BUTALBITAL, ACETAMINOPHEN, CAFFEINE AND CODEINE PHOSPHATE
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Butalbital is a barbiturate that enhances GABA-A receptor activity, producing sedation; acetaminophen inhibits cyclooxygenase (COX) enzymes centrally, reducing pain and fever; caffeine is a nonselective adenosine receptor antagonist, causing vasoconstriction and central nervous system stimulation; codeine is an opioid agonist at mu-opioid receptors, providing analgesia and antitussive effects.
| Metabolism | Butalbital is extensively metabolized by the liver via CYP2C19 and other enzymes, with metabolites excreted in urine; acetaminophen is primarily metabolized by glucuronidation and sulfation, with minor CYP2E1-mediated oxidation to NAPQI, a toxic metabolite; caffeine is metabolized primarily by CYP1A2 to paraxanthine, theobromine, and theophylline; codeine is O-demethylated by CYP2D6 to morphine (active), and N-demethylated to norcodeine by CYP3A4. |
| Excretion | Butalbital: ~60-70% renal as unchanged drug and metabolites; Acetaminophen: ~90-100% renal within 24 hours (2-5% unchanged, rest as glucuronide and sulfate conjugates); Caffeine: ~1-2% renal unchanged, rest metabolized; Codeine: ~90% renal (10% unchanged, 40% as codeine-6-glucuronide, rest as morphine and norcodeine metabolites). Biliary/fecal excretion minimal for all components. |
| Half-life | Butalbital: ~35 hours (range 30-50 h), long-acting barbiturate; Acetaminophen: ~2-3 hours; Caffeine: ~3-5 hours in adults; Codeine: ~2.5-3.5 hours; note that codeine's active metabolite morphine has half-life ~2-3 h, and renal impairment prolongs half-life of butalbital and codeine. |
| Protein binding | Butalbital: ~25-35% to albumin; Acetaminophen: ~10-25% at therapeutic concentrations; Caffeine: ~25-36% to albumin; Codeine: ~7-25% primarily to albumin. |
| Volume of Distribution | Butalbital: ~0.8 L/kg; Acetaminophen: ~0.9-1.0 L/kg; Caffeine: ~0.5-0.7 L/kg; Codeine: ~3-4 L/kg (large Vd due to tissue distribution). Composite: not applicable. |
| Bioavailability | Oral: Butalbital ~95% (well absorbed); Acetaminophen ~85-95% (some first-pass); Caffeine ~100%; Codeine ~50-60% (extensive first-pass metabolism to morphine). |
| Onset of Action | Oral: Butalbital ~30-60 min; Acetaminophen ~30-60 min; Caffeine ~30-45 min; Codeine ~30-60 min (peak analgesic effect 1-2 h). |
| Duration of Action | Butalbital: 4-6 hours; Acetaminophen: 4-6 hours; Caffeine: 3-5 hours; Codeine: 4-6 hours. Clinical duration is primarily limited by acetaminophen and codeine components, but cumulative effects of butalbital may prolong sedation. |
| Molecular Weight | Butalbital: 224.26 Da; Acetaminophen: 151.16 Da; Caffeine: 194.19 Da; Codeine phosphate: 397.36 Da (as the salt; codeine base 299.36 Da) |
1-2 capsules orally every 4 hours as needed for pain, not exceeding 6 capsules per day. Each capsule contains butalbital 50 mg, acetaminophen 300 mg, caffeine 40 mg, and codeine phosphate 30 mg.
| Dosage form | CAPSULE |
| Renal impairment | For CrCl 50-90 mL/min: no adjustment. For CrCl 10-50 mL/min: use with caution, consider reducing dose by 50% or extending interval. For CrCl <10 mL/min: avoid due to risk of accumulation and hepatotoxicity. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50% or extend interval, avoid prolonged use. Child-Pugh C: contraindicated due to risk of hepatic encephalopathy and acetaminophen toxicity. |
| Pediatric use | Children ≥12 years: 1 capsule orally every 4 hours as needed, max 6 capsules/day. Children <12 years: not recommended. Weight-based dosing not established for this combination. |
| Geriatric use | Start at low end of dosing range (1 capsule every 6 hours), monitor for sedation and respiratory depression. Avoid in patients with impaired renal or hepatic function. Use non-opioid alternatives when possible. |
| 1st trimester | Avoid in first trimester due to risk of congenital malformations (e.g., neural tube defects) and potential respiratory depression. However, ACETAMINOPHEN is often the analgesic of choice. Codeine should be avoided due to opioid concerns and butalbital may be associated with pregnancy loss. |
| 2nd trimester | Avoid unless benefit outweighs risk. Butalbital and codeine may cause fetal dependence and withdrawal; acetaminophen is relatively safe in therapeutic doses. Caffeine in moderate amounts (<200 mg/day) is acceptable. |
| 3rd trimester | Avoid due to risk of neonatal withdrawal and respiratory depression. Prolonged use of butalbital and codeine can lead to neonatal abstinence syndrome. Acetaminophen is safe in usual doses; caffeine may cause irritability. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
| Placental transfer | All components cross the placenta. Acetaminophen: complete transfer, peak cord levels similar to maternal. Codeine: crosses placenta with fetal concentrations ~50-80% of maternal; morphine metabolites also detected. Butalbital: crosses readily due to lipophilicity. Caffeine: crosses freely, fetal levels similar to maternal. |
■ FDA Black Box Warning
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 mg per day, and often involve more than one acetaminophen-containing product.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any componentAcute or severe asthma or respiratory depressionParalytic ileusConcurrent use of MAO inhibitors or within 14 daysSevere hepatic impairment (for acetaminophen)Porphyria (butalbital is contraindicated)Breastfeeding in ultra-rapid CYP2D6 metabolizers (codeine)
| Precautions | Hepatotoxicity (acetaminophen), addiction/abuse potential (codeine, butalbital), respiratory depression (codeine), risk of medication-overuse headache, withdrawal symptoms with abrupt discontinuation, CYP2D6 ultra-rapid metabolizers risk of morphine toxicity with codeine. |
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| Breastfeeding | Butalbital, codeine, and acetaminophen are excreted into breast milk. Codeine is metabolized to morphine, which can pose a risk of infant respiratory depression, especially in ultra-rapid metabolizers of CYP2D6. The American Academy of Pediatrics recommends using codeine with caution and monitoring for infant sedation. Butalbital may cause sedation and poor feeding in infants. Caffeine is transferred in small amounts. Long-term use is not recommended. If used, limit duration and monitor infant for drowsiness, poor feeding, and respiratory depression. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | Butalbital and codeine are FDA Pregnancy Category C; acetaminophen is Category B. Codeine is metabolized to morphine; neonatal opioid withdrawal syndrome may occur with prolonged use. First trimester: codeine associated with congenital malformations in some studies; butalbital associated with increased risk of oral clefts. Second/third trimester: butalbital may cause neonatal withdrawal; codeine may cause respiratory depression. Acetaminophen is generally considered low risk. |
| Fetal Monitoring | Monitor maternal opioid withdrawal symptoms, respiratory status, and sedation. Fetal monitoring: nonstress test and biophysical profile if prolonged use after 24 weeks. Neonatal monitoring for withdrawal (NAS) signs if used near term. |
| Fertility Effects | No known significant effects on fertility. Opioids may affect hormonal regulation; chronic use may cause menstrual irregularities. Acetaminophen and caffeine at therapeutic doses not associated with impaired fertility. |
| Food/Dietary |
| Avoid alcohol; can increase hepatotoxicity (acetaminophen) and central nervous system depression (butalbital, codeine). Avoid grapefruit and grapefruit juice; may alter metabolism of codeine and butalbital. Caffeine content may be additive with other dietary caffeine sources (coffee, tea, cola, energy drinks); limit intake to prevent excessive stimulation, insomnia, or palpitations. No significant food interactions with acetaminophen beyond alcohol. |
| Clinical Pearls | This combination product contains butalbital (barbiturate), acetaminophen (analgesic), caffeine (stimulant), and codeine (opioid). It is a schedule III controlled substance due to codeine content. Use is contraindicated in patients with porphyria (butalbital) or severe hepatic impairment (acetaminophen). Maximum acetaminophen dose from all sources should not exceed 4 g/day; fatal hepatotoxicity can occur with overdose or chronic high doses. Butalbital can cause dependence and withdrawal; avoid abrupt discontinuation. Codeine is a prodrug metabolized by CYP2D6 to morphine; ultrarapid metabolizers (e.g., some ethnic groups) risk toxicity; contraindicated in children <12 years for postoperative tonsillectomy/adenoidectomy. Caffeine may exacerbate anxiety, insomnia, or GERD. Monitor for signs of respiratory depression, especially in elderly or opioid-naïve patients. Use lowest effective dose for shortest duration. |
| Patient Advice | This medication contains codeine, an opioid, and butalbital, a barbiturate, both of which can cause dependence if used long-term. · Do not exceed the recommended dose; taking more acetaminophen than directed can cause severe liver damage. · Avoid alcohol while taking this medication; alcohol plus acetaminophen increases liver injury risk, and alcohol plus butalbital/codeine increases sedation and respiratory depression. · Do not drive or operate heavy machinery until you know how this medication affects you; it may cause dizziness, drowsiness, or impaired coordination. · Inform your doctor if you have a history of drug or alcohol abuse, liver disease, breathing problems (e.g., asthma, COPD), or if you are pregnant or breastfeeding. · Do not stop taking this medication suddenly; withdrawal symptoms (e.g., anxiety, insomnia, muscle twitching) may occur. Your doctor will taper the dose if needed. · Store out of reach of children; accidental overdose of acetaminophen or opioids can be fatal. · If you have severe abdominal pain, nausea/vomiting, or headache that does not improve, contact your doctor; this medication may mask serious conditions. · Avoid other products containing acetaminophen, caffeine, or codeine to prevent overdose. · If you are a CYP2D6 ultrarapid metabolizer, codeine may cause dangerous levels of morphine; seek immediate medical attention if you experience extreme sleepiness, confusion, or slowed breathing. |