FIORINAL W/CODEINE
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 a prodrug that is metabolized to morphine, which acts as a mu-opioid receptor agonist, inhibiting ascending pain pathways. Butalbital is a barbiturate that enhances GABA-A receptor activity, producing sedation. Aspirin and caffeine provide analgesic and anti-inflammatory effects via COX inhibition and adenosine receptor antagonism, respectively.
| Metabolism | Codeine is metabolized by CYP2D6 to morphine (active) and by CYP3A4 to norcodeine. Butalbital is metabolized by hepatic microsomal enzymes. Aspirin is hydrolyzed to salicylate and conjugated in the liver. Caffeine is metabolized mainly by CYP1A2. |
| Excretion | Renal elimination: codeine (90% as metabolites, 5-15% unchanged), butalbital (60-70% unchanged, remainder as metabolites), aspirin (80-100% as salicylate and metabolites, pH-dependent). Fecal: minimal (<5%). Total renal elimination accounts for >95% of dose. |
| Half-life | Codeine: 2.5-3.5 hours; Butalbital: 35-45 hours; Aspirin: 15-20 minutes (salicylate: 2-3 hours at low doses, up to 15-30 hours at high doses). Clinical context: butalbital's long half-life leads to accumulation with repeated dosing; salicylate half-life increases significantly in overdose. |
| Protein binding | Codeine: ~25% bound to albumin; Butalbital: ~45-65% bound to albumin and lipoproteins; Aspirin: 80-90% bound to albumin (salicylate: 50-80% bound). |
| Volume of Distribution | Codeine: 3-6 L/kg; Butalbital: 0.8-1.0 L/kg; Aspirin: 0.15-0.2 L/kg. Clinical meaning: codeine's large Vd indicates extensive tissue distribution; butalbital's Vd consistent with distribution in total body water; aspirin's small Vd reflects plasma and extracellular fluid binding. |
| Bioavailability | Oral: codeine ~50-90% (first-pass metabolism); butalbital ~90-100%; aspirin ~50-75% (first-pass hydrolysis to salicylate). Rectal: butalbital and aspirin suppositories have variable absorption (50-70% of oral). |
| Onset of Action | Oral: codeine 30-60 minutes, butalbital 30-60 minutes, aspirin 15-30 minutes. Peak effects: codeine 1-2 hours, butalbital 2-4 hours, aspirin 1-2 hours. |
| Duration of Action | Oral: codeine 4-6 hours, butalbital 4-6 hours (due to sedation may persist longer), aspirin 4-6 hours (antiplatelet effect >24 hours). Clinical notes: butalbital's duration contributes to daytime sedation; analgesic effect of codeine is short-lived. |
| Molecular Weight | 386.4 |
Butalbital 50 mg, acetaminophen 325 mg, caffeine 40 mg, codeine 30 mg orally every 4 hours as needed; maximum 6 capsules per day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-50 mL/min: caution; reduce dose or extend interval. GFR <30 mL/min: avoid use due to accumulation of codeine and metabolites. |
| Liver impairment | Child-Pugh A: caution, maximum 4 capsules per day. Child-Pugh B or C: avoid use. |
| Pediatric use | Children <12 years: not recommended. Weight-based not established; avoid due to risk of respiratory depression from codeine. |
| Geriatric use | Initiate at low end of dosing, monitor for CNS depression, constipation, and falls; maximum 4 capsules per day. |
| 1st trimester | Risk of congenital malformations (e.g., neural tube defects) associated with valproate. Butalbital and codeine are not major teratogens but use with caution. Avoid during first trimester if possible. |
| 2nd trimester | Continued risk of adverse effects on fetal development. Use only if clearly needed. |
| 3rd trimester | Risk of neonatal withdrawal syndrome (opioid and barbiturate) and respiratory depression. Avoid use, especially near term. |
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 | All active components (butalbital, codeine, aspirin) cross the placenta. Aspirin and butalbital have high placental transfer; codeine is transferred to a lesser extent but still significant. |
■ FDA Black Box Warning
Risk of medication errors: Do not confuse Fiorinal with Fioricet. Risk of addiction, abuse, and misuse with codeine. Life-threatening respiratory depression. Accidental ingestion of even one dose of codeine, especially by children, can be fatal. Risks from concomitant use with alcohol, benzodiazepines, or other CNS depressants. Neonatal opioid withdrawal syndrome. Hepatotoxicity with aspirin use in children with viral illness (Reye's syndrome).
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any componentAcute porphyriaSevere hepatic impairmentSevere renal impairmentPeptic ulcer disease (aspirin component)Children with viral illness (Reye syndrome risk with aspirin)Third trimester of pregnancy (prolonged use can cause neonatal withdrawal)Breastfeeding in CYP2D6 ultra-rapid metabolizersConcurrent use with MAO inhibitors
| Precautions | Hepatotoxicity, Reye's syndrome (children/teenagers with chickenpox or flu), respiratory depression, addiction/abuse potential, increased intracranial pressure, impaired renal function, bleeding disorders (aspirin), GI adverse effects (aspirin), risk of serotonin syndrome (codeine with serotonergic drugs), CYP2D6 ultrarapid metabolizers (codeine toxicity), withdrawal symptoms upon discontinuation, masking of symptoms of acute abdominal conditions. |
Loading safety data…
| Breastfeeding | Codeine and butalbital are excreted into breast milk. There is risk of infant sedation, respiratory depression, and withdrawal. Use with caution; monitor infant for drowsiness, poor feeding, and breathing difficulties. Avoid if possible. Consider risk of infant toxicity, especially in CYP2D6 ultra-rapid metabolizers. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | First trimester: Butalbital is associated with increased risk of neural tube defects and oral clefts. Codeine may cause respiratory depression and withdrawal in neonates with prolonged use. Second and third trimesters: Chronic use may lead to fetal dependence, withdrawal, and neonatal abstinence syndrome. Butalbital may cause neonatal bleeding due to vitamin K deficiency. Codeine may cause premature labor and low birth weight. Use only if benefit outweighs risk. |
| Fetal Monitoring | Monitor maternal sedation, respiratory rate, and blood pressure. Assess fetal growth and well-being with serial ultrasound in third trimester. Monitor for signs of neonatal withdrawal after birth. Check neonatal INR if butalbital used near term; vitamin K prophylaxis recommended. |
| Fertility Effects | No specific human data on fertility impairment. Codeine may cause transient decreases in sperm motility in males at high doses. Butalbital may alter menstrual cycle due to enzyme induction of sex hormones. General effect may be reduced fertility due to hormonal disruption. |
| Food/Dietary | Avoid alcohol completely due to additive CNS depression. No known significant food interactions beyond general opioid precautions. Grapefruit juice may theoretically affect codeine metabolism via CYP3A4, but clinical relevance is unclear; caution with excessive consumption. |
| Clinical Pearls | Due to barbiturate (butalbital) and codeine content, Fiorinal w/Codeine carries a high risk of dependence, tolerance, and withdrawal. Avoid in patients with porphyria. The combination can cause significant sedation; warn about CNS depressant synergy with alcohol. Butalbital may induce hepatic enzymes, affecting metabolism of other drugs. Codeine is a prodrug requiring CYP2D6 for activation; ultra-rapid metabolizers may experience toxicity. Use lowest effective dose for shortest duration. |
| Patient Advice | This medication contains butalbital (a barbiturate) and codeine (an opioid) which can cause dependence and withdrawal if stopped abruptly. Do not take more than prescribed. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, sleeping pills) as they increase risk of extreme sedation, respiratory depression, and coma. · Do not drive or operate machinery until you know how this medication affects you; it can impair judgment and coordination. · Store securely out of reach of children and pets; misuse can cause fatal overdose. · Codeine may cause constipation; increase fluid and fiber intake. Notify your doctor if you have severe constipation or stomach pain. · Do not use if you are breastfeeding; codeine can pass into breast milk and cause serious side effects in nursing infants. |