COMPOUND 65
Clinical safety rating: caution
Comprehensive clinical and safety monograph for COMPOUND 65 (COMPOUND 65).
COMPOUND 65 acts as a selective serotonin reuptake inhibitor (SSRI), increasing serotonin levels in the synaptic cleft by blocking the serotonin transporter (SERT).
| Metabolism | Hepatic via CYP2D6 and CYP3A4 isoenzymes; active metabolite N-desmethyl compound. |
| Excretion | Renal excretion of unchanged drug accounts for 30-40%; hepatic metabolism with fecal elimination of metabolites accounts for 50-60%; biliary excretion is minimal (<5%). |
| Half-life | Terminal elimination half-life is 8-12 hours in healthy adults; prolonged to 15-20 hours in hepatic impairment; requires dose adjustment in severe hepatic disease. |
| Protein binding | 95-98% bound to serum albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 0.8-1.2 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral: 75-85% (first-pass metabolism reduces bioavailability by 15-25%); intramuscular: 90-100%. |
| Onset of Action | Oral: 30-45 minutes; intravenous: 1-2 minutes; intramuscular: 5-10 minutes. |
| Duration of Action | Oral: 4-6 hours; intravenous: 2-4 hours; intramuscular: 3-5 hours. Duration extended in hepatic impairment. |
25 mg orally every 8 hours as needed for pain; maximum 75 mg per day.
| Dosage form | CAPSULE |
| Renal impairment | GFR 30-50 mL/min: 25 mg every 12 hours; GFR <30 mL/min: 25 mg every 24 hours; not recommended in dialysis. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: 12.5 mg every 12 hours; Child-Pugh C: not recommended. |
| Pediatric use | Children ≥12 years: 12.5-25 mg orally every 6-8 hours as needed; maximum 75 mg/day. Children <12 years: not established. |
| Geriatric use | Start at 12.5 mg orally every 8 hours; increase cautiously to 25 mg if tolerated; maximum 50 mg per day. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for COMPOUND 65 (COMPOUND 65).
| Breastfeeding | Breastfeeding safety: Limited data; compound is excreted into breast milk (M/P ratio estimated 0.80-1.20 based on molecular properties). Caution advised due to potential for infant sedation and withdrawal. Consider benefits versus risks; alternative feeding methods recommended during therapy. |
| Teratogenic Risk | First trimester: Increased risk of congenital malformations, particularly neural tube defects and cardiac anomalies (based on animal studies and limited human data). Second trimester: Risk of fetal growth restriction and oligohydramnios. Third trimester: Potential for neonatal complications including withdrawal syndrome and respiratory depression at delivery. |
■ FDA Black Box Warning
WARNING: Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults taking antidepressants. Monitor closely for worsening or emergence of suicidal thoughts and behaviors.
| Serious Effects |
["Concomitant use with MAOIs or within 14 days of MAOI therapy","Concomitant use with pimozide","Known hypersensitivity to COMPOUND 65 or any inactive ingredients"]
| Precautions | ["Serotonin syndrome","Increased risk of bleeding","Activation of mania/hypomania","Seizure risk","Angle-closure glaucoma risk","Sexual dysfunction"] |
| Food/Dietary | Avoid alcohol consumption due to increased risk of hepatotoxicity and CNS depression. Grapefruit juice may increase propoxyphene levels by inhibiting CYP3A4, potentially leading to toxicity. High-fat meals may delay absorption but not significantly alter overall exposure. Maintain adequate hydration to prevent constipation. |
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| Fetal Monitoring | Monitor maternal liver function tests, renal function, and complete blood count monthly. Fetal ultrasound for growth and anatomy at 18-20 weeks, then serial growth scans every 4-6 weeks. Non-stress test and biophysical profile weekly from 32 weeks. Neonatal monitoring for withdrawal symptoms for 48 hours post-delivery. |
| Fertility Effects | In animal studies, reduced fertility and increased preimplantation loss. Human data limited; may cause menstrual irregularities and anovulation. Reversible upon discontinuation. Advise contraception during therapy and for 3 months after cessation. |
| Clinical Pearls | COMPOUND 65 is a fixed-dose combination of acetaminophen and propoxyphene. Propoxyphene is a weak mu-opioid receptor agonist with efficacy similar to codeine, but with a higher risk of QT prolongation and cardiotoxicity, especially at supratherapeutic doses. Avoid in patients with prolonged QT interval, electrolyte disturbances, or those on other QT-prolonging drugs. Hepatotoxicity can occur with acetaminophen component if doses exceed 4 g/day; monitor liver function. Propoxyphene is metabolized by CYP3A4 and CYP2D6; co-administration with inhibitors or inducers may alter efficacy or toxicity. |
| Patient Advice | Do not exceed 4 grams of acetaminophen per day; check all medications for acetaminophen content. · Take exactly as prescribed; overdose risk includes severe liver damage and potentially fatal heart rhythm abnormalities. · Avoid alcohol while taking this medication to reduce risk of liver injury. · Report any signs of allergic reaction (rash, difficulty breathing), chest pain, palpitations, or fainting. · This medication may cause dizziness or drowsiness; do not drive or operate heavy machinery until you know how it affects you. · Do not combine with other opioid medications without consulting your doctor. · Store in a secure place away from children and others; this is a controlled substance. · Do not abruptly stop without medical guidance to avoid withdrawal symptoms. |