Peringatan Keamanan

Overdose

Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone.label Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated.

Carcinogenicity & Mutagenicity

Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD).label No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD).

No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations.

Reproductive Toxicity

Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD).label

Lactation

An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose.label Breast milk concentrations have been observed to peak 3 hours after administration.

Duloxetine

DB00476

small molecule approved

Deskripsi

Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor.label It was originally discovered in 1993 and developed by Eli Lilly and Company as LY248686.A178741 Duloxetine first received approval from the FDA in August, 2004 as Cymbalta for the treatment of Major Depressive Disorder.L6454 It has since received approval for a variety of indications including the treatment of neuropathic pain, Generalized Anxiety disorder, osteoarthritis, and stress incontinence. Duloxetine continues to be investigated for the treatment of pain in cancer, surgery, and more.

Struktur Molekul 2D

Berat 297.415
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Mean of 12 h with a range of 8-17.[label,A14807]
Volume Distribusi Apparent Vd of 1620-1800 L.[label,A14807] Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma.[A14807]
Klirens (Clearance) There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h.[A14807] Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively.

Absorpsi

Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%.A14807 The population absorption constant (ka) is 0.168 h-1.The molecule is susceptible to hydrolysis in acidic environments necessitating the use of an enteric coating to protect it during transit through the stomach. This creates a 2 hour lag time from administration to the start of absorption. The Tmax is 6 hours including the lag time.label Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax.A14807 These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree.

Metabolisme

Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor.label,A14807 It is hydroxylated at the 4, 5, or 6 positions on the naphthalene ring with the 4-hydroxy metabolite proceeding directly to a glucuronide conjugate while the 5 and 6-hydroxy metabolites proceed through a catechol and a 5-hydroxy, 6-methoxy intermediate before undergoing glucuronide or sulfate conjugation. CYP2C9 is known to be a minor contributor to the 5-hydroxy metabolite. Another uncharacterized metabolite is known to be excreted in the feces but comprises <5% of the total excreted drug. Many other metabolites exist but have not been identified due their low contribution to the overall profile of duloxetine and lack of clinical significance.

Rute Eliminasi

About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites.label Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite.label,A14807 Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit.A14807

Interaksi Makanan

2 Data
  • 1. Avoid excessive or chronic alcohol consumption. Alcohol increases the risk of liver toxicity.
  • 2. Take with or without food. Do not sprinkle the contents of the capsules on food/liquids.

Interaksi Obat

1964 Data
Aldesleukin The risk or severity of orthostatic hypotension and syncope can be increased when Aldesleukin is combined with Duloxetine.
Streptokinase The risk or severity of orthostatic hypotension and syncope can be increased when Streptokinase is combined with Duloxetine.
Valsartan The risk or severity of orthostatic hypotension and syncope can be increased when Valsartan is combined with Duloxetine.
Ramipril The risk or severity of orthostatic hypotension and syncope can be increased when Ramipril is combined with Duloxetine.
Esmolol The risk or severity of orthostatic hypotension and syncope can be increased when Esmolol is combined with Duloxetine.
Betaxolol The risk or severity of orthostatic hypotension and syncope can be increased when Betaxolol is combined with Duloxetine.
Reserpine The risk or severity of orthostatic hypotension and syncope can be increased when Reserpine is combined with Duloxetine.
Torasemide The risk or severity of orthostatic hypotension and syncope can be increased when Torasemide is combined with Duloxetine.
Methyclothiazide The risk or severity of orthostatic hypotension and syncope can be increased when Methyclothiazide is combined with Duloxetine.
Metoprolol The risk or severity of orthostatic hypotension and syncope can be increased when Metoprolol is combined with Duloxetine.
Ropinirole The risk or severity of orthostatic hypotension and syncope can be increased when Ropinirole is combined with Duloxetine.
Isradipine The risk or severity of orthostatic hypotension and syncope can be increased when Isradipine is combined with Duloxetine.
Olmesartan The risk or severity of orthostatic hypotension and syncope can be increased when Olmesartan is combined with Duloxetine.
Morphine The risk or severity of orthostatic hypotension and syncope can be increased when Morphine is combined with Duloxetine.
Ropivacaine The risk or severity of orthostatic hypotension and syncope can be increased when Ropivacaine is combined with Duloxetine.
Bupivacaine The risk or severity of orthostatic hypotension and syncope can be increased when Bupivacaine is combined with Duloxetine.
Chlorthalidone The risk or severity of orthostatic hypotension and syncope can be increased when Chlorthalidone is combined with Duloxetine.
Tolcapone The risk or severity of orthostatic hypotension and syncope can be increased when Tolcapone is combined with Duloxetine.
Nitroprusside The risk or severity of orthostatic hypotension and syncope can be increased when Nitroprusside is combined with Duloxetine.
Olanzapine The risk or severity of orthostatic hypotension and syncope can be increased when Olanzapine is combined with Duloxetine.
Atenolol The risk or severity of orthostatic hypotension and syncope can be increased when Atenolol is combined with Duloxetine.
Diltiazem The risk or severity of orthostatic hypotension and syncope can be increased when Diltiazem is combined with Duloxetine.
Minoxidil The risk or severity of orthostatic hypotension and syncope can be increased when Minoxidil is combined with Duloxetine.
Clozapine The serum concentration of Clozapine can be increased when it is combined with Duloxetine.
Amlodipine The risk or severity of orthostatic hypotension and syncope can be increased when Amlodipine is combined with Duloxetine.
Triamterene The risk or severity of orthostatic hypotension and syncope can be increased when Triamterene is combined with Duloxetine.
Nimodipine The risk or severity of orthostatic hypotension and syncope can be increased when Nimodipine is combined with Duloxetine.
Nisoldipine The risk or severity of orthostatic hypotension and syncope can be increased when Nisoldipine is combined with Duloxetine.
Pramipexole The risk or severity of orthostatic hypotension and syncope can be increased when Pramipexole is combined with Duloxetine.
Spironolactone The risk or severity of orthostatic hypotension and syncope can be increased when Spironolactone is combined with Duloxetine.
Nitric Oxide The risk or severity of orthostatic hypotension and syncope can be increased when Nitric Oxide is combined with Duloxetine.
Bendroflumethiazide The risk or severity of orthostatic hypotension and syncope can be increased when Bendroflumethiazide is combined with Duloxetine.
Prazosin The risk or severity of orthostatic hypotension and syncope can be increased when Prazosin is combined with Duloxetine.
Imipramine The risk or severity of orthostatic hypotension and syncope can be increased when Imipramine is combined with Duloxetine.
Chlorpromazine The risk or severity of orthostatic hypotension and syncope can be increased when Chlorpromazine is combined with Duloxetine.
Nabilone The risk or severity of orthostatic hypotension and syncope can be increased when Nabilone is combined with Duloxetine.
Sotalol The risk or severity of orthostatic hypotension and syncope can be increased when Sotalol is combined with Duloxetine.
Fosinopril The risk or severity of orthostatic hypotension and syncope can be increased when Fosinopril is combined with Duloxetine.
Trandolapril The risk or severity of orthostatic hypotension and syncope can be increased when Trandolapril is combined with Duloxetine.
Metolazone The risk or severity of orthostatic hypotension and syncope can be increased when Metolazone is combined with Duloxetine.
Lercanidipine The risk or severity of orthostatic hypotension and syncope can be increased when Lercanidipine is combined with Duloxetine.
Benazepril The risk or severity of orthostatic hypotension and syncope can be increased when Benazepril is combined with Duloxetine.
Propranolol The risk or severity of orthostatic hypotension and syncope can be increased when Propranolol is combined with Duloxetine.
Enalapril The risk or severity of orthostatic hypotension and syncope can be increased when Enalapril is combined with Duloxetine.
Doxazosin The risk or severity of orthostatic hypotension and syncope can be increased when Doxazosin is combined with Duloxetine.
Amiloride The risk or severity of orthostatic hypotension and syncope can be increased when Amiloride is combined with Duloxetine.
Labetalol The risk or severity of orthostatic hypotension and syncope can be increased when Labetalol is combined with Duloxetine.
Thiopental The risk or severity of orthostatic hypotension and syncope can be increased when Thiopental is combined with Duloxetine.
Bisoprolol The risk or severity of orthostatic hypotension and syncope can be increased when Bisoprolol is combined with Duloxetine.
Nicardipine The risk or severity of orthostatic hypotension and syncope can be increased when Nicardipine is combined with Duloxetine.
Clofarabine The risk or severity of orthostatic hypotension and syncope can be increased when Clofarabine is combined with Duloxetine.
Dexmedetomidine The risk or severity of orthostatic hypotension and syncope can be increased when Dexmedetomidine is combined with Duloxetine.
Mecamylamine The risk or severity of orthostatic hypotension and syncope can be increased when Mecamylamine is combined with Duloxetine.
Verapamil The risk or severity of orthostatic hypotension and syncope can be increased when Verapamil is combined with Duloxetine.
Losartan The risk or severity of orthostatic hypotension and syncope can be increased when Losartan is combined with Duloxetine.
Thioridazine The risk or severity of orthostatic hypotension and syncope can be increased when Thioridazine is combined with Duloxetine.
Amphotericin B The risk or severity of orthostatic hypotension and syncope can be increased when Amphotericin B is combined with Duloxetine.
Moexipril The risk or severity of orthostatic hypotension and syncope can be increased when Moexipril is combined with Duloxetine.
Phentolamine The risk or severity of orthostatic hypotension and syncope can be increased when Phentolamine is combined with Duloxetine.
Furosemide The risk or severity of orthostatic hypotension and syncope can be increased when Furosemide is combined with Duloxetine.
Tizanidine The risk or severity of orthostatic hypotension and syncope can be increased when Tizanidine is combined with Duloxetine.
Eplerenone The risk or severity of orthostatic hypotension and syncope can be increased when Eplerenone is combined with Duloxetine.
Methazolamide The risk or severity of orthostatic hypotension and syncope can be increased when Methazolamide is combined with Duloxetine.
Tamsulosin The risk or severity of orthostatic hypotension and syncope can be increased when Tamsulosin is combined with Duloxetine.
Sufentanil The risk or severity of orthostatic hypotension and syncope can be increased when Sufentanil is combined with Duloxetine.
Apomorphine The risk or severity of orthostatic hypotension and syncope can be increased when Apomorphine is combined with Duloxetine.
Lisinopril The risk or severity of orthostatic hypotension and syncope can be increased when Lisinopril is combined with Duloxetine.
Nitroglycerin The risk or severity of orthostatic hypotension and syncope can be increased when Nitroglycerin is combined with Duloxetine.
Mannitol The risk or severity of orthostatic hypotension and syncope can be increased when Mannitol is combined with Duloxetine.
Isoflurane The risk or severity of orthostatic hypotension and syncope can be increased when Isoflurane is combined with Duloxetine.
Hydroflumethiazide The risk or severity of orthostatic hypotension and syncope can be increased when Hydroflumethiazide is combined with Duloxetine.
Perindopril The risk or severity of orthostatic hypotension and syncope can be increased when Perindopril is combined with Duloxetine.
Candesartan cilexetil The risk or severity of orthostatic hypotension and syncope can be increased when Candesartan cilexetil is combined with Duloxetine.
Tolazoline The risk or severity of orthostatic hypotension and syncope can be increased when Tolazoline is combined with Duloxetine.
Fenoldopam The risk or severity of orthostatic hypotension and syncope can be increased when Fenoldopam is combined with Duloxetine.
Indapamide The risk or severity of orthostatic hypotension and syncope can be increased when Indapamide is combined with Duloxetine.
Propofol The risk or severity of orthostatic hypotension and syncope can be increased when Propofol is combined with Duloxetine.
Conivaptan The risk or severity of orthostatic hypotension and syncope can be increased when Conivaptan is combined with Duloxetine.
Eprosartan The risk or severity of orthostatic hypotension and syncope can be increased when Eprosartan is combined with Duloxetine.
Chlorothiazide The risk or severity of orthostatic hypotension and syncope can be increased when Chlorothiazide is combined with Duloxetine.
Quinapril The risk or severity of orthostatic hypotension and syncope can be increased when Quinapril is combined with Duloxetine.
Isosorbide dinitrate The risk or severity of orthostatic hypotension and syncope can be increased when Isosorbide dinitrate is combined with Duloxetine.
Bumetanide The risk or severity of orthostatic hypotension and syncope can be increased when Bumetanide is combined with Duloxetine.
Remifentanil The risk or severity of orthostatic hypotension and syncope can be increased when Remifentanil is combined with Duloxetine.
Etacrynic acid The risk or severity of orthostatic hypotension and syncope can be increased when Etacrynic acid is combined with Duloxetine.
Levosimendan The risk or severity of orthostatic hypotension and syncope can be increased when Levosimendan is combined with Duloxetine.
Phenoxybenzamine The risk or severity of orthostatic hypotension and syncope can be increased when Phenoxybenzamine is combined with Duloxetine.
Pindolol The risk or severity of orthostatic hypotension and syncope can be increased when Pindolol is combined with Duloxetine.
Telmisartan The risk or severity of orthostatic hypotension and syncope can be increased when Telmisartan is combined with Duloxetine.
Methyldopa The risk or severity of orthostatic hypotension and syncope can be increased when Methyldopa is combined with Duloxetine.
Dipyridamole The risk or severity of orthostatic hypotension and syncope can be increased when Dipyridamole is combined with Duloxetine.
Hydrochlorothiazide The risk or severity of orthostatic hypotension and syncope can be increased when Hydrochlorothiazide is combined with Duloxetine.
Levobupivacaine The risk or severity of orthostatic hypotension and syncope can be increased when Levobupivacaine is combined with Duloxetine.
Guanfacine The risk or severity of orthostatic hypotension and syncope can be increased when Guanfacine is combined with Duloxetine.
Isosorbide mononitrate The risk or severity of orthostatic hypotension and syncope can be increased when Isosorbide mononitrate is combined with Duloxetine.
Felodipine The risk or severity of orthostatic hypotension and syncope can be increased when Felodipine is combined with Duloxetine.
Irbesartan The risk or severity of orthostatic hypotension and syncope can be increased when Irbesartan is combined with Duloxetine.
Nitrendipine The risk or severity of orthostatic hypotension and syncope can be increased when Nitrendipine is combined with Duloxetine.
Iloprost The risk or severity of orthostatic hypotension and syncope can be increased when Iloprost is combined with Duloxetine.
Papaverine The risk or severity of orthostatic hypotension and syncope can be increased when Papaverine is combined with Duloxetine.

Target Protein

Sodium-dependent serotonin transporter SLC6A4
Sodium-dependent noradrenaline transporter SLC6A2
Sodium-dependent dopamine transporter SLC6A3

Referensi & Sumber

Synthesis reference: Richard A. Berglund, "Intermediate useful for the asymmetric synthesis of duloxetine." U.S. Patent US5491243, issued June, 1991.
Artikel (PubMed)
  • PMID: 11282251
    Turcotte JE, Debonnel G, de Montigny C, Hebert C, Blier P: Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology. 2001 May;24(5):511-21.
  • PMID: 12211418
    Anttila S, Leinonen E: Duloxetine Eli Lilly. Curr Opin Investig Drugs. 2002 Aug;3(8):1217-21.
  • PMID: 12481192
    Karpa KD, Cavanaugh JE, Lakoski JM: Duloxetine pharmacology: profile of a dual monoamine modulator. CNS Drug Rev. 2002 Winter;8(4):361-76.
  • PMID: 2784100
    van Groeningen CJ, Peters GJ, Pinedo HM: Lack of effectiveness of combined 5-fluorouracil and leucovorin in patients with 5-fluorouracil-resistant advanced colorectal cancer. Eur J Cancer Clin Oncol. 1989 Jan;25(1):45-9.
  • PMID: 15316838
    Jost W, Marsalek P: Duloxetine: mechanism of action at the lower urinary tract and Onuf's nucleus. Clin Auton Res. 2004 Aug;14(4):220-7.
  • PMID: 19480470
    Carter NJ, McCormack PL: Duloxetine: a review of its use in the treatment of generalized anxiety disorder. CNS Drugs. 2009;23(6):523-41. doi: 10.2165/00023210-200923060-00006.
  • PMID: 21366359
    Knadler MP, Lobo E, Chappell J, Bergstrom R: Duloxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet. 2011 May;50(5):281-94. doi: 10.2165/11539240-000000000-00000.
  • PMID: 29424607
    Hershman DL, Lacchetti C, Loprinzi CL: Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2014 Nov;10(6):e421-e424. doi: 10.1200/JOP.2014.001776.
Menampilkan 8 dari 15 artikel.
Textbook
  • ISBN: 978-1-25-958473-2
    David R. Sibley; Lisa A. Hazelwood; Susan G. Amara (2018). 13. In Goodman & Gilman's: The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education.

Contoh Produk & Brand

Produk: 619 • International brands: 2
Produk
  • Accel-duloxetine
    Capsule, delayed release • 30 mg • Oral • Canada • Generic • Approved
  • Accel-duloxetine
    Capsule, delayed release • 60 mg • Oral • Canada • Generic • Approved
  • Ag-duloxetine
    Capsule, delayed release • 30 mg • Oral • Canada • Generic • Approved
  • Ag-duloxetine
    Capsule, delayed release • 60 mg • Oral • Canada • Generic • Approved
  • Apo-duloxetine
    Capsule, delayed release • 30 mg • Oral • Canada • Generic • Approved
  • Apo-duloxetine
    Capsule, delayed release • 60 mg • Oral • Canada • Generic • Approved
  • Ariclaim
    Capsule, delayed release • 30 mg • Oral • EU
  • Ariclaim
    Capsule, delayed release • 30 mg • Oral • EU
Menampilkan 8 dari 619 produk.
International Brands
  • Dulane
  • Duzela

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