Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
PROMETHAZINE W/ CODEINE vs ACTIFED
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.
ACTIFED contains triprolidine, a first-generation antihistamine that competitively inhibits histamine H1 receptors, and pseudoephedrine, a sympathomimetic amine that directly stimulates alpha-adrenergic receptors, causing vasoconstriction and decongestion.
Relief of mild to moderate pain,Cough suppression
Temporary relief of symptoms associated with allergic rhinitis (sneezing, rhinorrhea, pruritus),Temporary relief of nasal congestion due to common cold, hay fever, or other upper respiratory allergies
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.
1 tablet (pseudoephedrine HCl 60 mg, triprolidine HCl 2.5 mg) orally every 4-6 hours; maximum 4 tablets in 24 hours.
Promethazine: 10-19 hours (terminal). Codeine: 2.5-3.5 hours (terminal); prolonged in renal impairment.
Triprolidine: 3.2 hours; Pseudoephedrine: 5–8 hours (p H-dependent: alkaline urine prolongs). Terminal half-life for clinical use typically 4–6 hours.
Codeine: Hepatic via CYP2D6 (to morphine), CYP3A4 (to norcodeine); Promethazine: Hepatic via CYP2B6, CYP2D6, and glucuronidation.
Triprolidine: Hepatic metabolism via CYP450 enzymes. Pseudoephedrine: Partially metabolized in liver by N-demethylation; excreted unchanged in urine (70-90%).
Promethazine: renal (70% as metabolites, <1% unchanged), fecal (20-30%). Codeine: renal (90%, of which 5-10% unchanged, rest as metabolites), fecal (minor).
Renal: 80% (20% unchanged, 60% as metabolites). Fecal: 20% (unchanged and metabolites). Active tubular secretion of pseudoephedrine.
Promethazine: 93% (primarily to albumin). Codeine: 7-25% (to albumin).
Triprolidine: 60% bound to serum albumin; Pseudoephedrine: 20–30% bound to plasma proteins (mainly albumin).
Promethazine: 5-14 L/kg (extensive tissue distribution). Codeine: 3-6 L/kg (widely distributed).
Triprolidine: 2.5–4.0 L/kg; Pseudoephedrine: 2.6–3.5 L/kg. Indicates 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: Triprolidine 90–100%; Pseudoephedrine 100% (first-pass metabolism negligible).
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.
Cr Cl 30-50 m L/min: extend dosing interval to every 8 hours. Cr Cl 15-29 m L/min: every 12 hours. Cr Cl <15 m L/min: not recommended.
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 A: no adjustment. Child-Pugh B: consider extending interval to every 8 hours. Child-Pugh C: avoid use.
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 6-12 years: 1/2 tablet (pseudoephedrine 30 mg, triprolidine 1.25 mg) orally every 6 hours; max 2 tablets/24 hours. Children <6 years: not recommended.
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.
Start with 1/2 tablet (pseudoephedrine 30 mg, triprolidine 1.25 mg) orally every 8 hours; monitor for CNS excitation and anticholinergic effects.
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.
Cardiovascular effects: hypertension, palpitations, tachycardia, arrhythmias,CNS stimulation: nervousness, dizziness, insomnia, especially in elderly,May cause urinary retention in patients with prostatic hypertrophy,Use caution in patients with diabetes, hyperthyroidism, ischemic heart disease, increased intraocular pressure,Anticholinergic effects: dry mouth, blurred vision, constipation
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 triprolidine, pseudoephedrine, or any component,Severe hypertension or coronary artery disease,Monoamine oxidase inhibitor (MAOI) therapy (concurrent or within 14 days),Narrow-angle glaucoma,Urinary retention,During or within 14 days of MAOI use
Avoid alcohol; may enhance sedative effects. No specific food restrictions, but high-fat meals may delay absorption.
Avoid high-tyramine foods (aged cheese, cured meats, fermented products) as pseudoephedrine may potentiate vasopressor effects. Grapefruit juice may decrease pseudoephedrine absorption; separate administration by at least 4 hours.
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.
FDA Pregnancy Category C. First trimester: Limited human data; animal studies show fetal toxicity at high doses. Avoid unless benefit outweighs risk. Second/third trimesters: Risk of premature labor, neonatal respiratory depression, and withdrawal symptoms with prolonged use. Use lowest effective dose for shortest duration.
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.
Pseudoephedrine is excreted into breast milk; M/P ratio approximately 3.5. Triprolidine is present in milk. Potential for irritability, sleep disturbance in infants; may reduce milk supply. Use with caution; alternative preferred. Discontinue breastfeeding or drug based on necessity.
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 adjustment recommended for pregnancy; however, increased plasma volume may reduce drug concentrations. Use lowest effective dose due to limited safety data. Avoid in hypertension or preeclampsia.
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.
Actifed (pseudoephedrine + triprolidine) is contraindicated in patients with severe hypertension, coronary artery disease, or narrow-angle glaucoma. Pseudoephedrine can cause CNS stimulation and insomnia, so avoid evening dosing. Triprolidine is a first-generation antihistamine with significant anticholinergic effects; use caution in elderly or those with BPH, urinary retention, or asthma.
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 take with other cold or allergy medications containing decongestants or antihistamines.,Avoid alcohol and sedatives as they may increase drowsiness.,Do not crush or chew extended-release tablets; swallow whole.,Monitor for increased blood pressure or heart rate; discontinue if palpitations occur.,May cause dizziness; avoid driving or operating heavy machinery until you know how it affects you.
"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 ACTIFED, 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.. ACTIFED is a Decongestant/Antihistamine Combination that works by ACTIFED contains triprolidine, a first-generation antihistamine that competitively inhibits histamine H1 receptors, and pseudoephedrine, a sympathomimetic amine that directly stimulates alpha-adrenergic receptors, causing vasoconstriction and decongestion.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between PROMETHAZINE W/ CODEINE and ACTIFED 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 ACTIFED is: 1 tablet (pseudoephedrine HCl 60 mg, triprolidine HCl 2.5 mg) orally every 4-6 hours; maximum 4 tablets in 24 hours.. 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 ACTIFED 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. ACTIFED is classified as Category C. FDA Pregnancy Category C. First trimester: Limited human data; animal studies show fetal toxicity at high doses. Avoid unless benefit outweighs risk. Second/third trimesters: Risk . Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.