Phenergan (Promethazine)
promethazine hydrochloride
Indications for Promethazine
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Allergic rhinitis (perennial & seasonal) | Adults & children ≥2 years | Monotherapy or adjunctive | FDA Approved |
| Allergic conjunctivitis | Adults & children ≥2 years | Monotherapy | FDA Approved |
| Urticaria & angioedema (mild, uncomplicated) | Adults & children ≥2 years | Monotherapy | FDA Approved |
| Dermographism | Adults & children ≥2 years | Monotherapy | FDA Approved |
| Allergic reactions to blood or plasma | Adults | Prophylaxis | FDA Approved |
| Anaphylaxis (adjunctive) | Adults & children ≥2 years | Adjunctive to epinephrine | FDA Approved |
| Nausea & vomiting (perioperative / postoperative) | Adults & children ≥2 years | Treatment & prophylaxis | FDA Approved |
| Motion sickness | Adults & children ≥2 years | Prophylaxis & treatment | FDA Approved |
| Sedation (pre/postoperative, obstetric) | Adults & children ≥2 years | Monotherapy or adjunctive | FDA Approved |
| Adjunct to analgesics for postoperative pain | Adults | Adjunctive to meperidine or other analgesics | FDA Approved |
Promethazine occupies a broad therapeutic niche as one of the few first-generation antihistamines with reliable antiemetic and sedative properties. Its versatility across allergy, perioperative, and motion sickness settings makes it a commonly used agent, though its sedating profile and safety concerns in pediatric patients have shifted prescribing patterns toward second-generation antihistamines and newer antiemetics for many indications.
Nausea and vomiting of pregnancy (NVP): Promethazine is used as a second-line option for NVP when first-line agents such as doxylamine-pyridoxine are ineffective. The ACOG practice bulletin supports its use in refractory cases. (Evidence quality: moderate)
Migraine-associated nausea in the emergency department: Administered parenterally for acute nausea relief in migraine presentations, often combined with IV fluids and NSAIDs. (Evidence quality: moderate)
Pruritus (non-allergic): Occasionally used for pruritus in palliative care or cholestatic conditions when sedation is desirable. (Evidence quality: low)
Dosing
Adult Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Allergic rhinitis / urticaria — daytime control | 6.25–12.5 mg PO TID | 6.25–12.5 mg PO TID | 12.5 mg TID + 25 mg at bedtime | Titrate to lowest effective dose; sedation limits daytime use Consider second-gen antihistamine for long-term use |
| Allergic rhinitis / urticaria — bedtime monotherapy | 25 mg PO at bedtime | 25 mg PO at bedtime | 25 mg PO at bedtime | Preferred regimen when sedation is desirable |
| Motion sickness — prophylaxis | 25 mg PO 30–60 min before travel | 25 mg PO BID (morning + evening) | 50 mg/day | First dose 30–60 min before departure; repeat 8–12 h later if needed On multi-day travel, give AM + before evening meal |
| Nausea & vomiting — active treatment | 12.5–25 mg PO/PR/IM/IV | 12.5–25 mg q4–6h PRN | 25 mg q4–6h | IV route: dilute to ≤1 mg/mL in NS and infuse over 20–40 min through large vein (preferably central); IM preferred FDA 2023: do not administer IV via hand/wrist veins |
| Perioperative nausea — prophylaxis | 25 mg IM/IV | 25 mg q4–6h PRN | 25 mg q4h | Give toward end of surgery or in recovery |
| Sedation — preoperative | 25–50 mg PO/PR/IM | Single dose | 50 mg | Give the night before surgery or combined with analgesic + atropine preoperatively Reduce narcotic dose by 25–50% when co-administered |
| Sedation — routine (nighttime) | 25 mg PO at bedtime | 25–50 mg PO at bedtime | 50 mg | Not intended for chronic insomnia management |
| Transfusion reaction — prophylaxis | 25 mg PO/IM | Single dose pre-transfusion | 25 mg | Give before or during blood/plasma transfusion |
| Adjunct to postoperative analgesia | 25–50 mg IM/IV | 25 mg q4–6h PRN | 50 mg per dose | Reduce opioid dose by 25–50% when combined Established labor: up to 75 mg IM/IV, may repeat x2 at 4 h intervals (max 100 mg/24 h). Excessive promethazine relative to opioid may cause paradoxical restlessness |
Pediatric Dosing (≥2 Years Only)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Allergic conditions | 6.25–12.5 mg PO TID or 25 mg at bedtime | Lowest effective dose | 25 mg/dose | Weight-based: 0.125 mg/kg TID or 0.5 mg/kg at bedtime Use the lowest effective dose; avoid in children <2 y |
| Nausea & vomiting | 0.5 mg/lb (1.1 mg/kg) PO/PR/IM | 0.5 mg/lb q4–6h PRN | 25 mg/dose | Limit to prolonged vomiting of known etiology only Do not use for uncomplicated vomiting |
| Motion sickness | 12.5–25 mg PO BID | 12.5–25 mg PO BID | 25 mg/dose | Alternative: 0.5 mg/lb; give 30–60 min before travel |
| Sedation | 12.5–25 mg PO/PR at bedtime | Single dose | 25 mg | Weight-based: 0.5–1.1 mg/kg |
Promethazine is contraindicated in children under 2 years of age due to the risk of fatal respiratory depression. In children aged 2 years and older, always use the lowest effective dose and avoid co-administration with other respiratory depressants. Weight-based dosing does not guarantee safety in this population.
When promethazine is used alongside opioid analgesics, the FDA prescribing information recommends reducing the opioid dose by 25–50% and barbiturate doses by at least 50%. Failure to reduce co-administered CNS depressant doses can lead to excessive sedation and respiratory compromise.
Pharmacology
Mechanism of Action
Promethazine is a phenothiazine derivative that exerts its primary therapeutic effects through competitive antagonism at histamine H1 receptors. Unlike antipsychotic phenothiazines, its branched side chain and absence of ring substitution result in markedly reduced dopamine D2 receptor affinity (approximately one-tenth that of chlorpromazine). The drug also demonstrates significant muscarinic acetylcholine receptor antagonism, which underpins both its anticholinergic side-effect profile and its efficacy against motion sickness. The antiemetic activity likely arises from combined central anticholinergic action on the vestibular apparatus and antagonism at the chemoreceptor trigger zone. Promethazine additionally shows modest alpha-1 adrenergic blockade, which can contribute to orthostatic hypotension, and weak serotonergic (5-HT2A/2C) antagonism. Recent evidence suggests it may also act as a non-competitive NMDA receptor antagonist, which could contribute to its sedative properties.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | GI absorption >80%; oral bioavailability ~25% (first-pass); Tmax 1.5–3 h (oral), 4.4 h (syrup), 6.7–8.6 h (suppository); onset ~20 min (oral/IM/PR) | Extensive first-pass hepatic metabolism substantially reduces systemic exposure from oral dosing; clinical effects begin rapidly despite variable peak levels |
| Distribution | Vd ~1970 L (~30 L/kg); protein binding 76–93%; crosses placenta; excretion into breast milk uncertain | Very large volume of distribution reflects extensive tissue uptake; high lipophilicity facilitates CNS penetration and prolonged duration of action |
| Metabolism | Hepatic: sulfoxidation (predominant) & N-demethylation; CYP2D6 mediates hydroxylation; metabolites: promethazine sulfoxide, N-desmethylpromethazine | CYP2D6 poor metabolisers may experience enhanced or prolonged effects; clinically significant drug interactions via CYP2D6 are possible |
| Elimination | t½ 9–16 h (IV), 16–19 h (oral/rectal); <1% excreted unchanged in urine; metabolites excreted renally; clearance ~1.14 L/min | Clinical effects typically last 4–6 h (up to 12 h); prolonged half-life supports once-daily bedtime dosing for allergy; essentially no renal dose adjustment needed |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Drowsiness / sedation | >10% | Most prominent CNS effect; dose-related; peaks within first few days and may attenuate with continued use; counsel on driving impairment |
| Dry mouth | ~10–15% | Anticholinergic effect; encourage sipping water, sugar-free lozenges; monitor for dental caries with chronic use |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | ~5–10% | May impair ambulation; advise slow position changes particularly in the elderly |
| Blurred vision | ~3–7% | Anticholinergic effect; usually dose-dependent and reversible |
| Constipation | ~3–5% | Anticholinergic effect; increase fibre and fluid intake |
| Urinary retention | ~2–5% | Increased risk in elderly males with prostatic hypertrophy; monitor voiding |
| Nausea / GI discomfort | ~2–5% | Paradoxical in some patients; may improve if taken with food |
| Confusion / disorientation | ~2–5% | More prominent in elderly; contributes to Beers Criteria listing |
| Photosensitivity | ~1–3% | Phenothiazine class effect; advise sunscreen and protective clothing |
| Tachycardia | ~1–3% | Reflects anticholinergic activity and alpha blockade; usually mild |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Respiratory depression / apnea | Rare in adults; higher risk in children <2 y | Minutes to hours after dose | Immediate ventilatory support; naloxone is NOT effective; discontinue promethazine permanently |
| Neuroleptic malignant syndrome (NMS) | Very rare | Days to weeks | Discontinue immediately; ICU admission; supportive care with cooling, IV fluids, dantrolene/bromocriptine as indicated |
| Severe tissue injury / gangrene (injection) | Uncommon with proper technique | Within hours of injection | Stop infusion; assess for arterial injection or extravasation; surgical consultation; may require fasciotomy, skin graft, or amputation |
| Agranulocytosis / leukopenia | Very rare | Weeks to months | Obtain CBC; discontinue if confirmed; haematology referral |
| Cholestatic jaundice | Rare | Weeks | Check LFTs; discontinue; hepatology follow-up if needed |
| Extrapyramidal symptoms (dystonia, oculogyric crisis, torticollis) | Rare (higher in children / dehydrated patients) | Hours to days | Administer diphenhydramine or benztropine IM/IV; discontinue promethazine; avoid rechallenge |
| Seizures | Rare | Variable | Seizure management per protocol; discontinue promethazine; avoid in patients with known seizure disorders when possible |
Formal discontinuation rates from controlled trials are not well-documented in the FDA prescribing information for promethazine as a single-entity product, as many studies predate modern trial reporting standards. The drug is generally well-tolerated for short-term use. Discontinuation due to adverse effects is most commonly driven by intolerable sedation or anticholinergic symptoms.
Drowsiness is the most common reason patients discontinue promethazine. When used for allergy, a bedtime-only dosing strategy minimises daytime impairment. For antiemetic use, inform patients that sedation is expected and usually brief. In elderly patients, start at the lowest dose (6.25 mg) as sedation-related falls are a significant concern. Promethazine appears on the American Geriatrics Society Beers Criteria as a drug to avoid in older adults due to its anticholinergic burden and sedation risk.
Drug Interactions
Promethazine is metabolised primarily by hepatic sulfoxidation and CYP2D6-mediated hydroxylation. It does not significantly inhibit or induce CYP enzymes at therapeutic doses. The most clinically important interactions involve additive CNS depression and anticholinergic effects with co-administered agents.
Monitoring
-
Respiratory Status
Each dose (pediatric & perioperative)
Routine Monitor respiratory rate, oxygen saturation, and level of sedation. Particularly critical in children ≥2 years receiving any dose and in adults receiving IV/IM promethazine with opioids or other CNS depressants. -
Blood Pressure
With parenteral use
Routine Assess for orthostatic hypotension, especially when co-administered with antihypertensives or in volume-depleted patients. Rapid IV push is avoided to reduce hypotensive risk. -
Sedation Level
Ongoing during treatment
Routine Evaluate using a standardised sedation scale in perioperative settings. Excess sedation in outpatients should prompt dose reduction or switch to a non-sedating alternative. -
IV Injection Site
Continuous during infusion
Routine Monitor for pain, burning, or colour change at the injection site. Immediate cessation and assessment for arterial injection or extravasation is required if pain develops during infusion. -
CBC
If signs of infection on prolonged use
Trigger-based Check white blood cell count and differential if unexplained fever, sore throat, or mouth ulcers develop, as agranulocytosis and leukopenia have been reported. -
Liver Function
If jaundice or GI symptoms
Trigger-based Cholestatic jaundice has been reported. Obtain LFTs if the patient develops unexplained pruritus, dark urine, or scleral icterus. -
Involuntary Movements
Each visit
Routine Assess for extrapyramidal symptoms including dystonia, akathisia, and oculogyric crisis. Risk is elevated in children, dehydrated patients, and those receiving concurrent dopamine antagonists.
Contraindications & Cautions
Absolute Contraindications
- Children under 2 years of age — risk of fatal respiratory depression (FDA Boxed Warning)
- Comatose states — further CNS depression may be life-threatening
- Known hypersensitivity to promethazine or other phenothiazines
- Lower respiratory tract symptoms including asthma — anticholinergic drying of secretions may worsen obstruction
- Subcutaneous injection — causes severe chemical irritation and tissue necrosis
- Intra-arterial injection — may result in gangrene requiring amputation
- IV injection at concentrations >1 mg/mL (undiluted; injection formulations)
Relative Contraindications (Specialist Input Recommended)
- Seizure disorders — promethazine lowers the seizure threshold; benefit must clearly outweigh risk
- Bone marrow depression — may worsen leukopenia or agranulocytosis, especially with concurrent marrow-toxic agents
- Compromised respiratory function (COPD, sleep apnea) — increased risk of respiratory depression
- Hepatic impairment — extensively metabolised; increased exposure and prolonged effects likely
Use with Caution
- Elderly patients — increased sensitivity to sedation, anticholinergic effects, and orthostatic hypotension; listed on the Beers Criteria
- Narrow-angle glaucoma — anticholinergic effects may elevate intraocular pressure
- Prostatic hypertrophy / bladder neck obstruction — risk of urinary retention
- Stenosing peptic ulcer / pyloroduodenal obstruction — anticholinergic effects may worsen GI obstruction
- Cardiovascular disease — alpha blockade may contribute to hypotension
- Dehydrated children — increased susceptibility to dystonic reactions
- Pregnancy — former Category C; use only if benefit justifies fetal risk; may inhibit neonatal platelet aggregation if given within 2 weeks of delivery
Promethazine is contraindicated in children under 2 years of age due to postmarketing reports of fatal respiratory depression. A wide range of weight-based doses has caused respiratory failure in this population. In children aged 2 years and older, use the lowest effective dose, avoid co-prescribing respiratory depressants, and monitor closely.
Parenteral promethazine has caused gangrene, tissue necrosis, and thrombophlebitis regardless of the injection route. Some cases have required fasciotomy, skin grafting, or amputation. Deep intramuscular injection is the preferred parenteral route. If IV administration is necessary, dilute to a concentration no greater than 1 mg/mL and infuse through a large-bore IV catheter (preferably central venous) over 20–40 minutes. Do not use veins in the hand or wrist. Subcutaneous and intra-arterial injection are absolutely contraindicated.
Patient Counselling
Purpose of Therapy
Promethazine is prescribed to relieve allergy symptoms (sneezing, itching, runny nose, hives), prevent and treat nausea and vomiting, prevent motion sickness, or help with relaxation and sleep before or after surgery. The specific reason for the prescription should be discussed so the patient understands the expected duration and outcome of treatment.
How to Take
Tablets and liquid may be taken with or without food. If stomach upset occurs, taking the dose with a light meal or glass of milk may help. For motion sickness, the first dose should be taken 30 to 60 minutes before travel. For allergy symptoms, a bedtime dose is often preferred to minimise daytime drowsiness. Liquid doses must be measured with an accurate measuring device (not a household spoon). Rectal suppositories should be refrigerated and inserted as directed.
Sources
- Phenergan (promethazine HCl) Tablets and Suppositories — FDA-approved prescribing information. Wyeth Pharmaceuticals. FDA Label Primary regulatory source for approved indications, dosing, contraindications, warnings, and adverse effects for oral and rectal formulations.
- Phenergan (promethazine HCl) Injection — FDA-approved prescribing information. Hikma Pharmaceuticals. DailyMed Regulatory source for parenteral administration, including boxed warning on tissue injury and updated IV infusion guidance.
- FDA Drug Safety Communication: FDA requires updates to labeling for promethazine hydrochloride injection products. U.S. FDA. 2009 (updated 2024). FDA.gov Details the FDA-mandated labeling changes for IV administration including dilution requirements and infusion time guidance.
- Le CK, Stevens CA, Park JH, Clark RF. Promethazine: A Review of Therapeutic Uses and Toxicity. J Emerg Med. 2025;70:127–133. DOI Contemporary review of promethazine uses, overdose management, and toxicity profile relevant to emergency medicine practice.
- Le CK, Nahir A. Promethazine. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2024. NCBI Bookshelf Comprehensive peer-reviewed summary covering indications, pharmacology, dosing, and interprofessional considerations.
- American Geriatrics Society 2023 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2023;71(7):2052–2081. DOI Lists promethazine as a drug to avoid in older adults due to its high anticholinergic burden and sedation-related fall risk.
- ACOG Practice Bulletin No. 189: Nausea and Vomiting of Pregnancy. Obstet Gynecol. 2018;131(1):e15–e30. DOI Supports promethazine as a second-line antiemetic for nausea and vomiting of pregnancy refractory to first-line agents.
- Adolph O, Köster S, Georgieff M, Georgieff EM, Moulig W, Föhr KJ. Promethazine inhibits NMDA-induced currents — New pharmacological aspects of an old drug. Neuropharmacology. 2012;63(2):280–291. DOI Demonstrates promethazine’s non-competitive NMDA receptor antagonist activity (IC50 ~20 μM), which may contribute to its sedative and analgesic properties.
- Taylor G, Houston JB, Shaffer J, Mawer G. Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man. Br J Clin Pharmacol. 1983;15(3):287–293. DOI Landmark PK study establishing oral bioavailability (~25%), volume of distribution (1970 L), and hepatic clearance (1.14 L/min) of promethazine.
- Sharma A, Hamelin BA. Promethazine: pharmacokinetics, pharmacodynamics, and clinical use. Curr Ther Res Clin Exp. 2003;64(Suppl A):2–11. Clinical pharmacology review covering CYP2D6/CYP2B6-mediated metabolism, first-pass effect, and formulation-dependent PK variability.
- Strenkoski-Nix LC, Ermer J, DeCleene S, Cevallos W, Mayer PR. Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects. Am J Health Syst Pharm. 2000;57(16):1499–1505. DOI Characterises rectal vs. oral bioavailability and confirms pronounced pharmacokinetic variability across administration routes.