[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].
Adjunct to epinephrine and other standard measures for management of anaphylaxis after acute symptoms have been controlled.
Used IV or IM for management of other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated.
Allergic Rhinitis
Self-medication for temporary relief of rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal irritation or itching, or cough associated with allergic rhinitis (e.g., hay fever) or other upper respiratory allergies.
Used in fixed combination with other agents (e.g., acetaminophen, phenylephrine, pseudoephedrine) for relief of rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, and/or other symptoms (e.g., headache, nasal/sinus congestion) associated with seasonal or perennial allergic rhinitis or other upper respiratory allergies.
Use fixed-combination preparations only when symptoms amenable to each ingredient are present concurrently.
Common Cold
Self-medication for temporary relief of symptoms associated with the common cold (e.g., rhinorrhea, sneezing, cough).
Used in fixed combination with other agents (e.g., acetaminophen, phenylephrine, pseudoephedrine) for symptomatic relief of rhinorrhea, sneezing, and/or other symptoms associated with the common cold (e.g., headache, minor aches and pains, sore throat, cough, nasal congestion).
Insomnia
Self-medication for short-term (i.e., ≤2 weeks) management of occasional sleeplessness, particularly in individuals who have difficulty falling asleep.
Used in fixed combination with other agents (e.g., acetaminophen, aspirin) for short-term management of occasional sleeplessness.
Development of tolerance reported with repeated use.
Dermatologic Disorders
Systemic antihistamines may be more effective than topical, especially if pruritus is generalized, and less likely to cause sensitivity reactions than when applied topically for pruritus associated with various dermatologic conditions.
Motion Sickness
Prevention and treatment of nausea, vomiting, and/or vertigo associated with motion sickness.
Parkinsonian Syndrome
May be useful as alternative therapy in the management of tremor early in the course of parkinsonian syndrome. Also may be useful in the management of drug-induced extrapyramidal reactions.
Used IV for management of parkinsonian syndrome when oral therapy is impossible or contraindicated. Used specifically in geriatric patients who are unable to tolerate more potent agents; for mild cases of parkinsonism in younger patients; and in combination with centrally acting anticholinergic agents in other cases of parkinsonism.
Administer diphenhydramine citrate-containing preparations orally.
Oral Administration
Diphenhydramine hydrochloride chewable tablets: Chew thoroughly before swallowing.
Diphenhydramine citrate orally disintegrating tablets: Place tablet on the tongue, allow tablet to disintegrate (within a few seconds), then swallow with or without water.
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
IV injection preferred over deep IM injection.
IV use in a home-care setting should be employed under careful supervision.
Rate of Administration
≤25 mg/minute.
Dosage
Available as diphenhydramine hydrochloride and diphenhydramine citrate; dosage is expressed in terms of diphenhydramine hydrochloride or diphenhydramine citrate.
Diphenhydramine citrate available only in fixed-combination preparations.
12.5 mg diphenhydramine hydrochloride equivalent to 19 mg diphenhydramine citrate.
Fixed-combination preparations do not permit individual titration of dosages. When used in fixed combination with other agents (e.g., acetaminophen, aspirin, phenylephrine, pseudoephedrine), select a dosage that is within the usual therapeutic range for each ingredient. Because combinations and dosage strengths vary for fixed-combination preparations, consult manufacturer's product labeling for appropriate dosage of the specific preparation.
Pediatric Patients
Allergic Conditions and the Common Cold
Acute Allergic Reactions
IV or IM
Children >1 month of age: 5 mg/kg daily or 150 mg/m2 daily (up to a maximum of 300 mg daily) divided in 4 doses.
Alternatively, 1–2 mg/kg recommended by some experts.
Allergic Rhinitis and the Common Cold
Oral
Self-medication in children 2–5 years of age: 6.25 mg every 4–6 hours (as diphenhydramine hydrochloride) or 9.5 mg every 4 hours (as diphenhydramine citrate) when directed by a clinician; do not exceed 37.5 mg (as diphenhydramine hydrochloride) or 57 mg (as diphenhydramine citrate) in 24 hours. (See Pediatric Use under Cautions.)
Self-medication in children 6–11 years of age: 12.5–25 mg every 4–6 hours (as diphenhydramine hydrochloride) or 19 mg every 4 hours (as diphenhydramine citrate); do not exceed 150 mg (as diphenhydramine hydrochloride) or 76 mg (as diphenhydramine citrate) in 24 hours.
Self-medication in children ≥12 years of age: 25–50 mg every 4–6 hours (as diphenhydramine hydrochloride) or 38 mg every 4 hours (as diphenhydramine citrate); do not exceed 300 mg (as diphenhydramine hydrochloride) or 152 mg (as diphenhydramine citrate) in 24 hours.
Insomnia
Oral
Children 2–11 years of age†: 1 mg/kg (as diphenhydramine hydrochloride) 30 minutes before retiring; do not exceed 50 mg.
Self-medication in children ≥12 years of age: 50 mg (as diphenhydramine hydrochloride) or 76 mg (as diphenhydramine citrate) at bedtime as needed, or as directed by a clinician. Higher dosages do not produce substantially greater benefit but may be associated with a higher incidence of adverse (e.g., anticholinergic) effects.
Use not recommended for ≥7–10 nights.
Motion Sickness
Oral
Children 2–5 years of age†: 6.25 mg (as diphenhydramine hydrochloride) 30–60 minutes before travel and every 4–6 hours during travel; do not exceed 37.5 mg in 24 hours.
Self-medication in children 6–11 years of age: 12.5–25 mg (as diphenhydramine hydrochloride) 30–60 minutes before travel and every 4–6 hours during travel; do not exceed 150 mg in 24 hours.
Self-medication in children ≥12 years of age: 25–50 mg (as diphenhydramine hydrochloride) 30 minutes before exposure to motion and then every 4–6 hours (before meals and at bedtime) for duration of exposure; do not exceed 300 mg in 24 hours.
IV or IM
Children >1 month of age: 5 mg/kg daily or 150 mg/m2 daily (up to a maximum of 300 mg daily) divided in 4 doses.
Parkinsonian Syndrome
IV or IM
Children >1 month of age: 5 mg/kg daily or 150 mg/m2 daily (up to a maximum of 300 mg daily) divided in 4 doses.
Adults
Allergic Conditions and the Common Cold
Acute Allergic Reactions
IV or IM
10–50 mg; in a few patients, up to 100 mg may be required.
Alternatively, 25–50 mg recommended by some experts.
Allergic Rhinitis and the Common Cold
Oral
Self-medication: 25–50 mg every 4–6 hours (as diphenhydramine hydrochloride) or 38 mg every 4 hours (as diphenhydramine citrate); do not exceed 300 mg (as diphenhydramine hydrochloride) or 152 mg (as diphenhydramine citrate) in 24 hours.
Insomnia
Oral
Self-medication: 50 mg (as diphenhydramine hydrochloride) or 76 mg (as diphenhydramine citrate) at bedtime as needed, or as directed by a clinician. Higher dosages do not produce substantially greater benefit but may be associated with a higher incidence of adverse (e.g., anticholinergic) effects.
Use not recommended for ≥7–10 nights.
Motion Sickness
Oral
Self-medication: 25–50 mg (as diphenhydramine hydrochloride) 30 minutes before exposure to motion and then every 4–6 hours (before meals and at bedtime) for duration of exposure; do not exceed 300 mg in 24 hours.
IV or IM
10–50 mg; in a few patients, up to 100 mg may be required.
Parkinsonian Syndrome
Oral
Initially, 25 mg 3 times daily (as diphenhydramine hydrochloride). If necessary, gradually increase dosage to 50 mg 4 times daily.
IV or IM
10–50 mg; in a few patients, up to 100 mg may be required.
Prescribing Limits
Pediatric Patients
Oral
Children 2–5 years of age: Maximum 37.5 mg (as diphenhydramine hydrochloride) or 57 mg (as diphenhydramine citrate) in 24 hours. (See Pediatric Use under Cautions.)
Children 6–11 years of age: Maximum 150 mg (as diphenhydramine hydrochloride) or 76 mg (as diphenhydramine citrate) in 24 hours.
Children ≥12 years of age: Maximum 300 mg (as diphenhydramine hydrochloride) or 152 mg (as diphenhydramine citrate) in 24 hours.
IV or IM
Children >1 month: Maximum 300 mg daily.
Adults
Oral
Maximum 300 mg in 24 hours.
IV or IM
Maximum 400 mg daily.
Cautions
Contraindications
Use contraindicated in neonates and premature infants. (See Pediatric Use under Cautions.)
Injection should not be used as a local anesthetic. (See Local Necrosis under Cautions.)
Concomitant use with other preparations containing diphenhydramine, including oral and topical preparations.
Known hypersensitivity to diphenhydramine, other antihistamines with similar chemical structure, or any ingredient in the formulation.
Warnings/Precautions
Warnings
Concomitant Diseases
Patients with glaucoma, respiratory conditions (e.g., emphysema, chronic bronchitis), or difficulty urinating due to prostatic hypertrophy should consult a clinician before initiating therapy with diphenhydramine.
Risk of marked drowsiness. Among first generation antihistamines, ethanolamines (e.g., diphenhydramine) considered the most sedating and alkylamines (e.g., brompheniramine, chlorpheniramine) considered the least sedating.
Possible excitability (especially in children).
Caution when driving a motor vehicle, operating machinery, or engaging in other potentially hazardous tasks. (See CNS Depressants under Interactions.)
Diphenhydramine Toxicity
Risk of toxicity. (See Pediatric Use under Cautions.) Do not use more often than directed for any condition; do not concomitantly use more than one preparation containing diphenhydramine (e.g., avoid simultaneous use of oral and topical preparations).
Local Necrosis
Risk of local necrosis with subcutaneous or intradermal administration. Do not use diphenhydramine injection as a local anesthetic.
Sensitivity Reactions
Sulfite Sensitivity
Some formulations may contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.
General Precautions
Duration of Therapy
When used for insomnia, avoid using for self-medication for longer than 7–10 nights, and consult a clinician if insomnia persists continuously for >2 weeks.
Phenylketonuria
Certain preparations (e.g., Alka-Seltzer PM®, Benadryl® chewable tablets; Children's Benadryl® Allergy & Sinus Fastmelt orally disintegrating tablets) contain aspartame (NutraSweet®) which is metabolized in the GI tract to phenylalanine following oral administration.
Use of Fixed Combinations
When used in fixed combination with other agents (e.g., acetaminophen, aspirin, phenylephrine, pseudoephedrine), consider the cautions, precautions, and contraindications associated with the concomitant agent(s).
Specific Populations
Pregnancy
Category B.
Lactation
Has been detected in milk. Discontinue nursing or the drug because of potential risk to nursing infants.
Pediatric Use
Risk of diminished mental alertness. Risk of excitation in young pediatric patients.
Risk of diphenhydramine toxicity (e.g., dilated pupils, flushed face, hallucinations, ataxic gait, urinary retention) when oral preparations used concomitantly with topical preparations of diphenhydramine. (See Diphenhydramine Toxicity under Cautions.)
Potential for misuse and abuse following parenteral administration over a prolonged period of time.
Use with caution in infants and young children; should not be used in premature or full-term neonates. Children <6 years of age should receive oral diphenhydramine only under the direction of a physician.
Safety and efficacy of diphenhydramine as a nighttime sleep aid in children <12 years of age have not been established. Consider risk of possible CNS stimulation when used as nighttime sleep aids.
Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC 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 preparations in this age group; appropriate dosages not established. Therefore, FDA recommended 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. Clinicians should ask caregivers about use of OTC cough/cold preparations to avoid overdosage.
Geriatric Use
Possible increased risk of dizziness, sedation, and hypotension in patients ≥60 years of age.
Blocks H1-receptor sites, thereby preventing the action of histamine on the cell.
Suppresses flare and pruritus that accompany the endogenous release of histamine.
Exhibits some activities common to anticholinergics, ganglionic and adrenergic blocking agents, local anesthetics, and antispasmodics.
Antihistamines do not block the stimulating effect of histamine on gastric acid secretion, which is mediated by H2-receptors of the parietal cells.
Effects on parkinsonian syndrome and drug-induced extrapyramidal reactions are apparently related to central anticholinergic effects.
Advice to Patients
Risk of drowsiness; avoid alcohol and use caution when driving, operating machinery, or engaging in other hazardous tasks.
When used for insomnia, consult a clinician if sleeplessness persists continuously for >2 weeks.
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses. Importance of patients already receiving another CNS depressant (e.g., sedatives, tranquilizers) not undertaking self-medication without first consulting a clinician.
Importance of not using multiple diphenhydramine-containing preparations (either oral or topical) simultaneously because of risk of toxicity. (See Diphenhydramine Toxicity under Cautions.)
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
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.
In response to concerns regarding the safety and efficacy of cough and cold preparations in young children, many nonprescription cough and cold preparations specifically formulated for infants have been voluntarily withdrawn from the US market. Therefore, some of the preparations described below may no longer be commercially available in the US.
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.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
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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