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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Breastfeeding | Promethazine and phenylephrine are excreted in breast milk in trace amounts. M/P ratio not determined. Avoid use in breastfeeding due to potential infant sedation, irritability, and paradoxical excitement. Consider alternative agents. |
| 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. |
■ 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 |
["Pediatric patients <2 years (black box warning).","Comatose patients or those receiving large doses of CNS depressants.","Known hypersensitivity to promethazine, phenylephrine, or any components.","Concurrent use with MAO inhibitors or within 14 days.","Severe hypertension, coronary artery disease, narrow-angle glaucoma, urinary retention, or prostatic hypertrophy."]
| 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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| 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. |