BRAND NAMES
- International: Cymbalta
- Europe: Ariclaim PI, Cymbalta PI, Xeristar PI, Yentreve PI
- Italy: Cymbalta, Xeristar, Yentreve
- U.S.: Cymbalta PI
 MECHANISM OF ACTION
Duloxetine is a potent serotonin-norepinephrine reuptake inhibitor (SNRI) and a less potent inhibitor of dopamine reuptake. It prevents the neurotransmitters serotonin and noradrenaline from being taken back up into nerve cells in the brain and spinal cord. By blocking their re-uptake, duloxetine increases the amount of these neurotransmitters in the spaces between the nerve cells, increasing the level of communication between them.
It is thought that, by increasing the levels of serotonin and noradrenaline at the level of the nerves that control the urethral striated sphincter muscle, duloxetine causes a stronger closure of the urethra during urine storage. By closing the urethra more powerfully, Duloxetine prevents the unwanted loss of urine in women, during physical stress such as coughing or laughing.
Serotonin and noradrenaline are involved also in maintaining high mood and reducing the sensation of pain, blocking their re-uptake into nerve cells can improve the symptoms of depression, anxiety and neuropathic pain (The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system).
Duloxetine has no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors.
- Major Depressive Disorder (FDA and EMEA approved). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.
- Generalized Anxiety Disorder (FDA and EMEA approved). Generalized anxiety disorder is defined by the DSM-IV as excessive anxiety and worry, present more days than not, for at least 6 months. The excessive anxiety and worry must be difficult to control and must cause significant distress or impairment in normal functioning. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance.
- Diabetic Peripheral Neuropathic Pain (FDA and EMEA approved)
- Fibromyalgia (FDA approved)
- Chronic Musculoskeletal Pain (FDA approved)
- Treatment of women with moderate to severe Stress Urinary Incontinence (EMEA approved)
- Major Depressive Disorder: 60 mg once daily with or without food. Dosing may be started at 30 mg for one week, before increasing to 60 mg once daily
- Generalized Anxiety Disorder:60 mg once daily with or without food. Dosing may be started at 30 mg for one week, before increasing to 60 mg once daily
- Diabetic Peripheral Neuropathic Pain: 60 mg once daily with or without food.
- Fibromyalgia: 60 mg once daily with or without food. Dosing may be started at 30 mg for one week, before increasing to 60 mg once daily
- Chronic Musculoskeletal Pain: 60 mg once daily with or without food. Dosing may be started at 30 mg for one week, before increasing to 60 mg once daily
- Stress Urinary Incontinence: starting dose: 20 mg twice daily for two weeks. recommended dose: 40 mg twice daily with or without food. Dose escalation may decrease, though not eliminate, the risk of nausea and dizziness.
Discontinuing Duloxetine: A gradual dose reduction is recommended to avoid discontinuation symptoms like dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.
- Hypersensitivity to Duloxetine
- It's use within 14 days of stopping an MAOI because of an increased risk of serotonin syndrome
- Do not start Duloxetine in a patient who is being treated with linezolid or intravenous methylene blue
- Patients with uncontrolled narrow-angle glaucoma
- Duloxetine should not be used in combination with potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin or enoxacin). CYP1A2 is involved in duloxetine metabolism, concomitant use with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine.
- Liver disease resulting in hepatic impairment.
- Severe Renal Impairment
 WARNINGS AND PRECAUTIONS
- Suicidal thoughts and behaviours: Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. Duloxetine is not approved for use in pediatric patients.
- Hepatotoxicity: Cases of liver injury, sometimes fatal, has been reported. Duloxetine should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease
- Orthostatic Hypotension and Syncope: Cases have been reported with duloxetine therapy especially at the initiation of treatment
- Serotonin Syndrome Serotonin syndrome has been reported with SSRIs and SNRIs, including Duloxetine, both when taken alone, but especially when co-administered with other serotonergic agents (including Triptans, Tricyclic antidepressants, Fentanyl, Lithium, Tramadol, Tryptophan, Buspirone and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOI, both those intended to treat psychiatric disorders and also others, such as Linezolid and intravenous Methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).If such symptoms occur, discontinue Duloxetine and initiate supportive treatment. If concomitant use of Duloxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases
- Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, Aspirin, Warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding
- Severe Skin Reactions: Stevens-Johnson syndrome (serious illness with blistering of the skin, mouth, eyes and genitals), serious allergic reaction which causes swelling of the face or throat (angioedema) are rare side effects (may affects 1 to 10 users in 10,000). Duloxetine should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.
- Use with caution in patients with a history of seizures
- Blood Pressure: Cases of hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing hypertension. Monitor blood pressure prior to initiating treatment and periodically throughout treatment
- Hyponatremia: Hyponatremia has been reported with Duloxetine use, either alone or in combination with some diuretics (Hydrochlorothiazide, Furosemide). Hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Signs and symptoms include headache, new or increased seizure frequency, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to fall. Severe Hyponatremia may cause hallucination, syncope, seizure, coma, respiratory arrest, and death.
- Mydriasis has been reported in association with duloxetine, therefore, caution should be used in patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.
- Duloxetine affect urethral resistance and can cause urinary hesitation and retention
- Monoamine oxidase inhibitors (MAOIs): Risk of serotonin syndrome (Contraindicated)
- Serotonergic medicinal products: Rare cases of Serotonin syndrome (See WARNINGS AND PRECAUTIONS)
- Potent inhibitors of CYP1A2 (e.g. Fluvoxamine): Increased Duloxetine plasma levels (should be avoided)
- Potent inhibitors of CYP2D6 may increase duloxetine concentrations
- Duloxetine is a moderate inhibitor of CYP2D6 : Caution is advised when co-administered with drugs that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (such as flecainide, propafenone and metoprolol).
 PREGNANCY AND LACTATION
- Pregnancy Category C (US). There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Nursing mothers: Duloxetine is excreted into the milk of lactating women. Because the safety of duloxetine in infants is not known, nursing while on Duloxetine is not recommended
 SIDE EFFECTS
Most common adverse reactions: nausea, dry mouth, somnolence, dizziness, constipation, decreased appetite, headache, fatigue and hyperhidrosis .
The majority of common adverse reactions were mild to moderate, they usually started early in therapy, and most tended to subside even as therapy was continued.
For more serious adverse effects see WARNINGS AND PRECAUTIONS
 RELATED LINKS
|Tricyclic antidepressants||Amitriptyline (Elavil, Laroxyl) • Clomipramine (Anafranil) • Doxepin (Sinequan) • Imipramine (Tofranil) • Nortriptyline (Aventyl, Pamelor) • Trimipramine (Surmontil)|
|Selective serotonin reuptake inhibitors (SSRIs)||Citalopram (Celexa, Seropram) • Escitalopram (Cipralex, Lexapro) • Fluoxetine (Prozac) • Fluvoxamine (Luvox, Maveral) • Paroxetine (Paxil, Seroxat) • Sertraline (Zoloft)|
|Serotonin–norepinephrine reuptake inhibitors (SNRIs)||Desvenlafaxine (Pristiq) • Duloxetine (Cymbalta, Xeristar) • Venlafaxine (Efexor, Effexor)|
|Serotonin antagonists and reuptake inhibitors (SARIs)||Trazodone (Desyrel, Oleptro)|
|Norepinephrine reuptake inhibitors (NRIs)||Maprotiline (Ludiomil) • Reboxetine (Edronax)|
|Norepinephrine-dopamine reuptake inhibitors (NDRIs)||Bupropion (Wellbutrin)|
|Noradrenergic and specific serotonergic antidepressants (NaSSAs)||Mianserin (Lantanon) • Mirtazapine (Remeron)|
|Norepinephrine-dopamine disinhibitors (NDDIs)||Agomelatine (Valdoxan, Thymanax)|
|Monoamine oxidase inhibitors Nonselective||Tranylcypromine (Parnate)|
|Monoamine oxidase inhibitors B-Selective||Selegiline (Transdermal) (Emsam)|
|Others||5-Hydroxytryptophan • S-Adenosyl methionine • Hypericum (St John's wort)|