Acetaminophen, diphenhydramine, and phenylephrine

Acetaminophen, diphenhydramine, and phenylephrine: Drug information
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(For additional information see “Acetaminophen, diphenhydramine, and phenylephrine: Patient drug information”)

Brand Names: U.S. Benadryl® Allergy and Cold [OTC]; Benadryl® Allergy and Sinus Headache [OTC]; Benadry® Maximum Strength Severe Allergy and Sinus Headache [OTC]; Cold Control PE [OTC]; One Tab™ Allergy & Sinus [OTC]; One Tab™ Cold & Flu [OTC]; Sudafed PE® Nighttime Cold [OTC]; Sudafed PE® Severe Cold [OTC]; Theraflu® Nighttime Severe Cold & Cough [OTC]; Theraflu® Sugar-Free Nighttime Severe Cold & Cough [OTC]; Theraflu® Warming Relief ™ Flu & Sore Throat [OTC]; Theraflu® Warming Relief™ Nighttime Severe Cold & Cough [OTC]; Tylenol® Allergy Multi-Symptom Nighttime [OTC]; Tylenol® Children’s Plus Cold and Allergy [OTC]
Pharmacologic Category Alpha-Adrenergic Agonist; Analgesic, Miscellaneous; Decongestant; Ethanolamine Derivative; Histamine H1; Antagonist Histamine H1 Antagonist, First Generation
Dosing: Adult Hay fever/cold symptoms: Oral: General dosing guidelines; refer to specific product labeling:
Caplet (Benadryl® Allergy and Cold, Benadryl® Allergy and Sinus Headache, Sudafed PE® Nighttime Cold, Sudafed PE® Severe Cold, Tylenol® Allergy Multi-Symptom Nighttime): Two caplets every 4 hours as needed; maximum: 12 caplets/24 hours

Powder for solution (Theraflu® Nighttime Severe Cold & Cough): One packet every 4 hours as needed; maximum: 6 doses/24 hours

Syrup (Theraflu® Warming Relief™ Flu & Sore Throat): 30 mL every 4 hours as needed; maximum: 6 doses/24 hours (180 mL/24 hours)

Dosing: Pediatric Hay fever/cold symptoms: Oral: General dosing guidelines; refer to specific product labeling:
Children 6-11 years (Benadryl® Allergy and Cold, Benadryl® Allergy and Sinus Headache, Sudafed PE® Severe Cold): One caplet every 4 hours as needed; maximum: 5 caplets/24 hours

Children 6-11 years; 48-95 lbs (Tylenol® Children’s Plus Cold and Allergy): 10 mL every 4 hours as needed; maximum: 5 doses/24 hours

Children ≥12 years: Refer to adult dosing.

Dosing: Geriatric Refer to adult dosing.
Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Caplet, oral:

Benadryl® Allergy and Cold, Benadryl® Allergy and Sinus Headache, Sudafed PE® Severe Cold: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg

Benadry® Maximum Strength Severe Allergy and Sinus Headache: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg

One Tab™ Allergy & Sinus: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg [dye free]

One Tab™ Cold and Flu: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg [dye free]

Cold Control PE: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg

Sudafed PE® Nighttime Cold: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg

Tylenol® Allergy Multi-Symptom Nighttime: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg [Cool Burst™ flavor]

Liquid, oral:

Tylenol® Children’s Plus Cold and Allergy: Acetaminophen 160 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 2.5 mg per 5 mL (120 mL) [contains sodium benzoate; bubble gum flavor]

Powder for solution, oral:

Theraflu® Nighttime Severe Cold & Cough: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (6s) [contains phenylalanine 13 mg, potassium 10 mg, and sodium 23 mg per packet; honey lemon flavor]

Theraflu® Sugar-Free Nighttime Severe Cold & Cough: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (6s) [sugar free; contains phenylalanine 13 mg, potassium 10 mg, and sodium 23 mg per packet; honey lemon flavor]

Syrup, oral:

Theraflu® Warming Relief™ Flu & Sore Throat: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 15 mL (245.5 mL) [contains ethanol, potassium 5 mg/15 mL, propylene glycol, sodium 5 mg/15 mL, sodium benzoate; cherry flavor]

Theraflu® Warming Relief™ Nighttime Severe Cold & Cough: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 15 mL (245.5 mL) [contains ethanol 10%, potassium 5 mg/15 mL, propylene glycol, sodium 5 mg/15 mL, sodium benzoate; cherry flavor]

Generic Equivalent Available: U.S. No
Administration Administer without regard to meals.
Caplet (Tylenol® Allergy Multi-Symptom Nighttime): Swallow whole; do not crush, chew, or dissolve.

Liquid (Tylenol® Children’s Plus Cold and Allergy): Shake well before use. Only use enclosed dosing cup; do not use other devices.

Powder for solution (Theraflu® Nighttime Severe Cold & Cough): Dissolve contents of packet into 8 oz of hot water; sip while hot and consume within 10-15 minutes

Use Temporary relief of symptoms of hay fever and the common cold, including sinus/nasal congestion and pain/pressure, headache, sneezing, runny nose, itchy/watery eyes, sore throat, fever, cough, and minor aches and pains
Medication Safety Issues
Other safety concerns:
Duplicate therapy issues: This product contains acetaminophen, which may be a component of combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

Adverse Reactions Significant See individual agents.
Contraindications Use with or within 14 days of MAO inhibitor therapy; concurrent use with other products containing acetaminophen, diphenhydramine (including topical) or phenylephrine
Warnings/Precautions
Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage.

• Hepatic impairment: Use caution in patients with hepatic impairment; acetaminophen may cause severe hepatic toxicity with acute overdose.

Concurrent drug therapy issues:

• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations:

• Pediatrics: Use with caution in children; may cause excitability. Do not exceed pediatric dosing recommendations. If no recommendations exist on OTC labeling for patient’s age, the product should not be administered without the guidance of a physician.

Other warnings/precautions:

• Dosage limit: Limit acetaminophen dose to <4 g/day (adults) or <2.6 g/day (children <12 years of age).

• Self-medication (OTC use): Patients with hypertension, thyroid disease, diabetes mellitus, glaucoma, cardiovascular disease, or prostatic hyperplasia should consult healthcare provider prior to use. Patients with chronic cough (associated with COPD or smoking) and/or productive cough (eg, copious amounts of phlegm) should be evaluated by a healthcare provider prior to use. Products containing acetaminophen are not recommended in patients consuming ≥3 alcoholic beverages/day; consult healthcare provider. If pain, nasal congestion, or cough increases in severity or persists >7 days in adults (or >5 days in children) during use, consult a physician. If redness, swelling, or rash occurs or if fever worsens or persists >3 days during therapy, consult healthcare provider. If sore throat is severe, accompanied by fever, nausea/vomiting, headache, swelling or rash, or last >2 days, discontinue use and consult healthcare provider. Discontinue use and contact healthcare provider if nervousness, dizziness, or sleeplessness occur.

Drug Interactions
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Amphetamines: May diminish the sedative effect of Antihistamines. Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Benzylpenicilloyl Polylysine: Antihistamines may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Suspend systemic H1 antagonists for benzylpenicilloyl-polylysine skin testing and delay testing until systemic antihistaminic effects have dissipated. A histamine skin test may be used to assess persistent antihistaminic effects. Risk D: Consider therapy modification

Benzylpenicilloyl Polylysine: Alpha1-Agonists may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Consider use of a histamine skin test as a positive control to assess a patient’s ability to mount a wheal and flare response. Risk D: Consider therapy modification

Betahistine: Antihistamines may diminish the therapeutic effect of Betahistine. Risk C: Monitor therapy

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

FentaNYL: Alpha1-Agonists may decrease the serum concentration of FentaNYL. Specifically, fentanyl nasal spray serum concentrations may decrease and onset of effect may be delayed. Risk C: Monitor therapy

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Imatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

MAO Inhibitors: May enhance the hypertensive effect of Alpha1-Agonists. Risk X: Avoid combination

Metyrapone: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Risk D: Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions See individual agents.
Dietary Considerations Take without regard to meals. Some products may contain phenylalanine, potassium, and/or sodium.
Mechanism of Action
Acetaminophen inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation.

Diphenhydramine is an H1-receptor antagonist.

Phenylephrine causes vasoconstriction of the arterioles of the nasal mucosa.

Pharmacodynamics/Kinetics See individual agents.

REFERENCES
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