Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
PROMETHAZINE W/ CODEINE vs ATARAX
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.
Hydroxyzine is a piperazine derivative with antihistaminic (H1-receptor antagonist) and anticholinergic properties; also exhibits sedative, anxiolytic, and antiemetic effects due to suppression of activity in subcortical areas of the CNS.
Relief of mild to moderate pain,Cough suppression
Pruritus due to allergic conditions (FDA approved),Anxiety and tension (FDA approved for psychoneurosis),Sedation before and after general anesthesia (FDA approved),Off-label: Nausea and vomiting, motion sickness, insomnia
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.
25 mg orally 3-4 times daily; maximum 100 mg per day. Also available as 50 mg intramuscular injection every 4-6 hours.
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, hepatic impairment, or renal insufficiency (up to 30-40 hours); steady-state achieved within 3-4 days.
Codeine: Hepatic via CYP2D6 (to morphine), CYP3A4 (to norcodeine); Promethazine: Hepatic via CYP2B6, CYP2D6, and glucuronidation.
Primarily hepatic via CYP3A4 and CYP2D6; major metabolite is cetirizine.
Promethazine: renal (70% as metabolites, <1% unchanged), fecal (20-30%). Codeine: renal (90%, of which 5-10% unchanged, rest as metabolites), fecal (minor).
Primarily hepatic metabolism via CYP3A4 and CYP2D6; renal excretion of metabolites accounts for approximately 70-80% of the dose, with less than 1% excreted unchanged; fecal excretion is about 10-15%.
Promethazine: 93% (primarily to albumin). Codeine: 7-25% (to albumin).
Approximately 93% bound primarily to albumin and alpha-1-acid glycoprotein.
Promethazine: 5-14 L/kg (extensive tissue distribution). Codeine: 3-6 L/kg (widely distributed).
Approximately 10-15 L/kg; large Vd indicates extensive tissue distribution, including penetration into the central nervous system.
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 100% (nearly complete absorption) with peak plasma concentrations at 2 hours; intramuscular bioavailability is similar to oral but with faster absorption.
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: administer every 24 hours. GFR <10 m L/min: contraindicated or reduce dose to 50% every 24 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. Class B: reduce dose by 50%. 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 >6 years: 0.6 mg/kg orally every 6 hours; maximum 2 mg/kg/day. Children <6 years: 0.5 mg/kg orally every 4-6 hours; maximum 50 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 12.5 mg orally twice daily; may increase gradually. Avoid use in patients with significant renal impairment or dementia due to 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.
Not applicable; no black box warning.
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.
Drowsiness and impairment of alertness; avoid driving or operating machinery,Potentiation of CNS depressants (alcohol, barbiturates, opioids),Anticholinergic effects (urinary retention, blurred vision, constipation),QT prolongation risk (especially with electrolyte disturbances, pre-existing QT prolongation, or concurrent QT-prolonging drugs),Use with caution in elderly due to increased risk of sedation and falls,Tardive dyskinesia with prolonged high-dose use
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 hydroxyzine or any component of the formulation,Early pregnancy (first trimester) due to potential fetal harm,Porphyria,Lactation (excreted in breast milk)
Avoid alcohol; may enhance sedative effects. No specific food restrictions, but high-fat meals may delay absorption.
No significant food interactions reported. However, alcohol should be avoided due to additive CNS depression. Grapefruit juice may theoretically increase hydroxyzine levels via CYP3A4 inhibition, but clinical significance is minimal; caution is advised.
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: Considered safe; large studies show no increased risk of major malformations. Second trimester: No known specific risks. Third trimester: Use near term may cause neonatal withdrawal or CNS depression (drowsiness, irritability, tremors) due to placental transfer.
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.
Atarax (hydroxyzine) is excreted into breast milk in small amounts; M/P ratio approximately 0.7. Use with caution; monitor infant for sedation, irritability, or feeding difficulties. The American Academy of Pediatrics considers it compatible with breastfeeding, but alternative agents may be preferred.
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 dose adjustment is typically required for non-sedating use. However, pharmacokinetic changes in pregnancy (increased plasma volume, altered clearance) may necessitate cautious titration; start at lowest effective dose and adjust based on clinical response. For severe pruritus in pregnancy, typical adult dosing (25 mg tid or qid) is used, but monitor for excessive sedation.
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.
ATARAX (hydroxyzine) is a first-generation antihistamine with anxiolytic and sedative properties. It is commonly used for pruritus, anxiety, and preoperative sedation. Note: QT prolongation risk at high doses; avoid in patients with known QT interval prolongation or concurrent use of other QT-prolonging agents. Onset of sedation is rapid, making it useful for sleep induction, but tolerance develops with chronic use. Anticholinergic effects (dry mouth, urinary retention) are dose-dependent.
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.
Take exactly as prescribed; do not exceed recommended dose.,Avoid alcohol and other CNS depressants (e.g., benzodiazepines, opioids) as they may increase drowsiness and dizziness.,Do not drive or operate heavy machinery until you know how this medication affects you.,Report any signs of allergic reaction (rash, difficulty breathing) or irregular heartbeat (palpitations, syncope) immediately.,Hydrate adequately to reduce dry mouth; sugar-free gum or candy can help.,Do not discontinue abruptly; follow your doctor's instructions for tapering if needed.
"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 ATARAX, 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.. ATARAX is a Antihistamine that works by Hydroxyzine is a piperazine derivative with antihistaminic (H1-receptor antagonist) and anticholinergic properties; also exhibits sedative, anxiolytic, and antiemetic effects due to suppression of activity in subcortical areas of the CNS.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between PROMETHAZINE W/ CODEINE and ATARAX 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 ATARAX is: 25 mg orally 3-4 times daily; maximum 100 mg per day. Also available as 50 mg intramuscular injection every 4-6 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 ATARAX 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. ATARAX is classified as Category C. First trimester: Considered safe; large studies show no increased risk of major malformations. Second trimester: No known specific risks. Third trimester: Use near term may cause n. Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.