Prevent an allergic reaction from happening at school.

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.{51}

1) Phenylephrine and Acetaminophen  *
2) Pseudoephedrine and Acetaminophen
3) Pseudoephedrine and Ibuprofen

VA CLASSIFICATION
Primary: RE599


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



Category:


Decongestant-analgesic—

Indications

Accepted

Congestion, nasal (treatment)
Congestion, sinus (treatment) and
Headache, sinus (treatment)—Decongestant and analgesic combinations are indicated for the temporary relief of nasal and sinus congestion and headache pain caused by sinusitis, common colds , allergy, and hay fever. {01}

—The therapeutic effectiveness of oral phenylephrine as a nasal decongestant has been questioned, especially at the usual oral dose. {24} {26}

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){52}, requested that manufacturers voluntarily discontinue marketing products that contain PPA and that consumers work with their healthcare providers to select alternative products.{51}



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Sympathomimetic amines: Phenylephrine; Pseudoephedrine
    Anti-inflammatory drugs, nonsteroidal (NSAIDs): Ibuprofen; Salicylates (Aspirin; Salicylamide)
Molecular weight—
    Acetaminophen: 151.16
    Aspirin: 180.16
    Caffeine: 212.21 (monohydrate); 194.19 (anhydrous)
    Ibuprofen: 206.28
    Phenylephrine hydrochloride: 203.67
    Pseudoephedrine hydrochloride: 201.70
    Salicylamide: 137.14

pKa—
    Ibuprofen: 4.43
    Pseudoephedrine: 9.4 {26}

Mechanism of action/Effect:


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. {25}



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.

Ibuprofen: NSAIDs inhibit the activity of the enzyme cyclo-oxygenase, resulting in decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid. Ibuprofen may block pain impulse generation via a peripheral action that may involve reduction of the activity of prostaglandins, and possibly inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation.



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:

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.

Ibuprofen—NSAIDs inhibit platelet aggregation. However, their antiplatelet effect, unlike that of aspirin, is reversible. Recovery of platelet function may occur within 1 day after discontinuation of ibuprofen.

Absorption:

Sympathomimetic amines—Except for phenylephrine, most sympathomimetics are well absorbed from the gastrointestinal tract after oral administration. {26} Phenylephrine has reduced bioavailability (about 38%) from the gastrointestinal tract because of first-pass metabolism by monoamine oxidase in the stomach and liver. {26}

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.

Ibuprofen—Rapid; rate of absorption may be decreased by food.

Caffeine—Well absorbed from the gastrointestinal tract.

Protein binding:

Acetaminophen—Not significant with usual analgesic doses.

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

Salicylamide—Not extensively bound to plasma proteins.

Ibuprofen—High (to albumin).

Caffeine—Low.

Biotransformation:


Sympathomimetic amines:

Phenylephrine: Extensive, in the intestinal wall and in the liver. Sulfate conjugates are formed largely in the intestinal wall. Also, undergoes oxidative deamination by monoamine oxidase. {26}

Pseudoephedrine: Incompletely metabolized in the liver; less than 1% by N-demethylation to the active metabolite norpseudoephedrine {26}.



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.



Salicylamide:

Not hydrolyzed to salicylate in vivo . Although it is chemically and pharmacologically related to the salicylates, it is not considered a true salicylate.



Ibuprofen:

Hepatic.



Caffeine:

Hepatic.


Half-life:


Sympathomimetic amines {26}:


Phenylephrine—

2.1 to 3.4 hours.



Pseudoephedrine—

4.5 to 8 hours.

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




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.



Salicylate (from aspirin):

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



Ibuprofen:

1.8 to 2 hours.



Caffeine:

3 to 4 hours.


Onset of action:

Pseudoephedrine—30 minutes.

Ibuprofen—30 minutes.

Time to peak concentration:


Sympathomimetic amines {26}:

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

Pseudoephedrine: 1.97 hours (to achieve a concentration of 422 ng/mL).



Analgesics:

Acetaminophen: 0.5 to 2 hours.

Aspirin: Generally 1 to 2 hours with single doses.

Ibuprofen: 1.2 to 2.1 hours.


Peak serum concentration:

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

Ibuprofen—22 to 27 mcg per mL with 200-mg doses.

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:

Acetaminophen—1 to 3 hours.

Duration of action:

Pseudoephedrine—3 to 4 hours.

Acetaminophen—3 to 4 hours.

Ibuprofen—4 to 6 hours.

Elimination:


Sympathomimetic amines—
        Renal.


Phenylephrine—
        2.6% of the administered oral dose is excreted unchanged; 80 to 86% of unchanged phenylephrine and metabolites are 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. {25}




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.





Salicylamide—
        Excreted as conjugated metabolites.



Ibuprofen—
        Renal; 100% of dose excreted, with less than 1% excreted unchanged.



Caffeine—
        Renal, primarily as metabolites; about 10% of a dose is excreted unchanged.




Precautions to Consider

Cross-sensitivity and/or related problems


Sympathomimetic amines

Patients sensitive to other sympathomimetics (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 salicylamide.

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



Ibuprofen

Patients sensitive to one of the NSAIDs, including aspirin and NSAIDs no longer commercially available (such as oxyphenbutazone, suprofen, and zomepirac) may be sensitive to any of the other NSAIDs also.

NSAIDs may cause bronchoconstriction or anaphylaxis in aspirin-sensitive asthmatics, especially those with the triad of aspirin intolerance, asthma, and nasal polyps.


Pregnancy/Reproduction
{01}
Although the occasional use of decongestant and analgesic combinations during pregnancy (at the recommended OTC doses on the package label) is not likely to result in adverse effects to the fetus or newborn infant, the following information should be considered:
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—

Sympathomimetic amines


Phenylephrine—

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



Pseudoephedrine—

Studies in humans have not been done with pseudoephedrine.

Studies in animals have not shown that pseudoephedrine causes teratogenic effects on the fetus. However, pseudoephedrine has caused reduced average weight, length, and rate of skeletal ossification in the animal fetus.




Acetaminophen

Problems in humans have not been documented. Acetaminophen crosses the placenta, but controlled studies have not been done.



Salicylates


First trimester—

Salicylates readily cross the placenta. It has been reported that salicylate use during pregnancy may increase the risk of birth defects in humans; however, controlled studies using aspirin have not shown proof of teratogenicity. Studies in humans with salicylamide have not been done.

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).



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.

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. {15}

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.

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.




Ibuprofen

Although studies in humans have not been done, use of NSAIDs during the second half of pregnancy is not recommended because of possible adverse effects on the fetus, such as premature closure of the ductus arteriosus, which may lead to persistent pulmonary hypertension in the neonate.



Caffeine

Studies in humans have not shown that caffeine causes birth defects.

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).



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.

Breast-feeding


Sympathomimetic amines:

Small amounts of sympathomimetics are distributed into breast milk; use is not recommended in nursing mothers because of the high risk for infants receiving sympathomimetic amines. {03}

Pseudoephedrine: Approximately 0.5% of an oral dose is distributed into breast milk over 24 hours. {26}



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. {01}



Salicylates:

Problems in humans have not been documented with usual analgesic doses. However, salicylate is distributed into breast milk; with chronic, high-dose use, intake by the infant may be high enough to cause adverse effects. {01}

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).



Ibuprofen:

Studies in humans have failed to detect ibuprofen in breast milk using methodology capable of detecting the medication in a concentration of 1 mcg per mL. The maternal dosage was 400 mg 4 times a day. {01}



Caffeine:

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


Pediatrics


Sympathomimetic amines:

Very young children may be more sensitive to the effects, especially the vasopressor effects, of sympathomimetic amines. {07} {10}



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 {02}:

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.



Ibuprofen:

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of ibuprofen as an antipyretic in children 6 months of age or older. Safety and efficacy for use as an antipyretic in infants younger than 6 months of age have not been established.




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


Sympathomimetic amines {03}Geriatric patients may be more sensitive to other effects, especially the vasopressor effects, of sympathomimetic amines. Overdosage of sympathomimetics in geriatric patients may cause {01} confusion, hallucinations, seizures, and CNS depression.

Salicylates—Geriatric patients may be more susceptible to the toxic effects of salicylates possibly because of decreased renal function. {02}

Ibuprofen—Whether geriatric patients are at increased risk of serious gastrointestinal toxicity during NSAID therapy has not been established. However, NSAID-induced gastrointestinal ulceration and/or bleeding may be more likely to cause serious consequences, including fatalities, in geriatric patients than in younger adults. In addition, elderly patients are more likely to have age-related renal function impairment, which may increase the risk of NSAID-induced hepatic or renal toxicity and may also require dosage reduction to prevent accumulation of the medication.


Dental

NSAIDs may cause soreness, irritation, or ulceration of the oral mucosa. {01}

Most of the NSAIDs may rarely cause leukopenia and/or thrombocytopenia, which may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal, and patients should be instructed in proper oral hygiene, including caution in use of toothbrushes, dental floss, and toothpicks. {01}

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. {01} {02}


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


» Antidepressants, tricyclic or
» Maprotiline    (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 sympathomimetics; 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 and 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 sympathomimetic amines may prolong and intensify their cardiac stimulant and vasopressor effects [including headache, cardiac arrhythmias, vomiting, sudden and severe hypertensive and hyperpyretic crises] 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 {24} {26})


» 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 {27})


For acetaminophen-containing combinations (in addition to the interactions listed for other ingredients in combination)
» 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 analgesics, 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 {20} {21})


For salicylate-containing combinations (in addition to the interactions listed for other ingredients in combination)
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; also, concurrent use of aspirin and 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, 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 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 with aspirin, may cause increased risk to patients receiving anticoagulant or thrombolytic therapy)


Anticonvulsants, hydantoin {28} {29} {30} {31} {32}    (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; 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 those agents)


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


Bismuth subsalicylate    (ingestion of large repeated 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 or
» Platelet aggregation inhibitors, other (see Appendix II )    (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)

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


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 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 should be avoided because the potential for ototoxicity may be increased, especially with long-term, high-dose use or overdose of aspirin; hearing loss may occur and may progress to deafness even after discontinuation of aspirin; these effects may be reversible, but usually are permanent)

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


» Probenecid or
» Sulfinpyrazone    (concurrent use of aspirin 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 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] 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)


» 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 {20} {21})


For ibuprofen-containing combinations (in addition to the interactions listed for other ingredients in combination)
Acetaminophen    (prolonged concurrent use of acetaminophen with ibuprofen may increase the risk of adverse renal effects)


Alcohol or
Corticosteroids, glucocorticoid or
Corticotropin, chronic therapeutic use of or
Potassium supplements    (concurrent use may increase the risk of gastrointestinal side effects, including ulceration or hemorrhage)


Digitalis glycosides    (ibuprofen has been shown to increase serum digoxin concentrations; adjustment of digoxin dosage may be necessary during and following concurrent use)


» Anticoagulants, coumarin- or indandione-derivative or
Heparin or
Thrombolytic agents, such as:
Alteplase (tissue-type plasminogen activator, recombinant)
Anistreplase
Streptokinase
Urokinase     (inhibition of platelet aggregation by ibuprofen may be hazardous to patients receiving anticoagulant or thrombolytic therapy)


Antidiabetic agents, oral or
Insulin    (ibuprofen may increase the hypoglycemic effect of these medications because prostaglandins are directly involved in regulatory mechanisms of glucose metabolism and possibly because of displacement of the oral antidiabetics from serum proteins; dosage adjustments of the antidiabetic agent may be necessary; glipizide and glyburide, due to their nonionic binding characteristics, may not be affected as much as the other oral antidiabetic agents; however, caution with concurrent use is recommended)


Antihypertensives or
Diuretics, especially:
» Triamterene    (ibuprofen may interfere with antihypertensive therapy by reducing or reversing the effects of the antihypertensive; concurrent use with ibuprofen may decrease the diuretic, natriuretic, and antihypertensive effects of diuretics, probably by inhibiting renal prostaglandin synthesis)


» Blood dyscrasia–causing medications, other (see Appendix II ), or
» Bone marrow depressants (see Appendix II ) or
» Radiation therapy    (concurrent use of bone marrow depressants or radiation therapy with ibuprofen may increase the risk of serious hematologic adverse effects)


» Cefamandole or
» Cefoperazone or
» Cefotetan or
» Plicamycin    (these medications may cause hypoprothrombinemia and/or inhibition of platelet aggregation; concurrent use with ibuprofen 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 ibuprofen)


Colchicine    (concurrent use with ibuprofen may increase the risk of gastrointestinal ulceration or hemorrhage; in addition, inhibition of platelet aggregation by ibuprofen, added to colchicine's effects on blood clotting mechanisms [colchicine may cause thrombocytopenia with chronic use and clotting defects, including disseminated intravascular coagulation, with overdose], may increase the risk of bleeding at sites other than the gastrointestinal tract)


Gold compounds    (concurrent use with ibuprofen may increase the risk of adverse renal effects )


» Lithium    (ibuprofen may increase steady-state plasma lithium concentration)


Methotrexate    (although not well documented, the possibility exists that ibuprofen may decrease methotrexate excretion and increase its plasma concentration to potentially toxic levels)


Nephrotoxic medications, other (see Appendix II )    (concurrent use with ibuprofen may increase the risk and/or severity of renal adverse effects)


Photosensitizing medications, other    (concurrent use with ibuprofen may cause additive photosensitizing effects )


Platelet aggregation inhibitors, other (see Appendix II )    (concurrent use of any of these medications with ibuprofen may increase the risk of bleeding because of additive inhibition of platelet aggregation as well as the potential occurrence of gastrointestinal ulceration or hemorrhage during therapy with ibuprofen)

    (concurrent use of sulfinpyrazone with ibuprofen may also increase the risk of gastrointestinal ulceration or hemorrhage)


» Probenecid    (probenecid may decrease excretion and increase the serum concentration of ibuprofen, possibly enhancing effectiveness and/or increasing the potential for toxicity; a decrease in dosage of the ibuprofen may be necessary if adverse effects occur)


For caffeine-containing combinations (in addition to the interactions listed for other ingredients in combination)
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

For acetaminophen-containing combinations (in addition to alterations listed for other ingredients in combination):
Glucose, blood, determinations    (acetaminophen may cause falsely decreased blood 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 aspirin-containing combinations (in addition to alterations listed for other ingredients in combination):
Gerhardt test for urine aceto-acetic acid    (interference may occur 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, depending on method used)

With physiology/laboratory test values

For acetaminophen-containing combinations (in addition to alterations listed for other ingredients in combination)
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 aspirin-containing combinations (in addition to alterations listed for other ingredients in combination)
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 because of increased potassium excretion caused by direct effect on renal tubules)


Uric acid, serum    (concentrations may be increased with doses 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)


For ibuprofen-containing combinations (in addition to alterations listed for other ingredients in combination)
Bleeding time    (may be prolonged because of suppressed platelet aggregation; effects may persist for less than 1 day following discontinuation of therapy)


Glucose, blood    (concentrations may be decreased)


Blood urea nitrogen (BUN) and
Creatinine, serum and
Potassium, serum    (concentrations may be increased)


Creatinine clearance    (may be decreased)


Hematocrit or
Hemoglobin    (values may be decreased)


Liver function test, especially serum transaminase activity    (values may be increased)


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 aspirin-containing combinations (in addition to problems listed for other ingredients in combination):
» Bleeding ulcers or
» Hemorrhagic states, other active    (may be exacerbated because of antiplatelet action of aspirin and decreased procoagulant factor synthesis [with high doses])


» Hemophilia or other bleeding problems, including coagulation or platelet function disorders    (increased risk of hemorrhage)


» Thrombocytopenia    (increased risk of hemorrhage because of inhibition of platelet aggregation )


For aspirin- or ibuprofen-containing combinations (in addition to problems listed for other ingredients in combination):
» Symptoms of nasal polyps associated with bronchospasm, or angioedema, anaphylaxis, or other severe allergic reactions induced by aspirin or other NSAIDs    (high risk of severe allergic reactions because of cross-sensitivity)


Risk-benefit should be considered when the following medical problems exist

For all combinations:
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 )


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)

    (decreased metabolism of ibuprofen; also, increased risk of renal failure )


Hypertension    (vasoconstrictive properties of sympathomimetic amines may exacerbate condition )


» Hypertension, severe    (pressor effect of sympathomimetic amines may precipitate a hypertensive crisis and/or intracranial hemorrhage {14}; also, ibuprofen may cause fluid retention and edema, thus possibly exacerbating condition )


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


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


Sensitivity to any of the ingredients of the combination
For acetaminophen-containing combinations (in addition to problems listed for other ingredients in combination):
» Alcoholism, active, or
» Viral hepatitis    (increased risk of hepatotoxicity)


For salicylate-containing combinations (in addition to problems listed for other ingredients in combination):
Anemia    (may be exacerbated because of increased gastrointestinal blood loss due to 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, especially with aspirin)


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


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


For ibuprofen-containing combinations (in addition to problems listed for other ingredients in combination):
Anemia or
Asthma    (may be exacerbated)


Conditions predisposing to gastrointestinal toxicity, such as:
Alcoholism, active
» Peptic ulcer, ulcerative colitis, or upper gastrointestinal disease, active or history of
Tobacco use, or recent history of    (increased risk of gastrointestinal toxicity)


Conditions predisposing to fluid retention, such as:
Compromised cardiac function
Hypertension    (ibuprofen may cause fluid retention and edema; hypertension may be exacerbated )


Congestive heart failure or
Diabetes mellitus or
Edema, pre-existing, or
Extracellular volume depletion or
Sepsis    (increased risk of renal failure)


» Hemophilia or other bleeding problems including coagulation or platelet function disorders    (increased risk of bleeding because ibuprofen inhibits platelet aggregation and may cause gastrointestinal ulceration or hemorrhage)


» Stomatitis    (may be induced by ibuprofen; one symptom of possible ibuprofen-induced blood dyscrasias may be masked)


» Symptoms of bronchospasm, allergic rhinitis, or urticaria, mild, induced by aspirin or other NSAIDs    (possibility of cross-sensitivity)


Systemic lupus erythematosus (SLE)    (patient predisposed to NSAID-induced central nervous system and/or renal adverse effects)


For caffeine-containing combinations (in addition to problems listed for other ingredients in combination):
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 reaction (skin rash, hives or itching)
    
anemia (unusual tiredness or weakness)
    
dizziness, severe
    
nervousness or restlessness, severe
    
psychotic episodes (mood or mental changes)—usually associated with previous history of psychiatric illness
    
shortness of breath or troubled breathing
    
slow or irregular heartbeat

Symptoms of overdose
    
CNS stimulation (hallucinations; seizures; trouble in sleeping)
    
hypertension (continuing headache; slow or fast heartbeat)


For acetaminophen-containing combinations (in addition to side effects listed for all combinations)
Incidence rare
    
Azotemia, uremia, renal colic, or sterile pyuria —with prolonged use of high doses in patients with severe renal function impairment
    
renal tubular necrosis in overdosage (bloody or cloudy urine; difficult or painful urination; sudden decrease in amount of urine)
    
blood dyscrasias (unexplained sore throat and fever; unusual bleeding or bruising)
    
hepatitis (yellow eyes or skin)

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

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 side effects listed for all combinations)
Incidence more frequent
    
Gastrointestinal irritation (mild stomach pain; nausea with or without vomiting)

Incidence less frequent or rare
    
Anaphylaxis (bluish discoloration or flushing or redness of skin; coughing; difficulty in swallowing; severe dizziness or feeling faint; skin rash, hives [may include giant urticaria], and/or itching; stuffy nose; swelling of eyelids, face, or lips; tightness in chest, troubled breathing, and/or wheezing, especially in asthmatic patients)
    
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.



For ibuprofen-containing combinations (in addition to side effects listed for all combinations)
Incidence less frequent
    
Fluid retention (increased blood pressure; decrease in amount of urine; swelling of face, fingers, feet, and/or lower legs; weight gain, rapid)
    
ringing or buzzing in ears

Incidence rare
    
Agranulocytosis (fever with or without chills; sores, ulcers, or white spots on lips or in mouth; sore throat)
    
amblyopia, toxic (blurred vision or any change in vision)
    
anaphylaxis (changes in facial skin color; skin rash, hives, and/or itching; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing)—may include anaphylactic shock with sudden, severe decrease in blood pressure and collapse
    
anemia, aplastic [pancytopenia] (shortness of breath, troubled breathing, tightness in chest, and/or wheezing; sores, ulcers, or white spots on lips or in mouth; swollen and/or painful glands; unusual bleeding or bruising; unusual tiredness or weakness)
    
anemia, hemolytic (troubled breathing, exertional; unusual tiredness or weakness)
    
blurred vision or any change in vision
    
bronchospastic allergic reaction (shortness of breath, troubled breathing, tightness in chest, and/or wheezing)
    
confusion
    
congestive heart failure, or exacerbation of (chest pain; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; decrease in amount of urine; swelling of face, fingers, feet, or lower legs; unusual tiredness; weight gain)
    
cystitis or other lower urinary tract irritation (bloody or cloudy urine; difficult, burning, or painful urination; frequent urge to urinate)
    
decreased hearing or any change in hearing
    
dry, irritated, or swollen eyes
    
erythema multiforme (fever with or without chills; muscle cramps or pain; skin rash; sores, ulcers, or white spots on lips or in mouth)
    
esophagitis or gastritis (burning feeling in throat, chest, or stomach)
    
gastrointestinal ulceration, possibly with perforation and/or bleeding (abdominal pain, cramping, or burning, severe; bloody or black, tarry stools; vomiting of blood or material that looks like coffee grounds; nausea, heartburn, and/or indigestion, severe and continuing)
    
hepatitis (fever with or without chills, skin rash, swelling and/or tenderness in upper abdominal or stomach area, swollen and/or painful glands, unusual bleeding or bruising, unusual tiredness or weakness, yellow eyes or skin)
    
increased blood pressure
    
leukopenia [neutropenia] (fever with or without chills, sore throat, unusual tiredness or weakness)
    
meningitis, aseptic (headache, severe, with fever and stiff neck)
    
mental depression or other mood or mental changes
    
pancreatitis, acute (abdominal pain, fever with or without chills, swelling and/or tenderness in upper abdominal or stomach area)
    
polyuria (large increase in frequency and quantity of urination, sudden)
    
renal impairment or failure (increased blood pressure; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; sudden decrease in amount of urine; swelling of face, fingers, feet, and/or lower legs; thirst, continuing; unusual tiredness or weakness; weight gain)
    
rhinitis, allergic (unexplained runny nose or sneezing)
    
Stevens-Johnson syndrome (bleeding or crusting sores on lips; chest pain; fever with or without chills; muscle cramps or pain; skin rash; sores, ulcers, or white spots in mouth; sore throat)
    
stomatitis, aphthous (sores, ulcers, or white spots on lips or in mouth)
    
thrombocytopenia with or without purpura (spitting blood, unusual bleeding or bruising)




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
    
Nervousness or restlessness


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


For salicylamide-containing combinations (in addition to side effects listed for all combinations)
Incidence less frequent
    
Drowsiness


For ibuprofen-containing combinations (in addition to side effects listed for all combinations)
Incidence more frequent
    
Abdominal or stomach cramps, pain, or discomfort, mild to moderate
    
dizziness or lightheadedness
    
heartburn or indigestion
    
nausea

Incidence less frequent
    
Bloated feeling or gas
    
constipation
    
decreased appetite or loss of appetite
    
diarrhea
    
headache, mild to moderate
    
vomiting






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 post-ingestion 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 post-ingestion 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 3.0).
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. {02} {17} {18}
   • 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.
   • Instituting 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.For ibuprofen-containing combinations:

   • Emptying the stomach via induction of emesis (in alert patients only) or gastric lavage. However, syrup of ipecac may induce symptoms similar to those of NSAID toxicity, which may complicate diagnosis, and is therefore not recommended for induction of emesis.
   • Administering activated charcoal. The efficacy of activated charcoal in decreasing absorption of these medications when given more than 2 hours (6 hours for piroxicam) following ingestion of the overdose has not been determined. However, there is some evidence that repeated administration of activated charcoal may interrupt enterohepatic circulation and/or bind any of the medication that has diffused from the circulation into the intestine, thereby increasing nonrenal excretion.
   • Antacids may also relieve adverse gastrointestinal effects.
   • Monitoring and supporting vital functions.
   • Instituting symptomatic and other supportive treatment as necessary. Certain adverse effects of NSAIDs, including nephritis or nephrotic syndrome, thrombocytopenia, hemolytic anemia, and severe cutaneous or other hypersensitivity reactions, may respond to glucocorticoid administration.
   • Administering as required: plasma volume expanders for severe hypotension; diazepam (5 to 10 mg [adults] or 0.1 to 0.3 mg/kg [children]) for convulsions; Vitamin K 1 (10 to 20 mg, intravenously) for hypoprothrombinemia; and/or dopamine (2.5 mcg per kg of body weight per minute) plus dobutamine (5 to 40 mcg per kg of body weight per minute), intravenously, to prevent, or reverse early indications of, renal failure.
   • Inducing diuresis may be helpful.



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, 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 other sympathomimetic amines, salicylates or other nonsteroidal anti-inflammatory drugs

Pregnancy—Concern with high doses and long-term therapy because of salicylate effects; use of aspirin-containing combinations not recommended during third trimester; use of ibuprofen-containing combinations during second half of pregnancy not recommended because of potential adverse effect on fetal blood flow





Breast-feeding—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 sensitivity to vasopressor and psychiatric effects of sympathomimetic amines; also, increased susceptibility to toxic effects of salicylates, especially if fever and dehydration present; possible association between aspirin usage and Reyes syndrome




Use in adolescents—
Possible association between aspirin usage and Reyes syndrome






Use in the elderly—Increased susceptibility to effects of sympathomimetic amines and toxic effects of salicylates; increased risk of toxicity with ibuprofen
Other medications, especially for high blood pressure or depression, CNS depressants or stimulants, and others that may interact with acetaminophen, ibuprofen, and/or salicylates depending on specific ingredients of combination
Other medical problems, especially hypertension (for all combinations); alcoholism or hepatitis (for acetaminophen-containing combinations); hemophilia or other bleeding problems (for aspirin-containing combinations); asthma, gastritis, or peptic ulcer (with salicylate-containing combinations); clotting defects, peptic ulcer or other gastrointestinal tract disease, or stomatitis (for ibuprofen-containing combinations)

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

» 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

For salicylate-containing combinations
Taking with food or a full glass (240 mL) of water to minimize gastrointestinal irritation

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

For ibuprofen-containing combinations
Taking with food or antacids (a magnesium- and aluminum-containing antacid may be preferred) to reduce gastrointestinal irritation; not lying down for 15 to 30 minutes after taking

Precautions while using this medication
Checking with physician if symptoms persist or become worse, or if high fever is present

» Caution if taking appetite suppressants

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

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

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

» Avoiding use of alcoholic beverages while taking these medications; alcohol consumption may increase risk of ibuprofen- or salicylate-induced gastrointestinal toxicity and acetaminophen-induced liver toxicity

» 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

For ibuprofen-containing combinations
» Caution if drowsiness or dizziness occurs


Side/adverse effects
Signs of potential side effects, especially allergic reactions, anemia, cardiac effects, CNS stimulation, psychotic episodes, severe dizziness, severe nervousness or restlessness (for all combinations); blood dyscrasias, hepatitis, hepatotoxicity (for acetaminophen-containing); signs of gastrointestinal irritation or bleeding (for ibuprofen- or salicylate-containing); and cutaneous adverse effects, hepatitis, renal impairment (for ibuprofen-containing)

DECONGESTANTS AND ANALGESICS


Oral Dosage Forms

DECONGESTANTS AND ANALGESICS

Note: Products containing phenylpropanolamine were removed from the U.S. and Canadian Markets in November 2000.{51}


For Adult and Pediatric
Dose listing (refer to Table 1)

Table 1. Oral Dosage Forms


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



Brand or
generic name
[availability]
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 Sinus Daytime Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
Available in a
dual package
that also
contains
Actifed Sinus Nighttime Tablets
2 tabs q 6 hr
(max 8 total
Daytime and Nighttime
tabs/day)
Not
recommended
 
Actifed Sinus Daytime Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
Available in a
dual package
that also
contains
Actifed Sinus Nighttime Caplets
2 tabs q 6 hr
(max 8 total
Daytime and Nighttime
tabs/day)
Not
recommended
 
Advil Cold and Sinus Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Ibuprofen
200 mg
  1–2 tabs
q 4–6 hr
(max 6 tabs/day)
   
Advil Cold and Sinus Caplets Tablets USP (OTC)
[U.S./Canada]
Pseudoephedrine HCl
30 mg
Ibuprofen
200 mg
  1–2 tabs
q 4–6 hr
(max 6 tabs/day)
   
Allerest No-Drowsiness Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen 325 mg
  2 tabs q 4–6 hr
(max 8 tabs daily)
6–12 yrs:
1 tab q 4–6 hr
(max 4 tabs/day)
 
Coldrine Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
325 mg
Sodium
metabisulfate
2 tabs q 6 hr
   
Contac Allergy/Sinus Day Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
60 mg
Acetaminophen
650 mg
Available in a
dual package
that also
contains
Contac Allergy/Sinus Night Caplets
1 tab q 6 hr
(max 4 tabs/day)
   
Dristan Cold Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 4–6 hr
(max 8 tabs/
day)
   
Dristan N.D. Caplets Tablets USP (OTC)
[Canada]
Pseudoephedrine HCl
30 mg
Acetaminophen
325 mg
  2 tabs q 4 hr
(max 8 tabs/
day)
6–12 yrs:
1 tab q 4 hr
(max 4 tabs/
day)
 
Dristan N.D. Extra Strength Caplets Tablets USP (OTC)
[Canada]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  1–2 tabs
q 4–6 hr
(max 8 tabs/
day)
   
Dristan Sinus Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Ibuprofen
200 mg
  1–2 tabs
q 4–6 hr
   
Motrin IB Sinus Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Ibuprofen
200 mg
  1–2 tabs
q 4–6 hr
(max 6 tabs/day)
   
Motrin IB Sinus Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Ibuprofen
200 mg
  1–2 tabs
q 4–6 hr
(max 6 tabs/day)
   
Neo Citran Extra Strength Sinus for Oral Solution
(OTC)
[Canada]
Phenylephrine HCl
10 mg/pouch
Acetaminophen
650 mg/pouch
Vitamin C
50 mg/pouch
Contents of 1
pouch dissolved
in 225 mL
hot water
   
Ornex Maximum Strength Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 4–6 hr
(max 8 tabs/day)
   
PhenAPAP Without Drowsiness Tablets (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
325 mg
  2 tabs q 4 hr
(max 8 tabs/
day)
   
Sinarest No-Drowsiness Caplets Tablets USP (OTC)
[U.S.]
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)
 
Sine-Aid Maximum Strength Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 4–6 hr
(max 8 tabs/
day)
Not
recommended
 
Sine-Aid Maximum Strength Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 4–6 hr
(max 8 tabs/
day)
Not
recommended
 
Sine-Off Maximum Strength No Drowsiness Formula Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 6 hr
(max 8 tabs/
day)
   
Sinus-Relief Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
325 mg
  2 tabs q 4 hr
(max 8 tabs/day)
   
Sinutab No Drowsiness Caplets Tablets USP (OTC)
[Canada]
Pseudoephedrine HCl
30 mg
Acetaminophen
325 mg
Scored
Tartrazine free
2 tabs
q 4–6 hr
(max 8 tabs/
day)
>6 yrs: 1 tab
q 4–6 hr
(max 4 tabs/
day)
 
Sinutab No Drowsiness Extra Strength Caplets Tablets USP (OTC)
[Canada]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
Tartrazine free
1–2 tabs
q 4–6 hr
(max 8 tabs/
day)
   
Sinutab Sinus Maximum Strength Without Drowsiness Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen 500 mg
  2 tabs q 6 hr
(max 8 tabs/24 hr)
   
Sudafed Head Cold and Sinus Extra Strength Caplets Tablets USP (OTC)
[Canada]
Pseudoephedrine HCl
60 mg
Acetaminophen
500 mg
  1 tab q 4–6 hr
(max 4 tabs/
day)
   
Sudafed Sinus Maximum Strength Without Drowsiness Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 6 hr
(max 8 tabs/day)
Not
recommended
 
Sudafed Sinus Maximum Strength Without Drowsiness Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 6 hr
(max 8 tabs/day)
Not
recommended
 
Tylenol Sinus Maximum Strength Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 4–6 hr
(max 8 tabs/
day)
Not
recommended
 
Tylenol Sinus Maximum Strength Caplets Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 4–6 hr
(max 8 tabs/
day)
Not
recommended
 
Tylenol Sinus Maximum Strength Gelcaps Capsules USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 caps q 4–6 hr
(max 8 caps/day)
Not
recommended
 
Tylenol Sinus Maximum Strength Geltabs Tablets USP (OTC)
[U.S.]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
  2 tabs q 4–6 hr
(max 8 tabs/day)
Not
recommended
 
Tylenol Sinus Medication Regular Strength Caplets Tablets USP (OTC)
[Canada]
Pseudoephedrine HCl
30 mg
Acetaminophen
325 mg
Tartrazine free
1–2 tabs
q 4–6 hr
(max 8 tabs/day)
   
Tylenol Sinus Medication Extra Strength Caplets Tablets USP (OTC)
[Canada]
Pseudoephedrine HCl
30 mg
Acetaminophen
500 mg
Tartrazine free
1–2 tabs
q 4–6 hr
(max 8 tabs/day)
   
* Geriatric patients may be more sensitive to the effects of usual adult dose
 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



Strength(s) usually available
U.S.—
See Table 1. Oral Dosage Forms.

Canada—
See Table 1. Oral Dosage Forms.

{53}

Revised: 05/28/2002



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  1. Novafed A (Marion Merrell Dow) and Trinalin Repetabs (Key). In: PDR Physicians' desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989.
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  1. Goodman RP, et al. The effect of phenylpropanolamine on cardiovascular and sympathetic nervous system function. Clin Pharmacol Ther 1986; 40: 144-7.
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  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. Kase CS, et al. Intracerebral hemorrhage and phenylpropanolamine use. Neurology 1987 Mar; 37: 399-404.
  1. Fed Regist 1990 July 5. Proposed FDA labeling requirement for OTC aspirin to include prohibition against taking during third trimester unless directed by a physician.
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  1. Dugandzic RM, Tierney MG, Dickinson GE, et al. Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Ann Emerg Med 1989 Nov; 18: 1186-90..
  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. Langtry HD, and Campoli-Richards DM. Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs. 1989; 37: 408-50.
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  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 1990; 18(1): 37-60.
  1. Dilantin/Phenytoin “Right Dose” Program. Advances in the management of acute seizures in hospitalized patients. Health Sciences Institute, 1990.
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  1. Emertabs product label (Pharmetics—Canada), Rec 11/94.
  1. Coricidin Non-Drowsy Sinus Formula product label (Schering—Canada), Rec 11/94.
  1. Actifed Sinus Caplets and Tablets product labels (Warner-Lambert—US), Rec 12/94 and 2/95.
  1. Sinutab Sinus product label (Parke-Davis—US), Rec 2/95.
  1. Dynafed Maximum Strength product label (BDI—US), Rec 2/95.
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