PHRENILIN WITH CAFFEINE AND 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.
Combination analgesic; butalbital is a barbiturate that potentiates GABA-A activity; acetaminophen inhibits cyclooxygenase (COX) and modulates cannabinoid receptors; caffeine is a nonselective adenosine receptor antagonist; codeine is a prodrug converted to morphine, a mu-opioid agonist.
| Metabolism | Butalbital: hepatic (CYP2C19); Acetaminophen: hepatic (CYP1A2, CYP2E1, conjugation); Caffeine: hepatic (CYP1A2); Codeine: hepatic via CYP2D6 to morphine; also metabolized by CYP3A4 to norcodeine. |
| Excretion | Renal: butalbital ~60% unchanged; codeine ~90% as metabolites (free and conjugated morphine, norcodeine); caffeine <2% unchanged, ~80% as metabolites (paraxanthine, theobromine, theophylline) via renal excretion. Biliary/fecal: minimal. |
| Half-life | Butalbital: 35–50 hours; codeine: 2.5–3.5 hours; caffeine: 4–6 hours (adults), prolonged in liver disease. Clinical context: butalbital's long half-life leads to accumulation with repeated dosing; codeine's short half-life requires frequent dosing. |
| Protein binding | Butalbital: ~45% (albumin); codeine: ~7–25% (albumin); caffeine: ~10–30% (albumin). |
| Volume of Distribution | Butalbital: 0.8 L/kg; codeine: 3–4 L/kg; caffeine: 0.5–0.7 L/kg. Clinical meaning: codeine's high Vd indicates extensive tissue distribution; butalbital and caffeine are more confined to extracellular water. |
| Bioavailability | Oral: butalbital ~90%; codeine ~90% (but extensive first-pass metabolism to morphine); caffeine ~100%. |
| Onset of Action | Oral: butalbital 30–60 min; codeine 30–60 min; caffeine 45–60 min. |
| Duration of Action | Butalbital: 4–6 hours (analgesia, sedation); codeine: 4–6 hours; caffeine: 4–6 hours. Clinical note: sedation from butalbital may persist longer than analgesia. |
1-2 capsules orally every 4 hours as needed, not to exceed 8 capsules per day. Each capsule contains butalbital 50 mg, caffeine 40 mg, and codeine phosphate 30 mg.
| Dosage form | CAPSULE |
| Renal impairment | No specific guidelines available. Use with caution in renal impairment; consider reducing dose or extending interval. Monitor for CNS depression and constipation. For GFR < 30 mL/min, use is not recommended. |
| Liver impairment | Contraindicated in patients with severe hepatic impairment (Child-Pugh class C). In mild to moderate hepatic impairment (Child-Pugh A or B), use with caution; consider reducing dose or extending interval. Monitor for excessive sedation. |
| Pediatric use | Not recommended for use in children under 12 years of age. For children 12-18 years, weight-based dosing for codeine: 0.5-1 mg/kg codeine component every 4-6 hours as needed; maximum codeine dose 60 mg/dose. Butalbital and caffeine dosing not established in pediatrics; alternative therapy recommended. |
| Geriatric use | Start at the lower end of the dosing range (e.g., 1 capsule every 6 hours as needed). Monitor for increased sensitivity to CNS depressant effects, falls, confusion, and constipation. Consider reducing total daily dose. Avoid in frail elderly. |
| 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 and caffeine are excreted into breast milk; butalbital is present in low levels. M/P ratio for codeine is approximately 2.0; for caffeine, ~0.5-0.7. Use with caution due to risk of infant sedation, respiratory depression, and withdrawal. Consider alternative analgesics; monitor infant for drowsiness, feeding difficulties, or apnea. |
| Teratogenic Risk |
■ FDA Black Box Warning
Codeine is contraindicated in children younger than 12 years for pain relief, and contraindicated in children younger than 18 years for tonsillectomy/adenoidectomy due to risk of fatal respiratory depression.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any component; severe respiratory depression; acute or severe asthma; paralytic ileus; known CYP2D6 ultrarapid metabolizers; children <12 years (codeine); use after tonsillectomy/adenoidectomy in children <18 years; concurrent MAOI use or within 14 days; porphyria (butalbital).
| Precautions | Risk of respiratory depression; addiction and abuse potential; acetaminophen hepatotoxicity (dose-dependent); avoid in patients with severe hepatic impairment; CYP2D6 ultra-rapid metabolizers may experience toxicity with codeine; butalbital can cause dependence and withdrawal; avoid abrupt discontinuation; may impair mental/physical abilities. |
Loading safety data…
| First trimester: Codeine (FDA Category C) and butalbital (Category C/D near term) may be associated with increased risk of congenital malformations; caffeine (Category C) at high doses may increase risk of miscarriage. Second and third trimesters: Chronic use may lead to fetal dependence, neonatal withdrawal syndrome; butalbital near term may cause neonatal bleeding due to vitamin K deficiency; codeine may cause respiratory depression if used near delivery. |
| Fetal Monitoring | Monitor maternal blood pressure, respiratory rate, and pain scores. Assess for signs of sedation or respiratory depression. For fetus: ultrasonography for growth restriction if used chronically. At delivery, monitor neonatal respiratory status, Apgar scores, and signs of withdrawal (e.g., irritability, tremors, feeding problems). |
| Fertility Effects | Data limited. Codeine and butalbital may affect ovulation via CNS depressant effects; caffeine at high doses may impair fertility. No definitive evidence of long-term infertility. Discontinuation during pregnancy planning should be based on clinical need. |