Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), has been approved for the treatment of major depressive disorder (MDD) and for the management of diabetic peripheral neuropathic pain (DPN). The drug is believed to potentiate serotonergic and noradrenergic activity in the CNS.
Dosage. For treatment of MDD, administer at a total dose of 40 mg/d (given as 20 mg bid) to 60 mg/d (given either once a day or as 30 mg bid) without regard to meals. For treatment of DPN, administer at a total dose of 60 mg/d, given once a day without regard to meals. Periodically reassess patients to determine maintenance therapy and appropriate dosage. When discontinuing duloxetine therapy, gradually reduce the dose to avoid discontinuation symptoms.
Geriatric dosage adjustments. None recommended.
Pharmacokinetics. The pharmacokinetics after 1 dose, 40 mg, was compared in healthy older females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the [C.sub.max], but the AUC of duloxetine was higher (about 25%) and the half-life about 4 hours longer in the older females. Typical values for clearance decrease by approximately 1% for each year between ages 25 to 75. Monitoring of renal function in older patients is recommended.
Safety. Serious--sometimes fatal--reactions have been reported when duloxetine is taken in combination with a monoamine oxidase inhibitor (MAOI). These include hyperthermia, rigidity, myoclonus, autonomic instability with possible fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Duloxetine is not recommended for use in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. Allow 5 days after cessation of duloxetine before starting an MAOI.
Concomitant use with inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, may result in elevated plasma levels of duloxetine; these combinations should be avoided. Duloxetine should not be administered with thioridazine due to the risk of serious ventricular arrhythmias and sudden death.
Avoid duloxetine in patients with uncontrolled narrow-angle glaucoma; its use has been associated with an increased risk of mydriasis. Do not administer to patients with hepatic insufficiency.
Adverse events. Commonly observed adverse events associated with duloxetine therapy are nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, diarrhea, and increased sweating. In some cases, patients have experienced dizziness and hot flashes. Early in antidepressant therapy, patients may experience anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, or suicidal ideation. Discontinuation of SSRIs and SSNRIs (particularly when abrupt) may cause dysphoric mood, dizziness, sensory disturbances, confusion, headache, lethargy, emotional lability, tinnitus, or seizures. Some discontinuation events have been severe.
Pharmacokinetics. The pharmacokinetics after 1 dose, 40 mg, was compared in healthy older females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the [C.sub.max], but the AUC of duloxetine was higher (about 25%) and the half-life about 4 hours longer in the older females. Typical values for clearance decrease by approximately 1% for each year between ages 25 to 75. Monitoring of renal function in older patients is recommended.
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