PROMETHAZINE HYDROCHLORIDE AND PHENYLEPHRINE HYDROCHLORIDE
Clinical safety rating: safe
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
Promethazine is a phenothiazine derivative that acts as a histamine H1 receptor antagonist, antiemetic through blockade of dopamine D2 receptors in the chemoreceptor trigger zone, and sedative via central anticholinergic effects. Phenylephrine is a direct-acting sympathomimetic amine that selectively stimulates α1-adrenergic receptors, causing vasoconstriction and nasal decongestion.
| Metabolism | Promethazine is extensively metabolized in the liver via CYP2D6 and other pathways to sulfoxides and glucuronides. Phenylephrine undergoes first-pass metabolism in the gut and liver by monoamine oxidase (MAO) and sulfation. |
| Excretion | Promethazine: Renal excretion of metabolites and unchanged drug accounts for approximately 70-80% of elimination, with about 20-30% excreted in feces via biliary elimination. Phenylephrine: Primarily renal excretion as sulfate conjugates and unchanged drug; about 80% of a dose is excreted in urine within 48 hours, with minor fecal elimination (<10%). |
| Half-life | Promethazine: Terminal elimination half-life is approximately 10-14 hours in adults, ranging 5-14 hours; prolonged in hepatic impairment. Phenylephrine: Terminal elimination half-life is approximately 2-3 hours; clinically active for a shorter duration due to rapid metabolism. |
| Protein binding | Promethazine: Approximately 93% bound to plasma albumin and lipoproteins. Phenylephrine: Approximately 95% bound to plasma proteins, primarily albumin and α1-acid glycoprotein. |
| Volume of Distribution | Promethazine: Vd approximately 5-15 L/kg, indicating extensive tissue distribution; large Vd contributes to long half-life. Phenylephrine: Vd approximately 2-5 L/kg, moderate distribution to tissues. |
| Bioavailability | Promethazine: Oral bioavailability is approximately 25% due to extensive first-pass metabolism; IM bioavailability is near 100%; rectal bioavailability is about 70-80%. Phenylephrine: Oral bioavailability is approximately 38% due to presystemic metabolism in the gut wall and liver; IM and IV bioavailability are 100%. |
| Onset of Action | Oral promethazine: 20 minutes; IM promethazine: 20 minutes; rectal promethazine: 20-30 minutes. Oral phenylephrine: 15-20 minutes; IM/IV phenylephrine: immediate to 5 minutes. |
| Duration of Action | Promethazine: Duration of antiemetic/sedative effects is 4-12 hours depending on dose and route; may persist up to 24 hours. Phenylephrine: Decongestant effect lasts 4-6 hours after oral administration; vasopressor effect after IV is about 15-30 minutes. |
| Molecular Weight | Promethazine HCl: 320.88 Da; Phenylephrine HCl: 203.67 Da; Combined formulation: not applicable as separate entities. |
| Action Class | Antihistamine / Antiemetic (Promethazine); Alpha-1 Adrenergic Agonist (Phenylephrine) |
Each 5 mL oral solution contains promethazine hydrochloride 6.25 mg and phenylephrine hydrochloride 5 mg. Adults: 10 mL (2 teaspoonfuls) orally every 4-6 hours as needed; maximum 40 mL (8 teaspoonfuls) per 24 hours.
| Dosage form | SYRUP |
| Renal impairment | No specific dose adjustment guidelines available for this combination. Use with caution in renal impairment due to potential accumulation of promethazine and phenylephrine. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). In mild to moderate impairment (Child-Pugh A or B), use with caution and consider dose reduction; no established dose adjustment guidelines. |
| Pediatric use | Children 6-12 years: 5 mL (1 teaspoonful) orally every 4-6 hours; maximum 20 mL (4 teaspoonfuls) per 24 hours. Children 2-5 years: 2.5 mL (0.5 teaspoonful) orally every 4-6 hours; maximum 10 mL (2 teaspoonfuls) per 24 hours. Not recommended for children under 2 years. |
| Geriatric use | Elderly patients (≥65 years) are more sensitive to anticholinergic and sedative effects of promethazine and cardiovascular effects of phenylephrine. Initiate at the lower end of the dosing range (e.g., 5 mL orally every 6-8 hours) and titrate cautiously. Avoid use in patients with controlled hypertension or other cardiovascular conditions unless benefits outweigh risks. |
| 1st trimester | Avoid use due to potential teratogenic effects; animal studies show fetal abnormalities and limited human data suggest possible risk. |
| 2nd trimester | Use only if clearly needed; promethazine may cause maternal sedation and phenylephrine may reduce uteroplacental blood flow. |
| 3rd trimester | Avoid near term; promethazine can cause respiratory depression in neonates and phenylephrine may induce uterine vasoconstriction. |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Placental transfer | Both promethazine (MW 284.4 Da) and phenylephrine (MW 203.7 Da) cross the placenta. Phenylephrine has limited transfer due to rapid metabolism, but high doses may achieve clinically relevant levels. Promethazine is extensively transferred and can accumulate in fetal tissues. |
■ FDA Black Box Warning
Promethazine should not be used in children younger than 2 years due to risk of fatal respiratory depression. Use caution in children 2 years and older.
| Common Effects | nausea/vomiting |
| Serious Effects | Respiratory depression (especially in children and elderly), Severe hypotension or hypertension, Cardiac arrhythmias (e.g., QT prolongation, torsades de pointes), Neuroleptic malignant syndrome (NMS), Seizures, Extrapyramidal symptoms (dystonia, akathisia, tardive dyskinesia), Agranulocytosis, leukopenia, thrombocytopenia, Cholestatic jaundice, Photosensitivity and severe skin reactions, Angle-closure glaucoma |
Hypersensitivity to promethazine, phenylephrine, or any componentComatose statesConcurrent use of MAOIs or within 14 days of MAOI therapySevere hypertension or coronary artery disease (for phenylephrine component)Narrow-angle glaucomaUrinary retentionSevere hepatic impairmentPediatric patients <2 years of age (risk of fatal respiratory depression with promethazine)
| Precautions | Respiratory depression (especially in children, elderly, or with concurrent CNS depressants)., Neuroleptic malignant syndrome (NMS) and tardive dyskinesia with prolonged use., Severe tissue injury from extravasation (IV promethazine)., Increased heart rate, hypertension, or arrhythmias (phenylephrine)., Avoid use in patients with severe coronary artery disease, uncontrolled hypertension, or hyperthyroidism. |
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| Breastfeeding | Promethazine is excreted in breast milk in small amounts and may cause sedation, irritability, or respiratory depression in nursing infants. Phenylephrine has minimal excretion but may reduce milk production due to vasoconstriction. Use caution and monitor infant for adverse effects. |
| Lactation Rating | L3 (Limited Data - Probably Compatible) |
| Teratogenic Risk | First trimester: Avoid due to potential anticholinergic effects and risk of teratogenicity; phenylephrine may reduce uterine blood flow. Second/third trimester: Use only if clearly needed; monitor for maternal hypotension and fetal distress. High doses near term may cause respiratory depression in neonate. |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and oxygenation. Assess fetal heart rate patterns. Observe neonate for signs of respiratory depression, sedation, or withdrawal if used near delivery. |
| Fertility Effects | No direct effect on fertility reported. Promethazine may cause ovulation suppression due to prolactin elevation. Phenylephrine may not significantly impact fertility. Use during pregnancy should not be based on fertility concerns alone. |
| Food/Dietary | No specific food interactions are reported. However, alcohol and other CNS depressants should be avoided due to additive sedation. Grapefruit juice has no known interaction with promethazine or phenylephrine. Maintain adequate hydration to counteract anticholinergic effects. |
| Clinical Pearls | Promethazine is a phenothiazine antiemetic with strong sedative and anticholinergic properties; phenylephrine is a selective alpha-1 agonist used for nasal decongestion. This combination may cause significant sedation and anticholinergic effects (dry mouth, blurred vision, urinary retention). Use with caution in elderly, patients with BPH, glaucoma, or cardiovascular disease. Avoid concurrent use with other CNS depressants. Promethazine can lower seizure threshold. Monitor for extrapyramidal reactions. Phenylephrine may cause hypertension, reflex bradycardia, and palpitations. Contraindicated in severe hypertension, coronary artery disease, and MAOI use. |
| Patient Advice | This medication may cause severe drowsiness; do not drive or operate machinery until you know how it affects you. · Avoid alcohol and other sedatives while taking this drug. · Do not exceed recommended dose; high doses of promethazine can cause serious side effects in children. · You may experience dry mouth, blurred vision, or dizziness; report any difficulty urinating or fast/irregular heartbeat. · Rise slowly from sitting or lying to minimize orthostatic hypotension. · Store at room temperature away from moisture and heat. · If you miss a dose, take it as soon as you remember unless it is near the time of the next dose; do not double dose. |