CYMBALTA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CYMBALTA (CYMBALTA).
Selective serotonin and norepinephrine reuptake inhibitor (SNRI); increases extracellular levels of serotonin and norepinephrine by inhibiting their reuptake into presynaptic neurons.
| Metabolism | Primarily metabolized by CYP2D6 and CYP1A2; forms multiple metabolites including the active metabolite 4-hydroxy-duloxetine. |
| Excretion | Renal: approximately 70% as metabolites (duloxetine glucuronide conjugates and sulfate conjugates), 20% as unchanged drug in urine; fecal: approximately 20% as metabolites; biliary: minor contribution. |
| Half-life | Terminal elimination half-life is approximately 12 hours (range 8–17 hours); supports once-daily dosing with consistent drug levels. |
| Protein binding | Approximately 90–95% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Vd approximately 1640 L (range 1000–2000 L), corresponding to about 20–30 L/kg (based on 70 kg); extensive tissue distribution. |
| Bioavailability | Oral: approximately 50% (range 30–80%) due to extensive first-pass metabolism; administration with food delays absorption but does not significantly affect extent. |
| Onset of Action | Oral: delayed, therapeutic effect (e.g., pain relief in diabetic neuropathy) may begin within 1–2 weeks; maximal effect may require 4–6 weeks. No immediate onset. |
| Duration of Action | Duration: approximately 24 hours with once-daily dosing due to half-life; clinical effect persists for 24 hours at steady state. Clinical note: dose adjustment needed for renal impairment. |
60 mg orally once daily, without regard to meals; some patients may benefit from a starting dose of 30 mg once daily for 1 week before increasing to 60 mg once daily.
| Dosage form | CAPSULE, DELAYED REL PELLETS |
| Renal impairment | No adjustment for mild-moderate renal impairment (CrCl 30-80 mL/min). Contraindicated in end-stage renal disease (CrCl <30 mL/min) or severe renal impairment requiring dialysis. |
| Liver impairment | Child-Pugh Class A: 30 mg once daily. Child-Pugh Class B: 30 mg once daily. Child-Pugh Class C: Use not recommended; no data available. Maximum dose 30 mg/day in any hepatic impairment. |
| Pediatric use | Not approved in pediatric patients; safety and efficacy not established for major depressive disorder. For generalized anxiety disorder, not approved in patients <18 years. |
| Geriatric use | Start at 30 mg once daily for 2 weeks; consider maximum dose of 60 mg once daily. Caution due to increased risk of hyponatremia and falls. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CYMBALTA (CYMBALTA).
| Breastfeeding | Limited data; M/P ratio unknown. Duloxetine is excreted in breast milk at low levels (mean infant dose ~1% of maternal weight-adjusted dose). Caution recommended; monitor infant for somnolence, feeding issues, and adequate weight gain. |
| Teratogenic Risk | First trimester: Studies show increased risk of cardiac malformations (primarily ventricular septal defects) with exposure, absolute risk increase ~2%. Late third trimester: Risk of persistent pulmonary hypertension of the newborn (PPHN) and neonatal adaptation syndrome (including respiratory distress, feeding difficulties, irritability). |
■ FDA Black Box Warning
Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders.
| Serious Effects |
["Concomitant use with MAOIs or within 14 days of MAOI discontinuation.","Uncontrolled narrow-angle glaucoma.","Hypersensitivity to duloxetine or any excipient."]
| Precautions | ["Hepatotoxicity: can cause liver injury; avoid in patients with substantial alcohol use or chronic liver disease.","Orthostatic hypotension and syncope.","Serotonin syndrome: risk with concomitant serotonergic drugs.","Activation of mania/hypomania.","Angle-closure glaucoma: may cause mydriasis and trigger angle closure.","Seizures: use with caution in patients with seizure disorders.","Hyponatremia: risk in elderly or volume-depleted patients.","Abrupt discontinuation: withdrawal symptoms including dizziness, nausea, headache, paresthesia."] |
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| Fetal Monitoring | Monitor maternal mood and anxiety symptoms. In late pregnancy, monitor for signs of preeclampsia and fetal heart rate. Neonates: Monitor for adaptation syndrome (irritability, poor feeding, respiratory distress) for 48-72 hours post-delivery. |
| Fertility Effects | In animal studies, duloxetine did not impair fertility. Human data are limited; no known significant effects on fertility in humans. |