Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
PROMETHAZINE W/ CODEINE vs ACTIDIL
Clinician-reviewed, head-to-head comparison of mechanism, dosing, pharmacokinetics, and safety profiles.
Last clinically reviewed: June 2026 · OpiCalc Medical Review Team
Codeine is a prodrug converted to morphine, a mu-opioid receptor agonist, which inhibits nociceptive transmission; promethazine is a phenothiazine derivative with H1-receptor antagonism, anticholinergic, and antiemetic effects.
H1-receptor antagonist; competes with histamine for H1-receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract, blocking histamine-induced bronchoconstriction, vasodilation, and increased capillary permeability.
Relief of mild to moderate pain,Cough suppression
Allergic rhinitis,Allergic conjunctivitis,Urticaria,Angioedema
10 m L (1 mg codeine, 6.25 mg promethazine per 5 m L) orally every 4-6 hours as needed for cough. Maximum: 60 m L per day. Do not exceed 5 days.
2.5 mg orally every 4 to 6 hours as needed; maximum 10 mg per day.
Promethazine: 10-19 hours (terminal). Codeine: 2.5-3.5 hours (terminal); prolonged in renal impairment.
Terminal elimination half-life is approximately 20-25 hours in healthy adults; may be prolonged in elderly or patients with hepatic impairment.
Codeine: Hepatic via CYP2D6 (to morphine), CYP3A4 (to norcodeine); Promethazine: Hepatic via CYP2B6, CYP2D6, and glucuronidation.
Hepatic via CYP450 isoenzymes (primarily CYP3A4 and CYP2D6); undergoes N-demethylation and N-oxidation.
Promethazine: renal (70% as metabolites, <1% unchanged), fecal (20-30%). Codeine: renal (90%, of which 5-10% unchanged, rest as metabolites), fecal (minor).
Renal excretion of unchanged drug and metabolites accounts for approximately 60-80% of the administered dose; biliary/fecal elimination comprises the remainder (20-40%).
Promethazine: 93% (primarily to albumin). Codeine: 7-25% (to albumin).
Approximately 90% bound to plasma proteins, primarily albumin.
Promethazine: 5-14 L/kg (extensive tissue distribution). Codeine: 3-6 L/kg (widely distributed).
2.5-4.0 L/kg, indicating extensive tissue distribution.
Promethazine: oral 25% (due to first-pass metabolism), IM ~88%. Codeine: oral 50-70% (converted to morphine via CYP2D6), IM ~80%.
Oral bioavailability is approximately 50-60% due to first-pass metabolism.
e GFR 30-59 m L/min: Administer every 6 hours; e GFR 15-29 m L/min: Administer every 8 hours; e GFR <15 m L/min: Avoid use or consider extended interval due to accumulation of codeine metabolites.
GFR 10-50 m L/min: 2.5 mg every 6-8 hours; GFR <10 m L/min: 2.5 mg every 8-12 hours.
Child-Pugh A: No adjustment; Child-Pugh B: Reduce dose by 50% or extend interval; Child-Pugh C: Avoid use due to risk of hepatic encephalopathy and impaired codeine metabolism.
Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 50%; Child-Pugh Class C: contraindicated.
Use not recommended in children <12 years due to risk of respiratory depression. For ages 12-18: 10-15 m L (with caution) every 4-6 hours as needed. Weight-based dosing: 0.5-1 mg/kg/dose of codeine (max 60 mg/day) with promethazine 0.25-0.5 mg/kg/dose (max 25 mg/dose).
Children 2-5 years: 1.25 mg orally every 4-6 hours (max 5 mg/day); Children 6-12 years: 1.25-2.5 mg every 4-6 hours (max 7.5 mg/day).
Initiate with 5 m L orally every 6-8 hours; titrate cautiously due to increased sensitivity, risk of sedation, and anticholinergic effects. Maximum daily dose: 40 m L. Avoid in patients with significant cognitive impairment.
Initiate at 1.25 mg orally every 6-8 hours; maximum 5 mg per day due to increased risk of anticholinergic effects and renal impairment.
Warning: Risk of respiratory depression, especially in children; fatal respiratory depression can occur. Codeine is contraindicated in children <12 years and should not be used in children <18 years after tonsillectomy/adenoidectomy. Also, risk of opioid addiction, abuse, and misuse.
None
Respiratory depression, risk of opioid-induced hyperalgesia, severe hypotension, seizures in patients with porphyria, sedation and impaired motor skills, risk of serotonin syndrome when combined with serotonergic drugs, avoid abrupt discontinuation, use caution in elderly, hepatic/renal impairment, and respiratory disorders.
May cause drowsiness and impair mental alertness,Avoid alcohol and other CNS depressants,Use with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or urinary retention,Elderly patients are more susceptible to anticholinergic effects
Hypersensitivity to codeine, promethazine, or any phenothiazine; children <12 years; postoperative management in children <18 years following tonsillectomy/adenoidectomy; significant respiratory depression; acute or severe bronchial asthma; GI obstruction; concurrent use of MAOIs or within 14 days.
Hypersensitivity to any component,Concurrent use with monoamine oxidase inhibitors
Avoid alcohol; may enhance sedative effects. No specific food restrictions, but high-fat meals may delay absorption.
No specific food interactions, but taking with food may reduce GI side effects. Alcohol should be strictly avoided due to additive CNS depression. Grapefruit juice is not documented to interact.
PROMETHAZINE W/ CODEINE is contraindicated during all trimesters. First trimester: codeine is associated with increased risk of congenital malformations (cardiac, cleft palate) due to opioid receptor activation. Promethazine may cause mild neural tube defects. Second/third trimesters: codeine can cause fetal opioid dependence and neonatal abstinence syndrome; promethazine may cause respiratory depression and thrombocytopenia in neonates. Chronic use may lead to preterm birth and low birth weight. Do not use during labor and delivery due to risk of respiratory depression in the neonate.
First trimester: Limited human data; animal studies show no teratogenicity. Second and third trimesters: Not associated with major congenital malformations. However, anticholinergic effects may cause neonatal tachycardia, irritability, and withdrawal symptoms if used near term.
Breastfeeding not recommended. Codeine is excreted into breast milk with a milk-to-plasma (M/P) ratio of approximately 2.5-3.0 (for morphine, codeine active metabolite). In mothers who are CYP2D6 ultra-rapid metabolizers, codeine can lead to life-threatening respiratory depression in infants. Promethazine is excreted in low amounts but may cause sedation and apnea in neonates.
Excretion into breast milk likely but negligible amounts; no adverse effects reported in infants. M/P ratio not established. Considered compatible with breastfeeding; monitor for sedation or irritability in neonate.
Pregnancy is a contraindication; thus, dosing adjustments are not applicable. If unavoidable, use the lowest effective dose for the shortest duration, but no safe dose established. Avoid during third trimester due to risk of neonatal respiratory depression. Codeine pharmacokinetics in pregnancy: increased clearance due to enhanced hepatic blood flow and CYP2D6 induction, but this is not a basis for dose adjustment as risk outweighs benefit.
No specific dose adjustments required in pregnancy; however, use lowest effective dose due to potential anticholinergic effects. Pharmacokinetics may be altered (increased volume of distribution), but no dose adjustment recommended.
Promethazine with codeine is contraindicated in children <6 years due to risk of fatal respiratory depression. Avoid in patients with asthma or COPD. Use with caution with other CNS depressants. Monitor for signs of serotonin syndrome if combined with serotonergic drugs.
ACTIDIL (triprolidine) is a first-generation antihistamine with sedative properties. Use cautiously in elderly due to risk of confusion, urinary retention, and falls. Avoid in patients with narrow-angle glaucoma, BPH, or asthma. Administer with food if GI upset occurs. Onset of action is 30-60 minutes; duration 4-6 hours.
May cause drowsiness; avoid driving or operating machinery.,Do not exceed recommended dose; risk of addiction and dependence.,Do not consume alcohol while taking this medication.,Take with food if gastrointestinal upset occurs.,Stop use and seek medical attention if breathing becomes difficult or you experience rash.
Do not drive or operate heavy machinery until you know how this medication affects you; it can cause drowsiness.,Avoid alcohol and other CNS depressants, as they may increase sedation.,Take exactly as prescribed; do not exceed recommended dose.,If you miss a dose, skip it; do not double the next dose.,Notify your doctor if you experience blurred vision, difficulty urinating, or severe drowsiness.,Do not use for prolonged periods without medical advice.
"Promethazine, a phenothiazine derivative with strong anticholinergic and sedative properties, combined with levocabastine, a histamine H1-receptor antagonist, results in additive anticholinergic and central nervous system (CNS) depressant effects. This synergy can lead to excessive sedation, impaired cognitive and motor function, and increased risk of anticholinergic side effects such as dry mouth, urinary retention, and constipation. Clinically, patients may experience heightened drowsiness, dizziness, and confusion, posing risks for falls or accidents, particularly in elderly or debilitated individuals."
"The combination of promethazine and gabapentin enacarbil results in additive central nervous system (CNS) depression, leading to enhanced sedative effects, dizziness, and impaired cognitive or motor function. This interaction is primarily mediated by the synergistic pharmacodynamic actions of both drugs on GABAergic and histaminergic pathways, increasing the risk of excessive sedation, respiratory depression, and falls, particularly in elderly or debilitated patients. Clinical outcomes may include profound drowsiness, confusion, and increased risk of accidental injury, necessitating cautious dose titration and monitoring."
"Gabapentin, a GABA analog with central nervous system depressant effects, interacts pharmacodynamically with the antihistamine and anticholinergic agent Promethazine. Co-administration results in additive sedation, dizziness, and cognitive impairment due to enhanced central nervous system depression. This increases the risk of falls, respiratory depression, and impaired psychomotor function, particularly in elderly patients."
No interactions on record
Explore head-to-head clinical comparisons of other medications in the same therapeutic classes.
Common clinical questions about PROMETHAZINE W/ CODEINE vs ACTIDIL, answered by our medical review team.
PROMETHAZINE W/ CODEINE is a Antihistamine / Antiemetic that works by Codeine is a prodrug converted to morphine, a mu-opioid receptor agonist, which inhibits nociceptive transmission; promethazine is a phenothiazine derivative with H1-receptor antagonism, anticholinergic, and antiemetic effects.. ACTIDIL is a Antihistamine that works by H1-receptor antagonist; competes with histamine for H1-receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract, blocking histamine-induced bronchoconstriction, vasodilation, and increased capillary permeability.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between PROMETHAZINE W/ CODEINE and ACTIDIL depend on the specific clinical indication. These are agents from distinct pharmacological classes and are not directly interchangeable by dose. A physician or clinical pharmacist should guide any therapeutic switching decisions.
The standard adult dose of PROMETHAZINE W/ CODEINE is: 10 m L (1 mg codeine, 6.25 mg promethazine per 5 m L) orally every 4-6 hours as needed for cough. Maximum: 60 m L per day. Do not exceed 5 days.. The standard adult dose of ACTIDIL is: 2.5 mg orally every 4 to 6 hours as needed; maximum 10 mg per day.. Dosing should always be individualized based on indication, renal and hepatic function, age, and other patient factors.
No direct drug-drug interaction has been formally documented between PROMETHAZINE W/ CODEINE and ACTIDIL in current clinical databases. However, individual patient risk factors including other medications, organ function, and comorbidities should always be evaluated by a qualified healthcare provider.
The maternal-fetal safety profiles differ. PROMETHAZINE W/ CODEINE is classified as Category A/B. PROMETHAZINE W/ CODEINE is contraindicated during all trimesters. First trimester: codeine is associated with increased risk of congenital malformations (cardiac, cleft palate) due. ACTIDIL is classified as Category C. First trimester: Limited human data; animal studies show no teratogenicity. Second and third trimesters: Not associated with major congenital malformations. However, anticholinergi. Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.