Acetaminophen, diphenhydramine, and phenylephrine

Name: Acetaminophen, diphenhydramine, and phenylephrine

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1 800 222 1222. An overdose of acetaminophen can be fatal.

The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.

This medicine side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

In rare cases, acetaminophen may cause a severe skin reaction that can be fatal. This could occur even if you have taken acetaminophen in the past and had no reaction. Stop taking this medicine and call your doctor right away if you have skin redness or a rash that spreads and causes blistering and peeling. If you have this type of reaction, you should never again take any medicine that contains acetaminophen.

Stop using this medicine and call your doctor at once if you have:

  • chest pain, rapid pulse, fast or uneven heart rate;

  • confusion, hallucinations, severe nervousness;

  • tremor, seizure (convulsions);

  • easy bruising or bleeding, unusual weakness;

  • little or no urinating;

  • nausea, pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of your skin or eyes); or

  • dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, chest pain, shortness of breath, uneven heartbeats, seizure).

Common side effects may include:

  • dizziness, drowsiness;

  • mild headache, blurred vision;

  • dry mouth, nose, or throat;

  • constipation;

  • feeling nervous; or

  • sleep problems (insomnia);

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

For Healthcare Professionals

Applies to acetaminophen / diphenhydramine / phenylephrine: oral liquid, oral powder for reconstitution, oral syrup, oral tablet

Cardiovascular

Cardiovascular side effects of acetaminophen have included two cases of hypotension.

Cardiovascular side effects of diphenhydramine have included hypotension, tachycardia, and palpitations.

Cardiovascular side effects of phenylephrine have included palpitations, arrhythmias, and cardiovascular collapse with hypotension.[Ref]

Two cases hypotension have been reported following the administration of acetaminophen. Both patients experienced significant decreases in blood pressure. One of the two patients required pressor agents to maintain adequate mean arterial pressures. Neither episode was associated with symptoms of anaphylaxis. Neither patient was rechallenged after resolution of the initial episode.[Ref]

Dermatologic

Dermatologic side effects have included erythematous skin rashes. Acetaminophen associated bullous erythema and purpura fulminans have also been reported. Acetaminophen has been associated with a risk of rare but potentially fatal serious skin reactions known as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).[Ref]

Gastrointestinal

One study has suggested that acetaminophen may precipitate acute biliary pain and cholestasis. The mechanism of this effect may be related to inhibition of prostaglandin and alterations in the regulation of the sphincter of Oddi.[Ref]

Gastrointestinal side effects of acetaminophen have included rare cases of acute pancreatitis.

Gastrointestinal side effects of diphenhydramine have included nausea and dry mouth.

Gastrointestinal side effects of phenylephrine have included nausea.[Ref]

Genitourinary

Genitourinary side effects of diphenhydramine have included urinary retention and dysuria.

Genitourinary side effects of phenylephrine have included dysuria.[Ref]

Hematologic

Hematologic side effects of acetaminophen have included rare cases of thrombocytopenia. Methemoglobinemia with resulting cyanosis has also been observed in the setting of acute overdose.

Hematologic side effects of diphenhydramine have rarely included hemolytic anemia, thrombocytopenia, and agranulocytosis.[Ref]

Hepatic

Alcoholic patients may develop hepatotoxicity after even modest doses of acetaminophen. In healthy patients, approximately 15 grams of acetaminophen is necessary to deplete liver glutathione stores by 70% in a 70 kg person. However, hepatotoxicity has been reported following smaller doses. Glutathione concentrations may be repleted by the antidote N-acetylcysteine. One case report has suggested that hypothermia may also be beneficial in decreasing liver damage during overdose.

In a recent retrospective study of 306 patients admitted for acetaminophen overdose, 6.9% had severe liver injury but all recovered. None of the 306 patients died.

A 19 year old female developed hepatotoxicity, reactive plasmacytosis and agranulocytosis followed by a leukemoid reaction after acute acetaminophen toxicity.[Ref]

Hepatic side effects of acetaminophen have included severe and sometimes fatal dose dependent hepatitis in alcoholic patients. Hepatotoxicity has been increased during fasting. Several cases of hepatotoxicity from chronic acetaminophen therapy at therapeutic doses have also been reported despite a lack of risk factors for toxicity.[Ref]

Hypersensitivity

Most commonly, hypersensitivity to diphenhydramine has manifested itself in patients receiving systemic drug after being sensitized to it by topical application. Sensitization with systemic administration has also been reported.[Ref]

Hypersensitivity side effects of acetaminophen have included rare reports of anaphylaxis and fixed drug eruptions.

Hypersensitivity side effects to diphenhydramine have included rash, pruritus and eczema. Photosensitivity reactions have also been reported.[Ref]

Nervous system

The CNS depressant effect of diphenhydramine parallels its plasma concentrations. The plasma concentration threshold for sedation is 30 to 42 ng/mL, and to cause mental impairment is 58 to 74 ng/mL. Patients should be warned against driving while taking diphenhydramine.

Dystonic reactions have been accompanied by dizziness, mental confusion, rigidity, lip and tongue protrusion, trismus, torticollis, and swallowing difficulties and generally resolve spontaneously. Toxic encephalopathy has been reported in a child with chicken pox treated generously with topical diphenhydramine.

Delirium has been reported in elderly patients with mild dementia following a small oral dose of diphenhydramine.[Ref]

Nervous system side effects of diphenhydramine have included depression with drowsiness and sedation in nearly all patients treated. Motor skills may be impaired. Dystonic reactions have been reported after single doses of diphenhydramine.

Nervous system side effects of phenylephrine have included headache, dizziness, nervousness, restlessness, tremor, insomnia, convulsions, and central nervous system depression.[Ref]

Renal

Renal side effects of acetaminophen have included acute tubular necrosis and interstitial nephritis. Adverse renal effects are most often observed after overdose, after chronic abuse (often with multiple analgesics), or in association with acetaminophen-related hepatotoxicity.[Ref]

Acute tubular necrosis usually occurs in conjunction with liver failure, but has been observed as an isolated finding in rare cases. A possible increase in the risk of renal cell carcinoma has been associated with chronic acetaminophen use as well.

A recent case control study of patients with end-stage renal disease suggested that long term consumption of acetaminophen may significantly increase the risk of end-stage renal disease particularly in patients taking more than two pills per day.[Ref]

Respiratory

Respiratory side effects of acetaminophen have included a case of eosinophilic pneumonia.

Respiratory side effects of phenylephrine have included respiratory difficulty.[Ref]

Psychiatric

Psychiatric side effects of phenylephrine have included hallucinations, fear, and anxiety.[Ref]

General

General side effects of phenylephrine have included pallor and weakness.[Ref]

Some side effects of acetaminophen / diphenhydramine / phenylephrine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Usual Adult Dose for Cold Symptoms

Acetaminophen/diphenhydramine/phenylephrine 325 mg-12.5 mg-5 mg oral tablet, or
Acetaminophen/diphenhydramine/phenylephrine 325 mg-25 mg-5 mg oral tablet:
2 tablets orally every 4 hours not to exceed 12 tablets daily.

Acetaminophen/diphenhydramine/phenylephrine 325 mg-12.5 mg-5 mg/15 mL oral syrup:
30 mL orally every 4 hours not to exceed 180 mL daily.

Acetaminophen/diphenhydramine/phenylephrine 650 mg-25 mg-10 mg oral powder for reconstitution (one packet):
one packet dissolved in 8 oz hot water orally every 4 hours; sip while hot. Consume entire drink within 10 to 15 minutes. Do not exceed 6 packets in 24 hours.

Acetaminophen/diphenhydramine/phenylephrine 160 mg-6.25 mg-2.5 mg/5 mL oral liquid:
20 mL orally every 4 hours not to exceed 6 doses in any 24 hour period.
Acetaminophen/diphenhydramine/phenylephrine 325 mg-12.5 mg-5 mg/10 mL oral liquid:
20 mL orally every 4 hours not to exceed 6 doses in any 24 hour period.
Acetaminophen/diphenhydramine/phenylephrine 650 mg-25 mg-10 mg/20 mL oral liquid:
20 mL orally every 4 hours not to exceed 6 doses in any 24 hour period.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Data not available

Acetaminophen / diphenhydramine / phenylephrine Pregnancy Warnings

Acetaminophen has not been formally assigned to a pregnancy category by the FDA. It is routinely used for short-term pain relief and fever in all stages of pregnancy. Acetaminophen is believed to be safe in pregnancy when used intermittently for short durations. Diphenhydramine has been assigned to pregnancy category B by the FDA. Animal studies have failed to reveal teratogenicity. The Collaborative Perinatal Project reported 595 first-trimester exposures and 2,948 exposures anytime during pregnancy. No relationship was found to large categories of malformations. Possible associations with individual malformation were found. One study reported a statistical relationship between diphenhydramine use in the first trimester and cleft palate. One case of withdrawal in an infant whose mother ingested 150 mg per day of diphenhydramine has been reported. This infant developed tremor on the fifth day of life which was treated with phenobarbital. Phenylephrine has been assigned to pregnancy category C by the FDA. Animal studies have not been reported. There are no controlled data in human pregnancy. Acetaminophen/diphenhydramine/phenylephrine is only recommended for use during pregnancy when benefit outweighs risk.

Acetaminophen / diphenhydramine / phenylephrine Breastfeeding Warnings

Acetaminophen is excreted into human milk in small concentrations. One case of a rash has been reported in a nursing infant. Acetaminophen is considered compatible with breast-feeding by the American Academy of Pediatrics. Diphenhydramine is excreted into human milk. Diphenhydramine may also inhibit lactation. Small amounts of phenylephrine are secreted in breast milk. The manufacturer recommends that due to the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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