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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
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 |
| Breastfeeding | Codeine is excreted into breast milk. M/P ratio for codeine is approximately 2.5. In mothers who are CYP2D6 ultra-rapid metabolizers, morphine levels may be elevated, posing risk of neonatal opioid toxicity (CNS depression, apnea). Acetaminophen and butalbital are excreted in low levels and considered compatible. Because of codeine risk, alternative analgesics are preferred; if used, monitor infant for sedation and poor feeding. |
■ 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 |
["Significant respiratory depression","Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment","Known or suspected gastrointestinal obstruction, including paralytic ileus","Hypersensitivity to codeine, butalbital, acetaminophen, or any component of the product","Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such use","Severe hepatic impairment (Child-Pugh Class C) for acetaminophen component"]
Loading safety data…
| 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"] |