropanolamine and risk of hemorrhagic stroke: Final report of The Hemorrhagic Stroke Project (HSP). Yale University School of Medicine, New Haven, CT, 5/10/2000.
  1. Red book 2002 Online. Montvale, NJ: Medical Economics Data; 5/13/2002.
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