Continuing Education Activity

Promethazine is a medication used in the management and treatment of allergic conditions, nausea and vomiting, motion sickness, and sedation. It also has off-label uses for nausea and vomiting in pregnancy. Promethazine is a phenothiazine derivative with antidopaminergic, antihistamine, and anticholinergic properties. This activity reviews the indications, method of action, administration, adverse reactions, contraindications, monitoring, and toxicity of promethazine. This activity will also highlight the pertinent interprofessional roles of the interprofessional team during the use of promethazine.


  • Identify the mechanism of action of promethazine.
  • Describe the adverse effects and contraindications of promethazine.
  • Review the appropriate monitoring and toxicity of promethazine.
  • Summarize interprofessional team strategies for improving care coordination and communication to advance promethazine in patients who present with conditions where it has therapeutic value and can improve outcomes.


Labeled Indications, FDA Approved:

  • Allergic Conditions: Promethazine is a first-generation antihistamine, and thus it is indicated for a variety of allergic conditions including seasonal allergic rhinitis, allergic conjunctivitis, uncomplicated skin manifestations of urticaria and angioedema, and adjunctive therapy to epinephrine for anaphylactic reactions.[1][2][3]
  • Nausea and Vomiting: Phenothiazines such as promethazine have substantial antiemetic activity. Clinicians use promethazine to control nausea and vomiting in association with anesthesia or chemotherapy. It is commonly used postoperatively as an antiemetic. The antiemetic activity increases with increased dosing; however, side effects also increase, which often limits maximal dosing.[4][5][6]
  • Motion Sickness: Promethazine can serve as prophylactic therapy for motion sickness. It is most effective when given 30 minutes to 1 hour before undergoing the triggering event.[7]
  • Sedation: Promethazine can be used as adjunctive therapy with other analgesics to provide preoperative, postoperative, or obstetric sedation.[8]

Off-Label Usage:

  • Nausea and vomiting associated with pregnancy: According to the American College of Obstetrics, promethazine is useful in nausea and vomiting during pregnancy when preferred agents do not provide symptomatic relief. A double-blinded randomized controlled trial of intravenous promethazine versus metoclopramide in women with hyperemesis gravidarum found similar efficacy between the two drugs in controlling nausea and vomiting at 24 hours but found increased side effects in the promethazine group such as dry mouth, drowsiness, dizziness, and dystonia. Research has also identified phenothiazines as a potential cause of congenital malformations in one study, but other studies attest to their safety. Promethazine is classified as category C by the FDA. Alternative therapies may be indicated before promethazine considering the risks to the fetus and adverse effects on the mother.[9][10][11]

Mechanism of Action

Promethazine is a phenothiazine derivative with antidopaminergic, antihistamine, and anticholinergic properties. Other phenothiazines derivatives include prochlorperazine and chlorpromazine. Promethazine is a direct antagonist at the mesolimbic dopamine receptors and alpha-adrenergic receptors in the brain. Promethazine exhibits its antihistamine effects as an H1-receptor blocker.[12][13]


Promethazine has several routes of administration, including oral, rectal, intramuscular, and intravenous. When administered orally, give with food, water, or milk to decrease gastrointestinal discomfort. The intramuscular injection must be into deep muscle tissue as the subcutaneous injection may result in tissue damage. Intravenous use should be used with caution as severe tissue damage may also occur. In selected patients, promethazine may be diluted before IV administration to prevent promethazine-induced tissue necrosis. The dosage of tablets, solutions, and suppository is generally 12.5 mg to 50 mg. There is also a syrup form of 6.25 mg/5 ml.[14][15]

In pediatrics, promethazine has the same routes of administration as adults. However, dosing adjustments are necessary based on the weight of the patient and the indication. Utilizing the lowest dose of efficacy is recommended.

There are no dosage adjustments for renal or hepatic impairment.

Adverse Effects

There are several potential adverse effects of promethazine administration related to its method of action. The most common side effects include sedation, confusion, and disorientation, which may impair physical and mental abilities. However, in some cases, promethazine may paradoxically cause excitability, restlessness, or rarely seizures.

Due to promethazine’s anticholinergic properties, it may cause anticholinergic side effects, which include blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. Due to these effects, promethazine categorizes as a potentially inappropriate drug in the elderly by the American Geriatrics Society.[16]

Promethazine’s antidopaminergic properties may result in extrapyramidal symptoms, which include pseuodoparkinsonism, acute dystonia, akathisia, and tardive dyskinesia. Promethazine, therefore, may worsen symptoms in patients with Parkinson disease.[16]

Black Box Warnings:

  1. In children less than two years old, reports exist of respiratory depression resulting in fatalities. For this reason, there is US Black Box Warning on the use of promethazine in children less than two years of age.[17][18]
  2. Promethazine may cause serious tissue injury on injection, including gangrene, regardless of the route of administration. This effect may occur as a result of extravasation, unintentional intra-arterial administration, and intraneuronal or perineuronal infiltration, which may manifest as burning, pain, erythema, edema, severe spasms, phlebitis, thrombophlebitis, venous thrombosis, sensory loss, paralysis, and palsies.[14][15]

Less common adverse effects that prescribers should be aware of include:

  • The neuroleptic malignant syndrome may have associations with promethazine usage as well, which manifests as increased body temperature, confusion or altered mental status, sweating, autonomic instability, and “lead pipe” rigidity.
  • Cardiovascular side effects to include arrhythmias and hypotension
  • Reports also exist of liver damage and cholestatic jaundice with its use.
  • Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia
  • Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermia


Promethazine contraindications include patients with hypersensitivity to the drug, any components of the drug, or other phenothiazines. It is contraindicated in children under two years of age due to the risk of potentially fatal respiratory depression. Promethazine is contraindicated for subcutaneous or intra-arterial administration due to the risk of tissue damage. Contraindications also include comatose patients and patients with lower respiratory tract symptoms.[17][14]


Due to promethazine’s side effect profile, any medical personnel who administers the drug should be aware of potential side effects. Healthcare providers need to monitor patients for burning or pain at the injection site, phlebitis, blistering, or swelling as this may indicate tissue damage. Extrapyramidal and anticholinergic side effects also require monitoring, and providers should be notified immediately if they appear. Promethazine is also CNS depressant, so safety measure such as side rails up and call light within reach should be in place.


The main feature of promethazine toxicity is CNS depression, tachycardia, respiratory depression, and delirium. For most overdoses, supportive care and monitoring are the treatment as there is no known antidote. Significant overdoses with profoundly depressed mental status or coma may require airway support, hemodynamic monitoring, and a higher level of care. Some studies have shown that early administration of charcoal within 2 hours may be beneficial. However, the evidence is still lacking, and further studies are necessary.[12]

Enhancing Healthcare Team Outcomes

Overall, promethazine is a relatively safe medication that is very useful in several circumstances, such as nausea/vomiting, allergic conditions, prevention of motion sickness, and pre/post-operative or obstetric sedation. However, any prescriber of the medication should be aware of the potential side effects and contraindications. Providers must be mindful of the two black box warning associated, which include potential to cause severe tissue damage with IM/IV injection and potentially fatal respiratory depression in children under two years of age.

Therefore, close interprofessional coordination between providers (MDs, DOs, NPs, PAs), nurses, pharmacists, and other healthcare workers is necessary to improve patient outcomes and decrease adverse events when using promethazine. Pharmacists can reconcile the patient's medication profile, and report back to the nurse or prescribing clinician if any interactions exist. Nurses will often be the first to see the patient and can monitor for apparent adverse effects, either reporting to the prescriber or checking with the pharmacist regarding the adverse event profile of promethazine. Nursing is also in charge of IV administration so that they will have first-line exposure to issues such as extravasation, and can inform the clinician. The entire interprofessional healthcare team must collaborate, each discipline bringing its expertise to support positive outcomes. [Level 5]

Article Details

Article Author

Brittin Southard

Article Editor:

Yasir Al Khalili


7/10/2020 2:02:19 AM

PubMed Link:




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