[Posted 01/13/2011] ISSUE: FDA notified healthcare professionals that it has asked drug manufacturers to limit the strength of acetaminophen in prescription drug products, predominantly combinations of acetaminophen and opioids, to 325 mg per tablet, capsule, or other dosage unit, making these products safer for patients. This action will help to reduce the risk of severe liver injury and allergic reactions associated with acetaminophen. A Boxed Warning highlighting the potential for severe liver injury and a Warning highlighting the potential for allergic reactions (swelling of the face, mouth, and throat, difficulty breathing, itching, or rash) will be added to the label of all prescription drug products that contain acetaminophen.
BACKGROUND: Acetaminophen, one of the most commonly used drugs in the United States, is widely and effectively used in both prescription and over-the-counter (OTC) products to reduce pain and fever. Examples of prescription products that contain acetaminophen include hydrocodone with acetaminophen (Vicodin, Lortab), and oxycodone with acetaminophen (Tylox, Percocet). OTC products containing acetaminophen (e.g., Tylenol) are not affected by this action. Information about the potential for liver injury is already required on the label for OTC products containing acetaminophen. FDA is continuing to evaluate ways to reduce the risk of acetaminophen related liver injury from OTC products. No drug shortages are expected, because the 3-year implementation period should permit adequate time for necessary reformulations.
RECOMMENDATION: Healthcare professionals were reminded to advise patients not to exceed the acetaminophen maximum total daily dose (4 grams/day), and not to drink alcohol while taking acetaminophen-containing medications.
Healthcare professionals were encouraged to inform patients that there is no immediate danger to patients who take these combination pain medications, and patients should continue to take them as directed by their health care provider. The Drug Safety Communication provides additional information for healthcare professionals, information for patients, a data summary and a list of all affected products. For more information visit the FDA website at: [Web] and [Web].
Self-medication in children ≥6 years of age and adults for the temporary relief of minor aches and pain associated with headache, muscular aches, backache, minor arthritis pain, common cold, toothache, and menstrual cramps. Self-medication in infants and children for the temporary relief of minor aches and pain associated with the common cold, flu, headache, sore throat, immunizations, toothache, muscle aches, sprains, and overexertion.
Self-medication in fixed combination with aspirin and caffeine for the temporary relief of mild to moderate pain associated with migraine headache. This combination also can be used for the treatment of severe migraine headache if previous attacks have responded to similar nonopiate analgesics or NSAIAs.
Symptomatic treatment of pain associated with osteoarthritis; considered an initial drug of choice for pain management in osteoarthritis patients.
Used in fixed combination with isometheptene and dichloralphenazone for symptomatic relief of tension and vascular headaches.
Self-medication to reduce fever in infants, children, and adults.
Dosage and Administration
Administration
Usually administered orally; may be administered rectally as suppositories in patients who cannot tolerate oral therapy.
Oral Administration
Swallow extended-release tablets whole; do not crush, chew, or dissolve in liquid.
Place orally disintegrating, fixed-combination acetaminophen/caffeine tablets on the tongue to dissolve; swallow with saliva. For best taste, do not chew.
Because combinations and dosage strengths vary for fixed-combination preparations, consult manufacturer’s product labeling for appropriate dosage of the specific preparation.
Pediatric Administration
Acetaminophen oral drops generally used in infants 0–23 months of age. Use the calibrated dosing device provided by the manufacturer for measurement of the dose.
Oral suspension may be used in children ≥4 months age. Use the calibrated dosage cup provided by the manufacturer for measurement of the dose.
80-mg chewable tablets or orally disintegrating tablets may be used in children ≥2 years of age.
160-mg chewable tablets or orally disintegrating tablets or 325-mg conventional tablets commonly used in children ≥6 years of age.
Orally disintegrating tablets (Tylenol® Meltaways) should be allowed to dissolve in the mouth or should be chewed before swallowing. Use caution to ensure that the correct number of tablets required for the intended dose is removed from the blister package.
Rectal Administration
Dividing suppositories in an attempt to administer lower dosages may not provide a predictable dose.
Some experts state that rectal acetaminophen preparations should not be used for self-medication in children unless such use is specifically discussed with a clinician and parents or caregivers are instructed to adhere to dosage and administration recommendations.
Dosage
Pediatric Patients
Dosage in children should be guided by body weight. (See Pediatric Use under Cautions.)
Pain
Oral
Dosage for Self-medication of Pain in Children up to 11 Years of Age
Age
Weight
Oral Dose
≤3 months
2.7–5 kg
40 mg
4–11 months
5–8 kg
80 mg
12–23 months
8–11 kg
120 mg
2–3 years
11–16 kg
160 mg
4–5 years
16–21.5 kg
240 mg
6–8 years
21.5–27 kg
320 mg
9–10 years
27–32.5 kg
400 mg
11 years
32.5–43 kg
480 mg
Dose may be given every 4–6 hours as necessary (up to 5 times in 24 hours).
For self-medication in children ≥12 years of age, 650 mg or 1 g every 4–6 hours as necessary (maximum 4 g daily).
Rectal
Dosage for Self-medication of Pain in Children 2–12 Years of Age
Age
Rectal Dose
2–4 years
160 mg
4–6 years
240 mg
6–9 years
320 mg
9–11 years
320–400 mg
11–12 years
320–480 mg
Dose may be given every 4–6 hours as necessary (up to 5 times in 24 hours).
Individualize dosage in children <2 years of age.
For self-medication in children ≥12 years of age, 325–650 mg every 4 hours as necessary.
Fever
Oral
Dosage for Self-medication of Fever in Children up to 11 Years of Age
Age
Weight
Oral Dose
≤3 months
2.7–5 kg
40 mg
4–11 months
5–8 kg
80 mg
12–23 months
8–11 kg
120 mg
2–3 years
11–16 kg
160 mg
4–5 years
16–21.5 kg
240 mg
6–8 years
21.5–27 kg
320 mg
9–10 years
27–32.5 kg
400 mg
11 years
32.5–43 kg
480 mg
Dose may be given every 4–6 hours as necessary (up to 5 times in 24 hours).
For self-medication in children ≥12 years of age, 650 mg or 1 g every 4–6 hours as necessary (maximum 4 g daily).
Rectal
Dosage for Self-medication of Fever in Children 2–12 Years of Age
Age
Rectal Dose
2–4 years
160 mg
4–6 years
240 mg
6–9 years
320 mg
9–11 years
320–400 mg
11–12 years
320–480 mg
Dose may be given every 4 hours as necessary (up to 5 times in 24 hours).
Individualize dosage in children <2 years of age.
For self-medication in children ≥12 years of age, 325–650 mg every 4 hours as necessary.
Adults
Pain
Oral
For self-medication, 650 mg or 1 g every 4–6 hours as necessary (maximum 4 g daily). Alternatively, 1.3 g as extended-release tablets every 8 hours.
Rectal
325–650 mg every 4 hours as necessary.
Pain Associated with Migraine Headache
Oral
Acetaminophen, aspirin, and caffeine for self-medication: 2 tablets (each containing acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg) as a single dose.
Acetaminophen, dichloralphenazone, and isometheptene mucate: 2 capsules (each containing acetaminophen 325 mg, dichloralphenazone 100 mg, and isometheptene mucate 65 mg) initially, followed by 1 capsule every hour until headache relieved (maximum 5 capsules in 12 hours).
Pain Associated with Tension Headache
Oral
Acetaminophen, dichloralphenazone, and isometheptene mucate: 1 or 2 capsules (each containing acetaminophen 325 mg, dichloralphenazone 100 mg, and isometheptene mucate 65 mg) every 4 hours (up to 8 capsules daily).
Pain Associated with Osteoarthritis
Oral
1 g 4 times daily. Alternatively, 1.3 g as extended-release tablets every 8 hours.
Fever
Oral
For self-medication, 650 mg or 1 g every 4–6 hours as necessary (maximum 4 g daily).
Rectal
325–650 mg every 4 hours as necessary.
Prescribing Limits
Pediatric Patients
Pain
Oral
Do not exceed recommended daily dosage. Self-medication should not exceed 5 days.
Fever
Oral
Do not exceed recommended daily dosage. Self-medication should not exceed 3 days.
Adults
Current limit is 4 g daily. Some experts recommend a maximum dosage of 3 g daily when used for long-term therapy (e.g., ≥2 weeks). FDA is evaluating whether data exist to support establishing a lower (i.e., <4 g daily) maximum daily dosage for certain patients (e.g., those who chronically ingest alcohol).
Pain
Oral or Rectal
Maximum 4 g daily. Self-medication should not exceed 10 days.
Pain Associated with Migraine Headache
Oral
Acetaminophen, aspirin, and caffeine: Maximum for self-medication is 2 tablets (each containing acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg) in 24 hours unless otherwise directed by a clinician.
Acetaminophen, dichloralphenazone, and isometheptene mucate: Maximum 5 capsules (each containing acetaminophen 325 mg, dichloralphenazone 100 mg, and isometheptene mucate 65 mg) in 12 hours.
Pain Associated with Tension Headache
Oral
Acetaminophen, dichloralphenazone, and isometheptene mucate: Maximum 8 capsules (each containing acetaminophen 325 mg, dichloralphenazone 100 mg, and isometheptene mucate 65 mg) in 24 hours.
Pain Associated with Osteoarthritis
Oral
Maximum 4 g daily.
Fever
Oral or Rectal
Maximum 4 g daily. Self-medication should not exceed 3 days.
Ingestion of a single toxic dose or multiple excessive doses can result in hepatotoxicity. Following suspected overdosage, evaluate necessity of antidote (acetylcysteine) therapy.
Increased serum ALT concentrations reported in healthy individuals receiving acetaminophen 4 g daily for 14 days in 1 study.
Sensitivity Reactions
Sensitivity reactions reported rarely. If such reactions occur, discontinue the drug.
Sulfite Sensitivity
Some formulations contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.
General Precautions
Do not use multiple acetaminophen-containing preparations concomitantly.
Phenylketonuria
Children’s Tylenol® and Junior Strength Tylenol® chewable tablets contain aspartame (NutraSweet®), which is metabolized in the GI tract to phenylalanine.
Distributed into milk; however, AAP considers acetaminophen to be usually compatible with breast-feeding.
Pediatric Use
Severe hepatotoxicity and death reported in children who apparently received acetaminophen dosages exceeding those recommended (10–15 mg/kg per dose with a maximum of 5 doses per day) for children. Contributing factors include improper interpretation of dosing information or failure to read such information, use of adult-strength preparations, use of excessive dosing because of the perception that desired therapeutic effects had not been achieved, and lack of knowledge about the potential toxicity of acetaminophen in excessive dosage.
Risk of overdosage and toxicity (including death) in children <2 years of age receiving preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection. Limited evidence of efficacy for these cold and cough preparations in this age group; appropriate dosages not established. Therefore, FDA recommends not to use such preparations in children <2 years of age; safety and efficacy in older children currently under evaluation. Because children 2–3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations recently agreed to voluntarily revise the product labeling to state that such preparations should not be used in children <4 years of age. During the transition period, some preparations on pharmacy shelves will have the new recommendation (“do not use in children <4 years of age”), while others will have the previous recommendation (“do not use in children <2 years of age”). FDA recommends that parents and caregivers adhere to dosage instructions and warnings on the product labeling that accompanies the preparation and consult a clinician about any concerns.
Interactions
Specific Drugs
Drug
Interaction
Comments
Alcohol
Increased risk of acetaminophen-induced hepatotoxicity
Avoid regular or excessive use of acetaminophen; alternatively, avoid chronic ingestion of alcohol (see Prescribing Limits: Adults, under Dosage and Administration)
Well absorbed following oral administration, with peak plasma concentration attained within 10–60 minutes (immediate-release preparations) or 60–120 minutes (extended-release preparations).
Poor or variable absorption following rectal administration; considerable variation in peak plasma concentrations attained; time to reach peak plasma concentration is substantially longer than after oral administration.
Food
Food may delay absorption following administration as extended-release tablets.
Distribution
Extent
Rapidly distributed to most body tissues. Crosses placenta and is distributed into breast milk.
Plasma Protein Binding
25%.
Elimination
Metabolism
Metabolized principally by sulfate and glucuronide conjugation; small amounts (5–10%) oxidized by CYP-dependent pathways (mainly CYP2E1 and CYP3A4) to a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is detoxified by glutathione and eliminated; any remaining toxic metabolite may bind to hepatocytes and cause cellular necrosis.
Elimination Route
Mainly excreted in urine as conjugates.
Half-life
1.25–3 hours.
Special Populations
Following toxic doses or in patients with liver damage, plasma half-life may be prolonged.
In patients with moderate to severe renal impairment, acetaminophen conjugates may accumulate.
Stability
Storage
Oral
Tablets
Room temperature. Protect orally disintegrating tablets (Tylenol® Meltaways) from high humidity. Protect grape-flavored orally disintegrating tablets from light.
Weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily. Inhibitory effect on cyclooxygenase-1 is limited; does not inhibit platelet function.
Advice to Patients
Risk of severe hepatic damage with use of excessive dosages, with concomitant use of multiple acetaminophen-containing preparations, and in those consuming substantial amounts of alcohol (e.g., ≥3 alcohol-containing drinks per day) concomitantly.
When used for self-medication, importance of reading the product labeling. Importance of not exceeding the recommended daily dosage and of not using other acetaminophen-containing products (e.g., some cold and cough products) concomitantly.
When used for self-medication in pediatric patients, importance of basing the dose on the child’s weight; importance of not exceeding the recommended daily dosage.
Importance of advising parents and caregivers about the appropriate dose, frequency, duration of therapy, and specific strength and formulation for an individual pediatric patient. Advise of the danger of substituting alternative dosage forms, particularly adult for pediatric formulations.
Importance of ensuring that the correct amount of medication required for the intended dose is administered (e.g., importance of using only the calibrated measuring device provided with the particular formulation for measuring the dose, importance of ensuring that the strength and number of dosage units correspond to the intended dose).
Importance of seeking quick medical attention if ingested dosage exceeds recommended dosage.
Importance of limiting alcohol intake.
Advise patients that paracetamol and APAP are other names for acetaminophen.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., cough/cold preparations) as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Pamprin® Cramp Caplets (with povidone and propylene glycol)
Chattem
325 mg with Propoxyphene Napsylate 50 mg*
Darvocet-N® 50 (C-IV)
Xanodyne
500 mg with Caffeine 60 mg and Pyrilamine Maleate 15 mg
Midol® Menstrual Complete Maximum Strength Caplets (with propylene glycol)
Bayer
Midol® Menstrual Complete Maximum Strength Gelcaps (with propylene glycol)
Bayer
500 mg with Diphenhydramine Hydrochloride 25 mg
Tylenol® PM Extra Strength Caplets
McNeil
Tylenol® PM Extra Strength Rapid Release Gelcaps (with benzyl alcohol, parabens, and propylene glycol)
McNeil
Tylenol® PM Extra Strength Geltabs® (with benzyl alcohol and parabens)
McNeil
500 mg with Pamabrom 25 mg
Midol® Teen Menstrual Formula Caplets® (with propylene glycol)
Bayer
500 mg with Propoxyphene Napsylate 100 mg
Darvocet A500® (C-IV; with povidone)
Xanodyne
650 mg with Propoxyphene Napsylate 100 mg*
Darvocet-N® 100 (C-IV)
Xanodyne
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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