Duloxetine

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Duloxetine quick reference

Duloxetine
Duloxetine general drug information
 Pronunciation doo LOX e teen (.wav file)
 Trade Name(s) Cymbalta
 How Supplied Capsules: 20 mg, 30 mg, 60 mg
 Generic Availability No generics available
 Patent Expiry Date July 18, 2014
 Classification Selective serotonin and norepinephrine reuptake inhibitor (SSNRI)
 Schedule Rx
 Pregnancy Category C
 Breast-feeding Duloxetine should not be used while breastfeeding.
Duloxetine chemical information
 IUPAC Name (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride
 Empirical Formula C18H19NOS•HCl
 Molecular Weight 333.88 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that is supplied as an oral capsule. It was approved for depression on August 3, 2004 and on September 28, 2004 it was approved for pain caused from diabetic neuropathy. In February 2007, it was approved for generalized anxiety disorder in patients 18 years and older.[1] This drug carries a Black Box warning for risk of suicidality in children and adolescents with major depressive disorder. It is important to monitor any child and adolescents put on this medication for worsening of depression or thoughts of suicide.[2]

A meta-analysis of studies involving duloxetine (9 studies), fluoxetine (22 studies) and venlafaxine (8 studies) for Major Depressive Disorder found that duloxetine and fluoxetine were comparable in tolerability and efficacy. Venlafaxine was found to be more effective, though it had a higher dropout rate than duloxetine.[3] A second meta-analysis found that extended-release venlafaxine was preferred in terms of rates of remission and response rates in Major Depressive Disorder.[4] A randomized controlled trial is needed to confirm these results.

Mechanism of Action

Duloxetine has been shown to be a potent inhibitor of serotonin and norepinephrine reuptake at the central nervous system. It is more effective at inhibiting the reuptake of serotonin than norepinephrine. It appears to be only a mild inhibitor of dopamine reuptake. It does not inhibit monoamine oxidase. The exact mechanism of duloxetine is unknown.[2]

Time Required for Therapeutic Response

  • Initial: 1-4 weeks to see improvement.[5]
  • Maximum: May take up to 4 to 6 weeks.

Pharmacokinetics

Absorption
After Duloxetine is taken orally, there is a 2-hour lag time before absorption begins. This is because the drug is enteric coated so that it is not broken down in the stomach. The maximal concentrations occur 6 hours after the dose is consumed. When duloxetine is taken with food, the maximum concentrations are prolonged until 10 hours. Additionally, morning versus evening dosing appears to play a role in the PK of duloxetine. When duloxetine is taken in the evening, there is a three hour delay in absorption and a 33% increase in the clearance.[2][6]

Distribution
The volume of distribution is approximately 1640 L. The protein binding of duloxetine is greater than 90%, with the principal binding to albumin and alpha1-acid glycoprotein.[2]

Metabolism
Duloxetine is metabolized by CYP 2D6 and 1A2. These two cytochrome enzymes are responsible for the oxidation of the naphthyl ring of duloxetine. The metabolites include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. There are numerous other metabolites which have been found in the urine.[2][7]

Excretion
70% of duloxetine is found in the urine as metabolites. 20% of duloxetine is excreted in the feces.[6]

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Special Population Pharmacokinetics

  • Renal insufficiency: Duloxetine is not recommended for patients with a creatinine clearance <30 ml/min.
  • Hepatic insufficiency: When patients with moderate liver impairment (Child-Pugh Class B) were given one 20 mg dose of duloxetine, their AUC increased 5-fold. The clearance was 15% of that in patients with normal hepatic function. Based on this PK study, the manufacturer recommends against using duloxetine in patients with any hepatic dysfunction.[2]
  • Hemodialysis: When patients with end stage renal disease receiving hemodialysis were given one 60 mg dose of duloxetine, the area under the curve (AUC) was 100% higher when compared to patients with normal renal function.[2]
  • Geriatric: The maximum concentrations of duloxetine were the same between elderly and middle aged females, though the AUC of duloxetine was 25% higher and the half life was 4 hours longer in the geriatric female population studied.[2]
  • Pediatric: No data.
  • Gender: The PK is unchanged.[2][8]
  • Smoking: Smokers have a 33% decrease in their AUC.

Indications and Dosages

FDA Approved Indications

Generalized anxiety disorder[9]

  • Starting dose:
    • 30 mg daily for 1 week, then titrate up as necessary
  • Maintenance dose:
    • 60 mg daily
    • Dosages up to 120 mg/day have been studied, however, no greater benefit over 60 mg/day was realized.
  • Titration schedule: Dosage increases should be made in increments of 30 mg/day.

Major depressive disorder[10][11]

  • Starting dose:
    • 40-60 mg daily
    • May be taken as a single dose or in two divided doses based on patient tolerability.
  • Maintenance dose:
    • Most typical maintenance dose is 60 mg daily
    • Dosages up to 120 mg/day have been studied, however, no greater benefit over 60 mg/day was realized.
  • Titration schedule: Dosage increases should be made in increments of 30 mg/day.

Diabetic peripheral neuropathy[12][13][14]

  • Starting dose:
    • 60 mg daily
    • May start at a lower dose if tolerability is of concern.
    • May be taken as a single dose or in two divided doses based on patient tolerability.
  • Maintenance dose:
    • May increase up to 60 mg twice a day.
    • No greater benefit over 60 mg/day was realized, and the 120 mg/day dose was not tolerated as well.
  • Titration schedule: Initial starting dose should be lower and drug should be titrated slowly if using in patient with renal impairment.

Non-FDA Approved Indications

Dosage Adjustment

Renal insufficiency: Do not use in patients with CrCl <30 mL/min[17]
Hepatic insufficiency: Do not use in patients with any hepatic impairment.[17]
Hemodialysis: Not recommended for patients on hemodialysis.[17]
Geriatric: No dosage adjustment needed. Monitor renal function.[17]
Pediatric: No data.

Dosage Limits

  • Adults: 60 mg/day (dosages up to 120 mg/day have been assayed, though no clinical benefit was noted)
  • Elderly: 60 mg/day (dosages up to 120 mg/day have been assayed, though no clinical benefit was noted)
  • Adolescents and children: no data


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Administration

  • Route: Oral
  • Method:
    • Swallow the capsule whole with a drink of water.
    • Do not cut, open or chew capsules.
    • Duloxetine capsules cannot be opened and sprinkled on food.

Monitoring Parameters

  • Depression which is getting worse
  • Suicidal ideation
  • Liver function tests; baseline and periodically throughout treatment
  • Blood pressure; measure before starting treatment and throughout treatment

Contraindications/Precautions

Contraindications

  • Known hypersensitivity to duloxetine or to any of the inactive ingredients.
  • Concurrent monoamine oxidase inhibitor use: duloxetine should not be used with monoamine oxidase inhibitors including isocarboxazid, phenelzine, selegiline or tranycypomine. This combination can lead to serotonin syndrome and may progress to hyperthermia, delirium, coma and death. MAOIs should be stopped 14 days before starting duloxetine. Duloxetine should be stopped for a minimum of five days before starting an MAOI.
  • Uncontrolled narrow-angle glaucoma
  • End-stage renal disease (CrCl <30 ml/min)
  • Hepatic insufficiency

Precautions

  • Black Box warning for the increase in suicide risk in children and adolescents. Adults and children may have an increase in suicidal intention and exacerbated depression when starting on this drug. Careful monitoring is essential.
  • Alcoholism or chronic liver disease: Duloxetine may increase serum transaminase levels (3 times UNL occurred in 0.9% of patients in clinical trials, with a mean time to elevation of two months). Post-marketing reports have described hepatitis, abdominal pain, hepatomegaly and increased transaminases to greater than 20 times the upper limit of normal. Additionally there have been cases of cholestatic jaundice with or without increases in transaminases.[2][20]
  • Orthostatic hypotension or syncope: This is especially of concern when initiating therapy or when changing doses. The risk of a drop of blood pressure is greater in patients who are also taking antidepressants or who are taking CYP 1A2 inhibitors.[2]
  • Hypertension: Duloxetine has been associated with an increase in BP up to 2.1 mmHg for systolic and 2.3mmHg for diastolic blood pressure.[2]
  • Bipolar disorder or mania
  • Seizure disorder: It is unknown how duloxetine will impact patients with a history of seizures. Use caution when prescribing. Seizures occurred in 0.04% of patients treated with duloxetine and 0.02% of patients treated with placebo in clinical trials.[2]
  • Hyponatremia
  • Controlled narrow-angle glaucoma: This population should not be prescribed duloxetine without careful clinical examination. Duloxetine increases the chances of mydriasis.[2]
  • Discontinuation of duloxetine: When duloxetine is discontinued, side effects such as dizziness, nausea, headache, paresthesia, vomiting and abnormal dreams are more prevalent than with placebo. Use a gradual dose reduction to safely titrate a patent off of duloxetine.[2][14]
  • Diabetes: The fasting blood glucose may be increased in patients treated with duloxetine. The mean fasting blood glucose in a 52 week clinical trial increased 12 mg/dL and in the placebo group decreased by 11.5 mg/dL. The HbA1c increased by 0.5% in the duloxetine group and by 0.2% in the placebo group.[2] In an analysis of three studies of 1,024 patients treated for diabetic peripheral neuropathy, the fasting glucose increased 0.50 mmol/L for patients treated with duloxetine for 12 weeks and increased 0.67 mmol/L in patients treated for one year.[21]

Pregnancy indications

Category C

When mice were given duloxetine at 11 times the maximum recommended dose for two years, there was an increased risk for hepatocellular adenomas and carcinomas.

Breast-feeding indications

Duloxetine is excreted in breast milk. Steady state concentrations are approximately 25% of those in plasma. This drug should not be used in mothers who are breastfeeding.[2]

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Duloxetine had a 10% discontinuation rate compared to 4% discontinuation rate in 1139 patients assayed in placebo controlled trials for major depressive disorder. The principle reason for discontinuation was largely nausea. Duloxetine had a 14% discontinuation rate in the 568 patients treated for diabetic peripheral neuropathy compared with a 7% rate of discontinuation for placebo. The reasons for stopping therapy with duloxetine included nausea, dizziness, somnolence and fatigue. Duloxetine was discontinued in 16% of patients (n=668) taking it for generalized anxiety disorder while 4% stopped in the placebo group. The reasons for discontinuation include nausea, vomiting, and dizziness.[2]

The most commonly complained of side effects include dry mouth, constipation, lowered appetite, fatigue, somnolence and elevated sweating.[2]

Duloxetine Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Nausea (14-38%), dry mouth (5-15%), constipation (11-15%), insomnia (11-13%), headache (13-15%) dizziness (9%-17%)
1-10% CNS Fatigue (8%-12%), somnolence (7%-21%), tremor (3-5%)
Cardiovascular Increased blood pressure
Dermatologic Hyperhidrosis (6-8%), increased sweating (6%), flushing (2%)
GI Diarrhea (8%), vomiting (5%), lowered appetite (8%), weight decreased (2%), dyspepsia (4%)
Genitourinary Pollakiuria (1-5%), orgasm abnormal (4%), libido decreased (3%), erectile dysfunction (4%)
Neuromuscular/skeletal Muscle cramps (4-5%), myalgia (1-4%)
Respiratory Nasopharyngitis (7-9%), cough (3-6%), pharyngolaryngeal pain (1-6%)
Miscellaneous Blurry vision (4%), anxiety (3%), pyrexia (3%)
<1% All Increased LFTs, urinary hesitation, hypertension, weight gain, palpitations, vertigo, abdominal pain, flatulence, chills, rigors, lethargy, dysuria, nocturia, micturation urgency, urinary incontinence, yawing, pruritis, rash

Overdosage Measures

There have been case reports that ingestion of 1000 mg of duloxetine can be fatal. The symptoms of overdose are consistent with serotonin syndrome, somnolence, vomiting and seizure activity.
Treatment:

  • Aimed at symptom control.
  • If serotonin syndrome is likely, cyproheptadine and temperature control may be initiated. The patient’s airway should be protected and cardiac monitoring should be instituted. Activated charcoal may be helpful in decreasing the absorption of duloxetine.[2]
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
20 mg capsule green/green capsule 20 mg/LILLY 3235
30 mg capsule white/dark blue capsule 30 mg/LILLY 3240
60 mg capsule green/dark blue capsule 60 mg/LILLY 3237
  • Inactive ingredients for capsules: FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, yellow iron oxide (20 mg and 60 mg capsules only)

Patient Information

  • Give a medication guide for children and teenagers, available on back of the package insert.
  • There is a risk of increased depression and suicide risk when starting this drug. Instruct the patient, family and/or caregivers to look for signs of worsening depression such as increased anxiety, agitation, panic attacks, insomnia, irritability, hostility, restlessness, mania, hypomania, or changes in behavior. If one of these signs is noted they should call their doctor or pharmacist right away.
  • Do not open the capsules; they must be swallowed whole with a drink of water.
  • May cause dizziness and drowsiness, use caution when driving or operating heavy machinery.
  • Do not drink alcohol; the combination can lead to liver injury.
  • Educate patient in the signs and symptoms of serotonin syndrome].
  • Caution patient to use extra care when standing because duloxetine may cause orthostatic hypotension, especially during duloxetine initiation.
  • Tell your healthcare professional right away if you are pregnant, plan on becoming pregnant, or are breast feeding.[2]
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References

  1. ↑ FDA approves antidepressant Cymbalta (duloxetine HCl) for treatment of generalized anxiety disorder. News Medical.net 26 Feb. 2007 [cited 10 March 2007]; Available from: http://www.news-medical.net/?id=22194
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 Eli Lilly and Company. Duloxetine Package Insert. Indianapolis, IN 46285; 2007.
  3. ↑ Eckert L, Lancon C. Duloxetine compared with fluoxetine and venlafaxine: use of meta-regression analysis for indirect comparisons. BMC psychiatry. 2006;6:30.
  4. ↑ Vis PM, van Baardewijk M, Einarson TR. Duloxetine and venlafaxine-XR in the treatment of major depressive disorder: a meta-analysis of randomized clinical trials. The Annals of Pharmacotherapy. 2005 Nov;39(11):1798-807.
  5. ↑ Hirschfeld RM, Mallinckrodt C, Lee TC, Detke MJ. Time course of depression-symptom improvement during treatment with duloxetine. Depression and anxiety. 2005;21(4):170-7.
  6. ↑ 6.0 6.1 Lantz RJ, Gillespie TA, Rash TJ, Kuo F, Skinner M, Kuan H-Y, et al. Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. Drug Metab Dispos 2003;31:1142-50.
  7. ↑ Skinner MH, Kuan HY, Pan A, Sathirakul K, Knadler MP, Gonzales CR, et al. Duloxetine is both an inhibitor an a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003;73(3):170-7.
  8. ↑ Kornstein SG, Wohlreich MM, Mallinckrodt CH, Watkin JG, Stewart DE. Duloxetine efficacy for major depressive disorder in male vs. female patients: data from 7 randomized, double-blind, placebo-controlled trials. The Journal of clinical psychiatry. 2006 May;67(5):761-70.
  9. ↑ FDA approves antidepressant Cymbalta (duloxetine HCl) for treatment of generalized anxiety disorder. News Medical.net 26 Feb. 2007 [cited 10 March 2007]; Available from: http://www.news-medical.net/?id=22194
  10. ↑ Perahia DG, Kajdasz DK, Royer MG, Walker DJ, Raskin J. Duloxetine in the treatment of major depressive disorder: an assessment of the relationship between outcomes and episode characteristics. International clinical psychopharmacology. 2006 Sep;21(5):285-95.
  11. ↑ Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. Duloxetine in the long-term treatment of major depressive disorder. The Journal of clinical psychiatry. 2003 Oct;64(10):1237-44.
  12. ↑ Wernicke JF, Pritchett YL, D'Souza DN, Waninger A, Tran P, Iyengar S, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006 Oct 24;67(8):1411-20.
  13. ↑ Raskin J, Wang F, Pritchett YL, Goldstein DJ. Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study. Pain medicine (Malden, Mass. 2006 Sep-Oct;7(5):373-85.
  14. ↑ 14.0 14.1 Perahia DG, Kajdasz DK, Desaiah D, Haddad PM. Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. Journal of affective disorders. 2005 Dec;89(1-3):207-12.
  15. ↑ Littlejohn GO, Guymer EK. Fibromyalgia syndrome: which antidepressant drug should we choose. Current pharmaceutical design. 2006;12(1):3-9.
  16. ↑ Arnold LM, Rosen A, Pritchett YL, D'Souza DN, Goldstein DJ, Iyengar S, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005 Dec 15;119(1-3):5-15.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 Criteria for nonformulary use of duloxetine. 17 October 2005 [cited 10 March 2007];Available from:http://www.pbm.va.gov/criteria/Duloxetine.pdf.
  18. ↑ Guay DR. Duloxetine for management of stress urinary incontinence. The American journal of geriatric pharmacotherapy. 2005 Mar;3(1):25-38.
  19. ↑ Mariappan P, Ballantyne Z, N'Dow JM, Alhasso AA. Serotonin and noradrenaline reuptake inhibitors (SNRI) for stress urinary incontinence in adults. Cochrane database of systematic reviews (Online). 2005(3):CD004742.
  20. ↑ Hanje AJ, Pell LJ, Votolato NA, Frankel WL, Kirkpatrick RB. Case report: fulminant hepatic failure involving duloxetine hydrochloride. Clin Gastroenterol Hepatol. 2006 Jul;4(7):912-7.
  21. ↑ Hardy T, Sachson R, Shen S, Armbruster M, Boulton AJ. Does treatment with duloxetine for neuropathic pain impact glycemic control? Diabetes care. 2007 Jan;30(1):21-6.

PUBMED References

Efficacy Trial Articles

  1. Wernicke JF, Pritchett YL, D'Souza DN, Waninger A, Tran P, Iyengar S, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006 Oct 24;67(8):1411-20.
  2. Raskin J, Wang F, Pritchett YL, Goldstein DJ. Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study. Pain medicine (Malden, Mass. 2006 Sep-Oct;7(5):373-85.
  3. Perahia DG, Kajdasz DK, Royer MG, Walker DJ, Raskin J. Duloxetine in the treatment of major depressive disorder: an assessment of the relationship between outcomes and episode characteristics. International clinical psychopharmacology. 2006 Sep;21(5):285-95.
  4. Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. Duloxetine in the long-term treatment of major depressive disorder. The Journal of clinical psychiatry. 2003 Oct;64(10):1237-44.
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Therapeutic Class Comparison Articles

  1. Eckert L, Lancon C. Duloxetine compared with fluoxetine and venlafaxine: use of meta-regression analysis for indirect comparisons. BMC psychiatry. 2006;6:30.
  2. Vis PM, van Baardewijk M, Einarson TR. Duloxetine and venlafaxine-XR in the treatment of major depressive disorder: a meta-analysis of randomized clinical trials. The Annals of pharmacotherapy. 2005 Nov;39(11):1798-807.

Pharmacokinetics Articles

  1. Bymaster FP, Lee TC, Knadler MP, Detke MJ, Iyengar S. The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Current pharmaceutical design. 2005;11(12):1475-93.
  2. Lantz RJ, Gillespie TA, Rash TJ, Kuo F, Skinner M, Kuan HY, et al. Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. Drug metabolism and disposition: the biological fate of chemicals. 2003 Sep;31(9):1142-50.
  3. Sharma A, Goldberg MJ, Cerimele BJ. Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol. 2000 Feb;40(2):161-7.
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Drug Interaction Articles

  1. Skinner MH, Kuan HY, Pan A, Sathirakul K, Knadler MP, Gonzales CR, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clinical pharmacology and therapeutics. 2003 Mar;73(3):170-7.

Adverse Effects Articles

  1. Hardy T, Sachson R, Shen S, Armbruster M, Boulton AJ. Does treatment with duloxetine for neuropathic pain impact glycemic control? Diabetes care. 2007 Jan;30(1):21-6.
  2. Hanje AJ, Pell LJ, Votolato NA, Frankel WL, Kirkpatrick RB. Case report: fulminant hepatic failure involving duloxetine hydrochloride. Clin Gastroenterol Hepatol. 2006 Jul;4(7):912-7.
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Compliance Articles

Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

Patient information pages

Other resources

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