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. |
| Molecular Weight | 297.37 |
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 | Limited human data; animal studies show risk of developmental toxicity at high doses. Use only if benefit outweighs risk. |
| 2nd trimester | Risk of preterm birth and low birth weight with late exposure; consider avoiding. |
| 3rd trimester | Risk of persistent pulmonary hypertension of the newborn (PPHN), poor neonatal adaptation syndrome (e.g., irritability, feeding difficulties). Avoid in late third trimester unless essential. |
Clinical note
Comprehensive clinical and safety monograph for CYMBALTA (CYMBALTA).
| Placental transfer | Crosses the placenta; fetal concentrations approximately 60% of maternal concentrations at term. |
| Breastfeeding | Duloxetine is excreted into breast milk in low amounts (infant dose ~1% of maternal weight-adjusted dose). Monitor infant for sedation, poor feeding. Caution in preterm infants or with prolonged use. |
■ 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 |
Concurrent use with MAOIs or within 14 days of discontinuing an MAOIUncontrolled narrow-angle glaucomaSevere hepatic impairment (Child-Pugh C)Known hypersensitivity to duloxetine or any of the excipients
| 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. |
| Food/Dietary | Avoid or limit alcohol as it can exacerbate hepatotoxicity. There are no specific food restrictions, but take with food to reduce nausea. Avoid excessive grapefruit consumption as it may theoretically affect CYP1A2 metabolism, though data are limited. |
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| Lactation Rating | L2 |
| 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). |
| 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. |
| Clinical Pearls | CYMBALTA (duloxetine) is a serotonin-norepinephrine reuptake inhibitor (SNRI) used for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain. Avoid abrupt discontinuation to prevent withdrawal symptoms. Monitor blood pressure regularly as it can cause hypertension. Contraindicated with MAOIs, uncontrolled narrow-angle glaucoma, and heavy alcohol use. Taper dose when discontinuing to reduce withdrawal risk. |
| Patient Advice | Take CYMBALTA exactly as prescribed; do not stop suddenly without consulting your doctor. · Avoid alcohol while taking this medication; alcohol can increase the risk of liver damage. · Report any signs of liver problems (dark urine, yellowing skin/eyes, right upper belly pain) immediately. · Notify your doctor if you experience worsening depression, suicidal thoughts, or unusual mood changes. · This drug may cause dizziness or drowsiness; avoid driving initially until you know how it affects you. · Do not take within 14 days of an MAO inhibitor (e.g., phenelzine, selegiline) to avoid serious interactions. |