FIORINAL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FIORINAL (FIORINAL).
FIORINAL is a combination of butalbital (barbiturate), aspirin (NSAID), and caffeine. Butalbital potentiates GABA-A receptor activity, producing sedative-hypnotic effects. Aspirin inhibits cyclooxygenase (COX-1 and COX-2), reducing prostaglandin synthesis, which provides analgesic and antipyretic effects. Caffeine is a non-selective adenosine receptor antagonist, enhancing analgesic efficacy.
| Metabolism | Butalbital is extensively metabolized in the liver via hydroxylation and glucuronidation, primarily by CYP2C9 and CYP2C19. Aspirin is hydrolyzed to salicylic acid, then conjugated with glycine (salicyluric acid) and glucuronidated. Caffeine is metabolized by CYP1A2 to paraxanthine, theobromine, and theophylline. |
| Excretion | Renal: 60% butalbital (mostly unchanged), 10% aspirin (salicylates, majorly as metabolites), 3% caffeine (metabolites and unchanged). Fecal: <5% overall. |
| Half-life | Butalbital 35-50 hours, aspirin 15-20 minutes (salicylate 2-3 hours at low doses, >20 hours at high doses), caffeine 3-5 hours. Prolonged in hepatic/renal impairment. |
| Protein binding | Butalbital 20-40% (albumin), aspirin 80-90% (albumin, concentration-dependent), caffeine 25-36% (albumin). |
| Volume of Distribution | Butalbital 0.8 L/kg, aspirin 0.15-0.2 L/kg, caffeine 0.6-0.8 L/kg. Indicates extensive tissue distribution for butalbital and caffeine. |
| Bioavailability | Oral: butalbital ~100%, aspirin 50-75% (first-pass metabolism), caffeine ~100%. |
| Onset of Action | Oral: butalbital 30-60 min, aspirin 5-30 min, caffeine 15-45 min. |
| Duration of Action | Butalbital 4-6 hours (longer with high doses), aspirin 4-6 hours (antiplatelet effect lasts days), caffeine 4-6 hours. |
1-2 capsules (butalbital 50 mg, acetaminophen 300 mg, caffeine 40 mg) orally every 4 hours as needed, not exceeding 6 capsules per day.
| Dosage form | TABLET |
| Renal impairment | No specific guidelines; contraindicated in severe renal impairment (CrCl <30 mL/min) due to acetaminophen accumulation. Use with caution in moderate impairment. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh Class C). For mild to moderate (Child-Pugh A or B), reduce dose by 50% or extend dosing interval. |
| Pediatric use | Not recommended for pediatric use; safety and efficacy not established. |
| Geriatric use | Start at lowest effective dose (e.g., 1 capsule every 4 hours) due to increased sensitivity to butalbital (sedation, confusion) and risk of acetaminophen hepatotoxicity; maximum daily acetaminophen dose 2 g. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for FIORINAL (FIORINAL).
| Breastfeeding | Aspirin excreted in milk (M/P ratio ~0.03-0.3); risk of Reye syndrome. Butalbital excreted in low amounts; may cause neonatal sedation. Caffeine excreted (M/P ~0.5-0.7); may cause irritability. Avoid breastfeeding during chronic use. |
| Teratogenic Risk | First trimester: Butalbital is associated with neural tube defects, cleft palate; aspirin increases risk of gastroschisis, cardiac defects. Second trimester: Aspirin may cause premature closure of ductus arteriosus. Third trimester: Aspirin increases risk of intracranial hemorrhage, premature closure of ductus arteriosus; butalbital may cause neonatal withdrawal. Caffeine is not a major teratogen but high doses may increase miscarriage risk. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Hypersensitivity to butalbital, aspirin, or caffeine","Active peptic ulcer disease","Hemophilia or bleeding disorders","Concomitant use of anticoagulants","Children with chickenpox or influenza-like symptoms (risk of Reye's syndrome)","Severe hepatic or renal impairment","Porphyria"]
| Precautions | ["Risk of Reye's syndrome in children with viral illness","Aspirin hypersensitivity (e.g., asthma, nasal polyps)","Gastrointestinal bleeding and ulceration","Hepatic impairment due to butalbital metabolism","Caffeine overdose from excessive use","Dependence and withdrawal with prolonged butalbital use"] |
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| Fetal Monitoring | Fetal ultrasound for anomalies; ductus arteriosus Doppler in third trimester; maternal platelet count, coagulation profile; neonatal monitoring for withdrawal if chronic butalbital use. |
| Fertility Effects | High-dose aspirin may inhibit prostaglandin synthesis, potentially impair ovulation; butalbital may induce hepatic enzymes affecting hormonal contraception efficacy. |