FIORICET 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.
FIORICET W/ CODEINE combines butalbital (barbiturate) that enhances GABA-A receptor activity, acetaminophen (analgesic/antipyretic) that inhibits cyclooxygenase and modulates cannabinoid receptors, and codeine (opioid mu-receptor agonist) that activates mu-opioid receptors to produce analgesia and antitussive effects.
| Metabolism | Codeine is metabolized primarily via glucuronidation and O-demethylation to morphine (via CYP2D6), and to a lesser extent N-demethylation to norcodeine (via CYP3A4). Butalbital is metabolized by hepatic microsomal enzymes. Acetaminophen is metabolized primarily via glucuronidation and sulfation; a minor pathway via CYP2E1 produces a toxic metabolite (NAPQI) hepatically. |
| Excretion | Codeine and its metabolites are primarily excreted renally (about 90% as conjugates and free drug). Acetaminophen is excreted renally as conjugates (85-90%) and as unchanged drug (<5%). Butalbital is excreted renally (about 90% as metabolites and unchanged). Caffeine metabolites are excreted renally. Fecal excretion is minimal. |
| Half-life | Codeine: 2.5-3.5 hours (converted to morphine; clinical effect wanes accordingly). Acetaminophen: 1.5-2.5 hours. Butalbital: 35-40 hours (prolonged in hepatic impairment; contributes to sedation). Caffeine: 3-5 hours. |
| Protein binding | Codeine: ~25% (primarily albumin). Acetaminophen: <20% (variable). Butalbital: 45-60% (albumin). Caffeine: ~30-40% (albumin). |
| Volume of Distribution | Codeine: ~2.5-4 L/kg. Acetaminophen: 0.7-1.2 L/kg. Butalbital: 0.8-1.0 L/kg. Caffeine: 0.5-0.8 L/kg. Indicates extensive tissue distribution for codeine. |
| Bioavailability | Codeine: ~50-90% (oral, extensive first-pass metabolism to morphine). Acetaminophen: ~60-100% (oral, rapidly absorbed). Butalbital: ~80-90% (oral). Caffeine: ~100% (oral). |
| Onset of Action | Codeine analgesia: 30-60 min (oral). Acetaminophen antipyresis: 30-60 min (oral). Butalbital sedation: 30-60 min (oral). Caffeine stimulation: 15-30 min (oral). |
| Duration of Action | Codeine analgesia: 4-6 hours. Acetaminophen: 4-6 hours. Butalbital: 6-8 hours of sedation; residual effects may last longer due to long half-life. Caffeine: 4-6 hours. |
| Molecular Weight | 424.46 |
1-2 capsules orally every 4 hours as needed, maximum 6 capsules per day.
| Dosage form | CAPSULE |
| Renal impairment | CrCl 10-50 mL/min: administer 75% of normal dose every 6 hours. CrCl <10 mL/min: administer 50% of normal dose every 6 hours. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose by 50%. Child-Pugh Class C: not recommended. |
| Pediatric use | For children ≥12 years: 1 capsule orally every 4 hours as needed, maximum 3 capsules per day. For children <12 years: not recommended. |
| Geriatric use | Start with lower doses (e.g., 1 capsule every 6 hours), titrate cautiously due to increased risk of respiratory depression and constipation. |
| 1st trimester | Avoid. Associated with increased risk of congenital malformations (cleft palate, gastroschisis) and spontaneous abortion. |
| 2nd trimester | Avoid. May cause fetal toxicity; use only if maternal benefit outweighs fetal risk. |
| 3rd trimester | Contraindicated. Risk of premature closure of ductus arteriosus, oligohydramnios, neonatal renal dysfunction, and respiratory depression. |
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 | Codeine, butalbital, and acetaminophen cross the placenta. Codeine undergoes extensive placental transfer with fetal-to-maternal ratio ~0.8. |
■ FDA Black Box Warning
Addiction, Abuse, and Misuse: Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing. Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following dose increase. Accidental Ingestion: Accidental ingestion of even one dose of codeine, especially by children, can result in a fatal overdose. Neonatal Opioid Withdrawal Syndrome: Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome. Cytochrome P450 3A4 Interaction: Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal opioid overdose. Risks from Concomitant Use with Benzodiazepines: Concomitant use of opioids with benzodiazepines or other CNS depressants may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. Hepatotoxicity: 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 4,000 mg per day, and often involve more than one acetaminophen-containing product.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any component (codeine, butalbital, acetaminophen, caffeine)Acute porphyriaSevere respiratory depressionConcurrent MAO inhibitor use or within 14 daysIn patients with known CYP2D6 ultra-rapid metabolizer status (codeine)
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| Breastfeeding |
| Codeine is excreted into breast milk; risk of infant respiratory depression, especially in CYP2D6 ultra-rapid metabolizers. Butalbital and acetaminophen are also excreted. Consider risk vs. benefit; monitor infant for sedation, poor feeding, and respiratory depression. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: Case-control studies suggest a possible small increased risk of congenital malformations (cleft palate, cardiac defects) with codeine use, but data are confounded. Acetaminophen is generally considered low risk, but butalbital use in early pregnancy has been associated with neural tube defects in some studies. Second and third trimesters: Chronic maternal codeine use can lead to neonatal opioid withdrawal syndrome. Butalbital may cause neonatal withdrawal and CNS depression. Acetaminophen is safe at therapeutic doses. Risks must be weighed against benefits; avoid prolonged use. |
| Fetal Monitoring | Maternal: Monitor for signs of opioid toxicity, respiratory depression, and constipation. Fetal: Ultrasound for fetal growth and anatomy if used in early pregnancy; electronic fetal monitoring during labor if used near term. Neonatal: Observe for withdrawal symptoms (irritability, hypertonia, tremors, poor feeding) in newborns exposed chronically in utero. If maternal CYP2D6 ultra-rapid metabolizer status is known, monitor neonate for opioid toxicity. |
| Fertility Effects | Limited data. There are no known significant effects on fertility from acetaminophen or butalbital. Codeine may suppress gonadotropin-releasing hormone and luteinizing hormone, potentially causing menstrual irregularities or impaired spermatogenesis, but clinical significance is unclear. Chronic use may affect libido. Reversible upon discontinuation. |
| Precautions | Addiction, abuse, and misuse, Life-threatening respiratory depression, Accidental ingestion (especially in children), Neonatal opioid withdrawal syndrome (prolonged use during pregnancy), Cytochrome P450 3A4 interaction risk (CYP3A4 inhibitors/inducers), Risks from concomitant use with benzodiazepines or other CNS depressants, Hepatotoxicity (acetaminophen, limit to <4000 mg/day, avoid multiple acetaminophen products), Serotonin syndrome with concomitant serotonergic drugs, Adrenal insufficiency, Hypotension, especially with volume-depleted patients, Anaphylaxis and hypersensitivity reactions (codeine/acetaminophen), Severe hypotension in patients with compromised ability to maintain blood pressure, Risks in patients with head injury, increased intracranial pressure, or impaired consciousness |
| Food/Dietary | Avoid alcohol and products containing alcohol. Grapefruit juice may increase codeine absorption via CYP3A inhibition. Caffeine-containing foods/drinks may add to side effects. High-tyramine foods (e.g., aged cheeses) not restricted but may rarely precipitate hypertensive crisis in susceptible individuals. |
| Clinical Pearls | Fioricet with Codeine contains acetaminophen, butalbital, caffeine, and codeine. Butalbital is a barbiturate that induces CYP3A4, potentially reducing efficacy of hormonal contraceptives. Codeine is a prodrug converted to morphine via CYP2D6; ultrarapid metabolizers risk toxicity. Do not exceed 4g/day acetaminophen due to hepatotoxicity. Contraindicated in porphyria. Use with caution in patients with respiratory depression or history of substance abuse. |
| Patient Advice | Do not exceed the prescribed dose, as acetaminophen overdose can cause severe liver damage. · Avoid alcohol while taking this medication to prevent liver injury and excessive sedation. · May cause drowsiness or dizziness; avoid driving or operating machinery until you know how you react. · This medication contains codeine, which can be habit-forming; use only as directed. · Codeine may cause constipation; increase fluid and fiber intake. · Store securely out of reach of children and dispose of unused medication properly. · If you are pregnant or breastfeeding, discuss risks with your healthcare provider. · Inform your doctor if you have breathing problems, liver disease, or a history of addiction. |