PROMETHACON

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PROMETHACON (PROMETHACON).

How it works

Promethazine is a phenothiazine derivative with antihistaminic (H1 receptor antagonist), antiemetic, sedative, and anticholinergic properties. It inhibits central and peripheral H1 receptors, blocks dopamine D2 receptors in the chemoreceptor trigger zone, and has weak alpha-adrenergic blockade.

What the body does with it

Metabolism	Primarily hepatic metabolism via glucuronidation and oxidation (CYP2D6 minor pathway). Major metabolites include promethazine sulfoxide and N-demethylpromethazine.
Excretion	Renal (80%) as inactive metabolites, 20% fecal via bile
Half-life	Terminal elimination half-life: 4-6 hours in healthy adults; prolonged to 10-14 hours in hepatic impairment
Protein binding	93% bound, primarily to albumin and alpha-1-acid glycoprotein
Volume of Distribution	Vd: 9-12 L/kg; large Vd indicates extensive tissue distribution and high lipid solubility
Bioavailability	Oral: 25-30% due to extensive first-pass metabolism; Rectal: 70-80%; Intramuscular: 100%
Onset of Action	Oral: 20-30 minutes; Intramuscular: 10-20 minutes; Intravenous: 3-5 minutes; Rectal: 30-45 minutes
Duration of Action	Antiemetic and sedative effects last 4-6 hours; antihistamine effects up to 12 hours

Classification & Brands

Dosing & administration

25-50 mg intramuscularly or intravenously every 4-6 hours as needed. Maximum intravenous rate: 25 mg/minute. Maximum daily dose: 150 mg.

Dosage form	SUPPOSITORY
Renal impairment	No specific dose adjustment required for renal impairment. Use caution in severe renal impairment (eGFR <30 mL/min) due to accumulation of metabolites.
Liver impairment	Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50% or reduce frequency to every 6-8 hours. Child-Pugh Class C: Avoid use or reduce dose to 25% of normal and monitor closely.
Pediatric use	Children ≥2 years: 0.5-1 mg/kg intramuscularly or intravenously every 4-6 hours as needed. Maximum single dose: 25 mg for children <12 years, 50 mg for children 12-18 years. Not recommended for children <2 years.
Geriatric use	Initiate with 12.5-25 mg intramuscularly or intravenously every 6-8 hours due to increased sensitivity and prolonged half-life. Titrate cautiously and monitor for sedation, hypotension, and anticholinergic effects. Maximum dose: 100 mg/day.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PROMETHACON (PROMETHACON).

Breastfeeding	Promethazine is excreted in breast milk. M/P ratio: 0.5–1.5. Potential for infant sedation, respiratory depression, and impaired neurodevelopment. Use lowest effective dose for shortest duration. Monitor infant for drowsiness, feeding difficulties, and weight gain.
Teratogenic Risk	First trimester: Increased risk of neural tube defects and oral clefts. Second and third trimesters: Risk of fetal growth restriction and preterm birth. Late third trimester: Neonatal withdrawal syndrome (tremors, irritability, poor feeding) if used chronically.

Warnings & precautions

■ FDA Black Box Warning

Promethazine should not be used in children younger than 2 years due to the risk of fatal respiratory depression. Use in children aged 2 years and older requires extreme caution, especially when combined with other respiratory depressants.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to promethazine or phenothiazines","Comatose states","CNS depression from alcohol, barbiturates, or narcotics","Concomitant use with MAOIs","Children under 2 years of age","Severe bone marrow suppression","Untreated narrow-angle glaucoma","Prostatic hypertrophy with urinary retention","Acute asthma attack (parenteral use)"]

Clinical Precautions

Precautions

["Respiratory depression, especially in children and elderly, avoid use with other CNS depressants","Severe tissue injury (including gangrene) from intra-arterial injection or extravasation","Bone marrow suppression (agranulocytosis, leukopenia, thrombocytopenia)","Neuroleptic malignant syndrome (rare)","Seizure threshold lowering","Anticholinergic effects (urinary retention, glaucoma exacerbation)","Tardive dyskinesia with prolonged use"]

Clinical Tips & Counseling

Drug interactions

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PROMETHACON

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PROMETHACON (PROMETHACON).

How it works

What the body does with it

Metabolism	Primarily hepatic metabolism via glucuronidation and oxidation (CYP2D6 minor pathway). Major metabolites include promethazine sulfoxide and N-demethylpromethazine.
Excretion	Renal (80%) as inactive metabolites, 20% fecal via bile
Half-life	Terminal elimination half-life: 4-6 hours in healthy adults; prolonged to 10-14 hours in hepatic impairment
Protein binding	93% bound, primarily to albumin and alpha-1-acid glycoprotein
Volume of Distribution	Vd: 9-12 L/kg; large Vd indicates extensive tissue distribution and high lipid solubility
Bioavailability	Oral: 25-30% due to extensive first-pass metabolism; Rectal: 70-80%; Intramuscular: 100%
Onset of Action	Oral: 20-30 minutes; Intramuscular: 10-20 minutes; Intravenous: 3-5 minutes; Rectal: 30-45 minutes
Duration of Action	Antiemetic and sedative effects last 4-6 hours; antihistamine effects up to 12 hours

Classification & Brands

Dosing & administration

25-50 mg intramuscularly or intravenously every 4-6 hours as needed. Maximum intravenous rate: 25 mg/minute. Maximum daily dose: 150 mg.

Dosage form	SUPPOSITORY
Renal impairment	No specific dose adjustment required for renal impairment. Use caution in severe renal impairment (eGFR <30 mL/min) due to accumulation of metabolites.
Liver impairment	Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50% or reduce frequency to every 6-8 hours. Child-Pugh Class C: Avoid use or reduce dose to 25% of normal and monitor closely.
Pediatric use	Children ≥2 years: 0.5-1 mg/kg intramuscularly or intravenously every 4-6 hours as needed. Maximum single dose: 25 mg for children <12 years, 50 mg for children 12-18 years. Not recommended for children <2 years.
Geriatric use	Initiate with 12.5-25 mg intramuscularly or intravenously every 6-8 hours due to increased sensitivity and prolonged half-life. Titrate cautiously and monitor for sedation, hypotension, and anticholinergic effects. Maximum dose: 100 mg/day.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PROMETHACON (PROMETHACON).

Breastfeeding	Promethazine is excreted in breast milk. M/P ratio: 0.5–1.5. Potential for infant sedation, respiratory depression, and impaired neurodevelopment. Use lowest effective dose for shortest duration. Monitor infant for drowsiness, feeding difficulties, and weight gain.
Teratogenic Risk	First trimester: Increased risk of neural tube defects and oral clefts. Second and third trimesters: Risk of fetal growth restriction and preterm birth. Late third trimester: Neonatal withdrawal syndrome (tremors, irritability, poor feeding) if used chronically.