Duloxetine

Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants in children and teenagers should be dispensed with each prescription.

May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin or NSAIDs due to ulcerogenic potential. Bleeding related to SNRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.

Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.

Severe skin reactions (including Stevens-Johnson syndrome and erythema multiforme) have been reported; discontinue immediately if blisters, peeling rash, mucosal erosions, or any other signs of hypersensitivity reactions are suspected.

Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).

Avoid use in patients with substantial ethanol intake, evidence of liver disease or hepatic impairment. Rare cases of hepatic failure (including fatalities) have been reported with use. Hepatitis with abdominal pain, hepatomegaly, elevated transaminase levels >20 times the upper limit of normal (ULN) with and without jaundice have all been observed. Discontinue therapy with the presentation of jaundice or other signs of hepatic dysfunction and do not reinitiate therapy unless another source or cause is identified.

Modest increases in serum glucose and hemoglobin A1c (HbA1c) levels have been observed in some diabetic patients receiving duloxetine for diabetic peripheral neuropathic pain (DPNP).

May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

May cause orthostatic hypotension/syncope, especially within the first week of therapy and after dose increases. Carefully monitor blood pressure with initiation of therapy, dose increases (especially in patients receiving >60 mg/day), or when using concomitant vasodilators or CYP1A2 inhibitors. Consider dose reduction or discontinuation of duloxetine if orthostatic hypotension or syncope occurs.

Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St John's wort) or drugs that impair serotonin metabolism (eg, MAO inhibitors, specifically linezolid, methylene blue, and others used for psychiatric disorders). Monitor patients closely for signs/symptoms of SS which may include mental status changes (eg, agitation, hallucinations, delirium), seizures, autonomic instability (eg, tachycardia, dizziness, diaphoresis), neuromuscular symptoms (eg, tremor, rigidity, myoclonus), or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Discontinue treatment (and any concomitant serotonergic agents) immediately if signs/symptoms arise.

May cause or exacerbate sexual dysfunction.

SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium • Urinary hesitancy: May cause increased urinary resistance; advise patient to report symptoms of urinary hesitation/difficulty. Disease-related concerns:

Use caution in patients with impaired gastric motility (eg, some diabetics); may affect stability of the capsule's enteric coating.

Avoid use in patients with chronic liver disease or cirrhosis.

Use caution in patients with hypertension. Although no statistically significant differences in the frequency of sustained elevations of blood pressure were observed in clinical trials when compared with placebo, modest increases in blood pressure have been reported with use. Additionally, rare cases of hypertensive crisis have been reported; blood pressure should be evaluated prior to initiating therapy and periodically thereafter; consider dose reduction or gradual discontinuation of therapy in individuals with sustained hypertension during therapy.

May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Duloxetine is not FDA approved for the treatment of bipolar depression.

Use with caution; clearance is decreased and plasma concentrations are increased; avoid use in patients with CrCl • Seizure disorders: Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism (Montgomery 2005). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Falls with serious consequences including bone fractures and hospitalization have been reported in patients receiving therapeutic doses of duloxetine. The risk of falling appears related to the degree of orthostatic decrease in blood pressure. Risks may also be greater in elderly patients, patients taking concomitant medications that induce orthostatic hypotension or are potent CYP1A2 inhibitors, and in patients taking doses >60 mg/day. Consider dose reduction or discontinuation of duloxetine if falls occur.

Some formulations may contain sucrose; patients with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should avoid use. Other warnings/precautions:

Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).