Acetaminophen, dextromethorphan, and phenylephrin

MEDICATION SAFETY ISSUES
Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

SPECIAL ALERTS
Health Canada: Labeling Changes for OTC Cough and Cold Preparations - December, 2008

Health Canada has issued an advisory to Canadian consumers regarding upcoming labeling changes for the use of over-the-counter (OTC) cough and cold medicines in children. Specific labeling changes as well as other important information may be found at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_184-eng.php.

Manufacturers Voluntarily Change Pediatric OTC Product Labeling - October 7, 2008

Leading manufacturers of over-the-counter (OTC) pediatric cough and cold products, in consultation with the Food and Drug Administration (FDA), have announced that they are voluntarily transitioning product labeling as it relates to children <4 years of age. The decision to change the labeling followed a meeting on October 2, 2008, conducted by the FDA to gather additional information related to the use of these products in children. The safety of the ingredients in these products was not in question. It was found that dosing errors and accidental ingestions were the leading cause of rare adverse events in children. The new product labeling will state "Do not use in children under four years of age." In addition, products with certain antihistamines will warn parents not to use these products to sedate or make a child sleepy. Labeling of adult products will not change. New product labels will be introduced during the 2008-2009 cough and cold season and some products will have the updated labeling by mid-October. Products with the old labeling will not be removed from the market. Prescription products are not affected.

It is important to note that these medications have not been shown to be unsafe when used correctly. Pharmacists may continue to see health care practitioners recommending these agents for use in pediatric patients, and should help to ensure that they are being used safely and at appropriate dosages. Parents should be advised that OTC cough and cold products are safe and effective when used as directed, but that they should not be used in children <4 years of age unless instructed to do so by their healthcare provider. Counseling tips from the Consumer Healthcare Products Association (CHPA) also include: Always follow dosing instructions exactly and use measuring devices provided with the medicine. Never give 2 medicines at the same time that contain the same active ingredient. Do not give a medicine intended for use in adults to a child.

Additional tips and information related to the labeling changes can be found on the following educational website of the CHPA: http://www.otcsafety.org.

The FDA had previously issued a Public Health Advisory reminding patients and caregivers that OTC cough and cold medications should not be used to treat infants and children <2 years of age. This is in response to the Centers for Disease Control and Prevention (CDC) report which noted that during 2004 and 2005, ~1519 children <2 years of age were seen in emergency departments for adverse effects, including overdose, associated with products containing nasal decongestants (eg, pseudoephedrine), antihistamines (eg, carbinoxamine), and cough suppressants (eg, dextromethorphan). In October of 2007, several manufacturers voluntarily removed these products in order to help reduce dosing errors and overdose in this age group.

For additional information, refer to the following websites:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm094913.htm

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116839.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5601a1.htm, Centers for Disease Control, "Infant Deaths Associated with Cough and Cold Medications - Two States, 2005,"MMWR Morb Mortal Wkly Rep, 2007, 56(01):1-4.

U.S. BRAND NAMES — Alka-Seltzer Plus® Day Cold [OTC]; Comtrex® Maximum Strength, Non-Drowsy Cold & Cough Relief [OTC]; Mapap® Multi-Symptom Cold [OTC]; Theraflu® Daytime Severe Cold & Cough [OTC]; Theraflu® Warming Relief Daytime Severe Cold & Cough [OTC]; Tylenol® Cold Head Congestion Daytime [OTC]; Tylenol® Cold Multi-Symptom Daytime [OTC]; Vicks® DayQuil® Cold/Flu Multi-Symptom [OTC]

PHARMACOLOGIC CATEGORY
Analgesic, Miscellaneous
Antitussive
Decongestant

DOSING: ADULTS — Product labeling: Relief of cold and flu symptoms: Oral:

Alka-Seltzer Plus® Day Cold: 2 capsules or 20 mL every 4 hours (maximum: 6 doses/24 hours)

Tylenol® Cold Head Congestion Daytime: 2 caplets every 4 hours (maximum: 6 doses/24 hours)

Tylenol® Cold Multi-Symptom Daytime: 2 caplets/gelcaps or 30 mL every 4 hours (maximum: 6 doses/24 hours)

Vicks® DayQuil® Cold/Flu Multi-Symptom Relief LiquiCaps: 2 capsules every 4 hours (maximum: 6 doses/24 hours)

Vicks® DayQuil® Cold/Flu Multi-Symptom Relief Liquid: 30 mL every 4 hours (maximum: 6 doses/24 hours)

DOSING: PEDIATRIC — Product labeling: Relief of cold and flu symptoms: Oral:

Vicks® DayQuil® Cold/Flu Multi-Symptom Relief Liquid:
Children 6-11 years: 15 mL every 4 hours, up to 5 doses/day (maximum: 75 mL/24 hours)
Children ≥ 12 years: Refer to adult dosing.

Alka-Seltzer Plus® Day Cold, Tylenol® Cold Head Congestion Daytime, Tylenol® Cold Multi-Symptom Daytime, Vicks® DayQuil® Cold/Flu Multi-Symptom Relief LiquiCaps: Children ≥ 12 years: Refer to adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Caplet:
Comtrex® Maximum Strength, Non-Drowsy Cold & Cough Relief: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg
Mapap® Multi-Symptom Cold: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg
Theraflu® Daytime Severe Cold & Cough: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg
Tylenol® Cold Head Congestion Daytime: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg [Cool Burst™ flavor]
Tylenol® Cold Multi-Symptom Daytime: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg [Cool Burst™ flavor]

Capsule, liquid gel:
Alka-Seltzer Plus® Day Cold: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg

Capsule, liquicap:
Vicks® DayQuil® Cold/Flu Multi-Symptom Relief: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg

Gelcap:
Tylenol® Cold Multi-Symptom Daytime: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg

Liquid:
Alka-Seltzer Plus® Day Cold: Acetaminophen 162.5 mg, dextromethorphan hydrobromide 5 mg, and phenylephrine hydrochloride 2.5 mg per 5 mL (180 mL) [alcohol free; contains sodium 3 mg/5 mL, propylene glycol, and sodium benzoate; berry flavor]
Tylenol® Cold Multi-Symptom Daytime: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg per 15 mL (240 mL) [contains sodium 5 mg/15 mL, sodium benzoate, and propylene glycol; Citrus Burst™ flavor]
Vicks® DayQuil® Cold/Flu Multi-Symptom Relief: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg per 15 mL (180 mL, 300 mL) [contains sodium 71 mg/15 mL and propylene glycol]

Powder for solution:
Theraflu® Daytime Severe Cold & Cough: Acetaminophen 650 mg, dextromethorphan 20 mg, and phenylephrine hydrochloride 10 mg/packet (6s) [contains phenylalanine 14 mg, potassium 10 mg, and sodium 20 mg/packet; berry flavor]

Syrup:
Theraflu® Warming Relief Daytime Severe Cold & Cough: Acetaminophen 325 mg, dextromethorphan hydrobromide 10 mg, and phenylephrine hydrochloride 5 mg per 15 mL (245.5 mL) [contains ethanol, propylene glycol, sodium 8 mg/15 mL, sodium benzoate; cherry flavor]

DOSAGE FORMS: CONCISE
Caplet:
Comtrex® Maximum Strength, Non-Drowsy Cold & Cough Relief [OTC], Mapap® Multi-Symptom Cold [OTC], Theraflu® Daytime Severe Cold & Cough [OTC], Tylenol® Cold Head Congestion Daytime [OTC], Tylenol® Cold Multi-Symptom Daytime [OTC]: Acetaminophen 325 mg, dextromethorphan 10 mg, and phenylephrine 5 mg

Capsule, liquid gel:
Alka-Seltzer Plus® Day Cold [OTC]: Acetaminophen 325 mg, dextromethorphan 10 mg, and phenylephrine 5 mg

Capsule, liquicap:
Vicks® DayQuil® Cold/Flu Multi-Symptom Relief [OTC]: Acetaminophen 325 mg, dextromethorphan 10 mg, and phenylephrine 5 mg

Gelcap:
Tylenol® Cold Multi-Symptom Daytime [OTC]: Acetaminophen 325 mg, dextromethorphan 10 mg, and phenylephrine 5 mg

Liquid:
Alka-Seltzer Plus® Day Cold [OTC]: Acetaminophen 162.5 mg, dextromethorphan 5 mg, and phenylephrine 2.5 mg per 5 mL
Tylenol® Cold Multi-Symptom Daytime [OTC], Vicks® DayQuil® Cold/Flu Multi-Symptom Relief [OTC]: Acetaminophen 325 mg, dextromethorphan 10 mg, and phenylephrine 5 mg per 15 mL

Powder for solution:
Theraflu® Daytime Severe Cold & Cough [OTC]: Acetaminophen 650 mg, dextromethorphan 20 mg, and phenylephrine 10 mg/packet (6s)

Syrup:
Theraflu® Warming Relief Daytime Severe Cold & Cough [OTC]: Acetaminophen 325 mg, dextromethorphan 10 mg, and phenylephrine 5 mg per 15 mL

GENERIC EQUIVALENT AVAILABLE — Yes: Caplet

ADMINISTRATION — Solid dosage forms should be swallowed whole; do not crush, chew or dissolve. Administer liquid capsule formulations with water.

USE — Temporary relief of common cold and flu symptoms (eg, pain, fever, cough, congestion)

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to acetaminophen, dextromethorphan, phenylephrine, or any component of the formulation; use of MAO inhibitors within 14 days

WARNINGS / PRECAUTIONS
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.

Special populations: Elderly: Use with caution in the elderly; more likely to experience adverse reactions to sympathomimetics. Pediatrics: Use with caution in children; 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.

Dosage form specific issues: Phenylalanine: Some products may contain phenylalanine. Sodium: Some products may contain sodium; use with caution in sodium restricted patients.

Other warnings/precautions: OTC labeling: Patients with hypertension, hyperthyroidism, diabetes mellitus, glaucoma, cardiovascular disease, or prostatic hyperplasia should consult a physician 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 a physician. 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 a physician. Do not use in children <2 years of age.

METABOLISM / TRANSPORT EFFECTS
Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Dextromethorphan: Substrate of CYP2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 2E1 (minor), 3A4 (minor); Inhibits CYP2D6 (weak)

DRUG INTERACTIONS
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

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

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

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

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 serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Risk X: Avoid combination

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

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

QuiNIDine: May decrease the metabolism of Dextromethorphan. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May enhance the adverse/toxic effect of Dextromethorphan. Exceptions: Fluvoxamine. Risk D: Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification

Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. 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 — Ethanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

DIETARY CONSIDERATIONS
Alka-Seltzer Plus® Day Cold liquid contains sodium 3 mg per 5 mL.

Theraflu® Daytime Severe Cold & Cough (powder for solution) contains phenylalanine 14 mg and sodium 20 mg per packet.

Theraflu® Warming Relief Daytime Severe Cold & Cough syrup contains sodium 8 mg per 15 mL.

Tylenol® Cold Multi-Symptom Daytime liquid contains sodium 5 mg per 15 mL.

Vicks® DayQuil® Cold/Flu Multi-Symptom Relief liquid contains sodium 71 mg per 15 mL.

INTERNATIONAL BRAND NAMES — Tusedex (PH)