PHENAPHEN W/ CODEINE NO. 2
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
Codeine is an opioid agonist with affinity for mu-opioid receptors, producing analgesia, cough suppression, and sedation. Acetaminophen is a centrally acting analgesic and antipyretic with unclear mechanism, possibly involving COX-2 inhibition and cannabinoid receptor activation.
| Metabolism | Acetaminophen: primarily via glucuronidation (UGT1A1, UGT1A6, UGT1A9) and sulfation; minor oxidation by CYP2E1 to NAPQI. Codeine: O-demethylation by CYP2D6 to morphine (active), N-demethylation by CYP3A4 to norcodeine, and glucuronidation. |
| Excretion | Phenacetin (active metabolite): renal elimination of conjugated metabolites, primarily as sulfate and glucuronide conjugates; ~60% renal. Codeine: ~90% renal, with 5-15% as free codeine, 10% as norcodeine, and 40-70% as conjugated morphine and norcodeine; ~10% fecal. Apap (acetaminophen): renal elimination of conjugated metabolites, with ~85% excreted in urine as sulfate and glucuronide conjugates, ~5% as unchanged drug, and <5% as cysteine/mercapturate conjugates. |
| Half-life | Phenacetin: terminal half-life ~0.5-2 hours (rapidly eliminated; active metabolite APAP has half-life ~2-3 hours). Codeine: terminal half-life ~2.5-4 hours (increased in CYP2D6 poor metabolizers). Acetaminophen: terminal half-life ~1.5-3 hours (prolonged in hepatic impairment or overdose). Clinical context: half-lives are shortened with chronic use due to autoinduction (phenacetin) and unchanged with therapeutic doses. |
| Protein binding | Phenacetin: ~30-40% bound to plasma proteins. Codeine: ~7-25% bound primarily to albumin. Acetaminophen: ~10-25% bound to albumin (minimal binding). |
| Volume of Distribution | Phenacetin: Vd ~1-2 L/kg. Codeine: Vd ~3-6 L/kg. Acetaminophen: Vd ~0.9-1.2 L/kg. Clinical meaning: Large Vd for codeine indicates extensive tissue distribution; smaller Vd for APAP reflects primarily extracellular distribution. |
| Bioavailability | Oral: Phenacetin ~100% absorbed (undergoes extensive first-pass metabolism to acetaminophen); codeine ~50-60% due to first-pass metabolism (up to 90% absorbed but first-pass reduces bioavailability); acetaminophen ~85-98% absorbed (oral bioavailability ~70-90% due to first-pass metabolism). |
| Onset of Action | Oral: Codeine analgesia onset ~30-60 minutes; antipyresis/analgesia from phenacetin and APAP onset ~30 minutes to 1 hour. |
| Duration of Action | Oral: Codeine analgesia lasts 4-6 hours; antipyretic effect from APAP and phenacetin lasts 3-4 hours. Clinical note: Duration may be extended with higher doses or in patients with hepatic impairment. |
| Molecular Weight | 325.79 |
1-2 tablets (codeine 15-30 mg, acetaminophen 325-650 mg) every 4 hours as needed for pain; maximum: 12 tablets per day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-59 mL/min: reduce dose interval to every 6 hours; GFR 10-29 mL/min: dose every 8 hours; GFR <10 mL/min: avoid or use with extreme caution, dose every 12 hours. |
| Liver impairment | Child-Pugh class A: no adjustment needed; Child-Pugh class B: reduce dose by 50%; Child-Pugh class C: avoid due to risk of hepatotoxicity and accumulation. |
| Pediatric use | Children 12-18 years: dose based on codeine 0.5-1 mg/kg/dose every 4-6 hours; maximum codeine 240 mg/day. Not recommended for children <12 years due to risk of respiratory depression. |
| Geriatric use | Start with lowest dose, e.g., 1 tablet every 6 hours; caution due to increased risk of respiratory depression, hepatotoxicity, and renal impairment. Avoid if possible. |
| 1st trimester | Risk of congenital malformations with codeine; acetaminophen generally considered safe. Avoid due to codeine. |
| 2nd trimester | Acetaminophen safe; codeine may cause respiratory depression in neonate if used near term. Use only if benefit outweighs risk. |
| 3rd trimester | Codeine associated with neonatal respiratory depression, withdrawal syndrome; acetaminophen safe. Avoid prolonged use. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
| FDA category | Positive |
| Placental transfer | Both acetaminophen and codeine cross the placenta. Codeine reaches fetal concentrations similar to maternal. Acetaminophen readily crosses. |
■ FDA Black Box Warning
Codeine should not be used in children younger than 12 years due to risk of respiratory depression and death. Avoid use in post-operative tonsillectomy/adenoidectomy in children. Do not use in children younger than 18 years with risk factors for respiratory depression (e.g., obesity, obstructive sleep apnea).
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to acetaminophen or codeineSevere respiratory depressionAcute or severe bronchial asthmaParalytic ileusConcurrent use of MAOIs or within 14 daysCYP2D6 ultra-rapid metabolizers (risk of morphine toxicity)Obstructive sleep apnea (severe)Respiratory insufficiency
| Precautions | Respiratory depression, especially in children; risk of addiction, abuse, and misuse; perioperative use in tonsillectomy/adenoidectomy; hepatotoxicity with acetaminophen overdose; hypersensitivity reactions; severe hypotension; risk of serotonin syndrome with concomitant serotonergic drugs; adrenal insufficiency; discontinuation syndrome; drug interactions with CNS depressants. |
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| Breastfeeding |
| Codeine is excreted into breast milk; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Acetaminophen is considered compatible. Avoid or use lowest effective dose for short term. |
| Lactation Rating | L4 (Possibly Hazardous) for codeine; L1 (Safe) for acetaminophen component |
| Teratogenic Risk | First trimester: Codeine is associated with neural tube defects and cardiovascular malformations; acetaminophen is generally considered low risk but high doses may be associated with gastroschisis. Second trimester: No specific major malformations reported, but chronic use may affect fetal growth. Third trimester: Acetaminophen is safe at therapeutic doses; codeine may cause neonatal respiratory depression, withdrawal, and opioid withdrawal syndrome. Chronic high-dose acetaminophen may cause fetal hepatotoxicity. |
| Fetal Monitoring | Maternal: Liver function tests with prolonged acetaminophen use; respiratory status with codeine. Fetal: Growth ultrasounds if chronic use; fetal heart rate monitoring during labor if codeine used near term. Neonatal: Observe for signs of opioid withdrawal (irritability, tremors, poor feeding) if codeine used chronically or in third trimester. |
| Fertility Effects | No significant adverse effects on fertility reported for either acetaminophen or codeine. Acetaminophen may slightly delay ovulation at high doses. Codeine may alter menstrual cycle due to opioid-induced hormonal changes. |
| Food/Dietary | Avoid alcohol: increases risk of hepatotoxicity and CNS depression. Grapefruit juice may alter codeine metabolism via CYP3A4 but interaction is minor; no specific dietary restrictions otherwise. |
| Clinical Pearls | Phenaphen w/ Codeine No. 2 contains codeine (15 mg) and acetaminophen (phenacetin-free). Codeine is a prodrug requiring CYP2D6 metabolism to morphine; poor metabolizers may have reduced efficacy, while ultra-rapid metabolizers risk toxicity. Use cautiously in children post-tonsillectomy due to FDA boxed warning. Monitor for acetaminophen hepatotoxicity; avoid exceeding 4 g/day from all sources. |
| Patient Advice | Do not exceed recommended doses due to acetaminophen liver toxicity risk. · Avoid alcohol while taking this medication. · This drug may cause drowsiness; avoid driving or operating machinery. · Inform your doctor if you have a history of liver disease, respiratory conditions, or allergies. · Do not share this medication; it can cause harm to others. · Keep out of reach of children; accidental overdose can be fatal. |