DULOXETINE HYDROCHLORIDE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Serotonin and norepinephrine reuptake inhibitor (SNRI); increases extracellular levels of serotonin and norepinephrine by inhibiting their reuptake into presynaptic neurons.
| Metabolism | Extensively metabolized in the liver via CYP1A2 and CYP2D6 to multiple inactive metabolites. |
| Excretion | Renal: 70% as metabolites, <1% unchanged; Fecal: 20% |
| Half-life | 12.1 hours (range 8-17 hours); steady-state achieved in 3 days |
| Protein binding | 90% bound to albumin and alpha-1-acid glycoprotein |
| Volume of Distribution | 3.4 L/kg (1640 L for 70 kg); extensive tissue distribution |
| Bioavailability | Oral: 50% (range 30-80%) due to first-pass metabolism |
| Onset of Action | Oral: 1-2 weeks for antidepressant effect; 1 week for pain relief |
| Duration of Action | 24 hours; once-daily dosing |
60 mg orally once daily, with or without food; may start at 30 mg once daily for 1 week to allow adjustment to the drug, then increase to 60 mg once daily; maximum 120 mg per day given in divided doses for major depressive disorder; for diabetic peripheral neuropathic pain, 60 mg once daily; for fibromyalgia, 60 mg once daily; for chronic musculoskeletal pain, 60 mg once daily.
| Dosage form | CAPSULE, DELAYED RELEASE |
| Renal impairment | For GFR 30-60 mL/min: reduce dose to 30 mg once daily; for GFR <30 mL/min: not recommended; consider discontinuation if CrCl <30 mL/min; avoid use in end-stage renal disease (ESRD) requiring dialysis. |
| Liver impairment | Child-Pugh Class A: no adjustment necessary; Child-Pugh Class B: reduce starting dose to 30 mg once daily, maximum 60 mg once daily; Child-Pugh Class C: not recommended. |
| Pediatric use | Not approved for use in pediatric patients aged <18 years; safety and efficacy not established; for pediatric generalized anxiety disorder (off-label), limited data suggest starting 30 mg once daily, titrated to 60 mg once daily; maximum 120 mg per day. |
| Geriatric use | In elderly patients, start at 30 mg once daily for 2 weeks, then increase to 60 mg once daily if tolerated; monitor for hyponatremia, falls, bleeding risk, and drug interactions; for patients >65 years, maximum 120 mg per day is not recommended; consider lower maintenance dose (e.g., 60 mg once daily). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
MAOIs can cause serotonin syndrome Can cause hepatotoxicity and increase suicidal thoughts and behaviors.
| Breastfeeding | Duloxetine is excreted into human milk with a relative infant dose (RID) of approximately 1.1-2.8% of the weight-adjusted maternal dose. M/P ratio is not well-defined due to low concentrations (mean milk/plasma ratio ~0.25). No adverse effects in breastfed infants have been reported in limited studies. Caution is advised with monitoring for infant irritability or poor feeding. |
| Teratogenic Risk | First trimester: Epidemiologic studies suggest a small increased risk of cardiovascular malformations (primarily ventricular septal defects) with exposure (RR 1.1-1.7). Second/third trimester: Late exposure may increase risk of persistent pulmonary hypertension of the newborn (PPHN) (odds ratio ~1.5-2.0). Third trimester use associated with neonatal adaptation syndrome (irritability, feeding difficulties, respiratory distress) in 25-30% of neonates. |
■ FDA Black Box Warning
Suicidality and Antidepressant Drugs: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with MDD and other psychiatric disorders.
| Common Effects | anxiety |
| Serious Effects |
["Concomitant use with MAOIs (or within 14 days of discontinuation) due to risk of serotonin syndrome.","Uncontrolled narrow-angle glaucoma (due to mydriasis).","Concomitant use with thioridazine (due to QT prolongation risk).","Hepatic impairment with evidence of hepatic injury (Child-Pugh Class B or C) for DPNP indication (but may be used cautiously in MDD without hepatic injury)."]
| Precautions | ["Suicide risk: Monitor for worsening depression and suicidality, especially early in treatment.","Hepatotoxicity: Use caution in patients with substantial alcohol use or pre-existing liver disease; can cause elevated liver enzymes and severe hepatic injury.","Serotonin syndrome: Risk, especially with concomitant use of serotonergic drugs.","Discontinuation syndrome: Abrupt discontinuation may cause dizziness, headache, nausea, irritability, and insomnia; taper gradually.","Mydriasis: May worsen narrow-angle glaucoma.","Blood pressure elevation: Monitor blood pressure, especially in patients with hypertension.","Hypomania/mania: May precipitate in patients with bipolar disorder.","Seizures: Use with caution in patients with seizure disorders.","Hyponatremia: May occur, especially in elderly or volume-depleted patients.","Sexual dysfunction: Can cause ejaculatory delay, decreased libido, or erectile dysfunction."] |
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| Fetal Monitoring | Monitor for maternal serotonin syndrome, hypertension, and bleeding risk. Fetal monitoring for growth parameters and amniotic fluid index recommended in third trimester. Neonatal assessment for adaptation syndrome (poor suck, tremors, jitteriness) postpartum. Consider serial ultrasounds to detect congenital heart defects if first trimester exposure. |
| Fertility Effects | In animal studies, duloxetine did not impair fertility at doses up to 2.7 times the maximum recommended human dose (MRHD). In humans, no dedicated fertility studies exist; however, SSRIs/SNRIs may cause reversible sexual dysfunction (delayed ejaculation, anorgasmia) affecting fertility indirectly. Hyperprolactinemia is rare but possible. |