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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyIdentification
- Name
- Venlafaxine
- Accession Number
- DB00285 (APRD00125)
- Type
- Small Molecule
- Groups
- Approved
- Description
Venlafaxine (Effexor) is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class first introduced by Wyeth in 1993. It is prescribed for the treatment of clinical depression and anxiety disorders. Due to the pronounced side effects and suspicions that venlafaxine may significantly increase the risk of suicide it is not recommended as a first line treatment of depression. However, it is often effective for depression not responding to SSRIs. Venlafaxine was the sixth most widely-used antidepressant based on the amount of retail prescriptions in the US (17.1 million) in 2006. [Wikipedia]
- Structure
Structure for Venlafaxine (DB00285)
- Synonyms
- Elafax
- Venlafaxina
- Venlafaxine
- Venlafaxinum
- Product Ingredients
Ingredient UNII CAS InChI Key Venlafaxine Hydrochloride 7D7RX5A8MO 99300-78-4 QYRYFNHXARDNFZ-UHFFFAOYSA-N - Product Images
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Act Venlafaxine XR Capsule, extended release 37.5 mg Oral Actavis Pharma Company 2008-02-13 Not applicable Canada 
Act Venlafaxine XR Capsule, extended release 150.0 mg Oral Actavis Pharma Company 2008-02-13 Not applicable Canada Act Venlafaxine XR Capsule, extended release 75.0 mg Oral Actavis Pharma Company 2008-02-13 Not applicable Canada Effexor Tablet 37.5 mg/1 Oral Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc. 1993-12-01 2011-05-01 US 
Effexor Tablet 100 mg/1 Oral Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc. 1993-12-01 2011-05-01 US Effexor Tablet 50 mg/1 Oral Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc. 1993-12-01 2011-05-01 US Effexor Tablet 75 mg/1 Oral Physicians Total Care, Inc. 1993-12-01 2011-05-31 US Effexor Tablet 75 mg/1 Oral Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc. 1993-12-01 2011-05-01 US Effexor Tablet 25 mg/1 Oral Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc. 1993-12-01 2011-05-01 US Effexor Tablet 37.5 mg/1 Oral Physicians Total Care, Inc. 1993-12-01 2011-05-31 US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Apo-venlafaxine XR Capsule, extended release 150 mg Oral Apotex Corporation 2013-04-16 Not applicable Canada Apo-venlafaxine XR Capsule, extended release 37.5 mg Oral Apotex Corporation 2013-04-16 Not applicable Canada Apo-venlafaxine XR Capsule, extended release 75 mg Oral Apotex Corporation 2013-04-16 Not applicable Canada Auro-venlafaxine XR Capsule, extended release 150 mg Oral Auro Pharma Inc 2016-03-14 Not applicable Canada Auro-venlafaxine XR Capsule, extended release 37.5 mg Oral Auro Pharma Inc 2016-03-14 Not applicable Canada Auro-venlafaxine XR Capsule, extended release 75 mg Oral Auro Pharma Inc 2016-03-14 Not applicable Canada Dom-venlafaxine XR Capsule, extended release 150 mg Oral Dominion Pharmacal 2013-05-30 Not applicable Canada Dom-venlafaxine XR Capsule, extended release 75 mg Oral Dominion Pharmacal 2013-05-23 Not applicable Canada Dom-venlafaxine XR Capsule, extended release 37.5 mg Oral Dominion Pharmacal 2013-05-23 Not applicable Canada Effexor Tablet 50 mg/1 Oral Directrx 2016-02-02 Not applicable US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Venlafaxine Venlafaxine Hydrochloride (225 mg/1) Tablet, extended release Oral Osmotica Pharmaceutical Corp. 2008-06-03 Not applicable US Venlafaxine Venlafaxine Hydrochloride (37.5 mg/1) Tablet, extended release Oral Osmotica Pharmaceutical Corp. 2008-06-03 Not applicable US Venlafaxine Venlafaxine Hydrochloride (150 mg/1) Tablet, extended release Oral Osmotica Pharmaceutical Corp. 2008-06-03 Not applicable US Venlafaxine Venlafaxine Hydrochloride (75 mg/1) Tablet, extended release Oral Osmotica Pharmaceutical Corp. 2008-06-03 Not applicable US - International/Other Brands
- Effexor / Elafax
- Categories
- Alcohols
- Amines
- Antidepressive Agents, Second-Generation
- BCRP/ABCG2 Inducers
- Central Nervous System Agents
- Central Nervous System Depressants
- Combined Inhibitors of Serotonin/Norepinephrine Reuptake
- Cyclohexanes
- Cyclohexanols
- Cycloparaffins
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (moderate)
- Cytochrome P-450 CYP2D6 Inhibitors (weak)
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (moderate)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Ethylamines
- Fatty Alcohols
- Hexanols
- Hypoglycemia-Associated Agents
- Lipids
- Membrane Transport Modulators
- Nervous System
- Neurotransmitter Agents
- Neurotransmitter Uptake Inhibitors
- Norepinephrine Uptake Inhibitors
- P-glycoprotein/ABCB1 Inhibitors
- P-glycoprotein/ABCB1 Substrates
- Phenethylamines
- Potential QTc-Prolonging Agents
- Psychoanaleptics
- Psychotropic Drugs
- QTc Prolonging Agents
- Selective Serotonin Reuptake Inhibitors
- Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
- Serotonin Agents
- Serotonin and Noradrenaline Reuptake Inhibitors
- Serotonin Modulators
- UNII
- GRZ5RCB1QG
- CAS number
- 93413-69-5
- Weight
- Average: 277.4018
Monoisotopic: 277.204179113 - Chemical Formula
- C17H27NO2
- InChI Key
- PNVNVHUZROJLTJ-UHFFFAOYSA-N
- InChI
- InChI=1S/C17H27NO2/c1-18(2)13-16(17(19)11-5-4-6-12-17)14-7-9-15(20-3)10-8-14/h7-10,16,19H,4-6,11-13H2,1-3H3
- IUPAC Name
- 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol
- SMILES
- COC1=CC=C(C=C1)C(CN(C)C)C1(O)CCCCC1
Pharmacology
- Indication
For the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (social phobia), panic disorder with or without agoraphobia, vasomotor symptoms in women with breast cancer and in postmenopausal women, and neuropathic pain.
- Associated Conditions
- Pharmacodynamics
Venlafaxine potentiates the neurotransmitter activity in the central nervous system. Furthermore, venlafaxine and its metabolite, O-desmethylvenlafaxine (ODV) potently inhibit the reuptake of serotonin and norepinephrine and weakly inhibit dopamine reuptake. Both molecules do not bind to muscarinic, histaminergic, or alpha-1 adrenergic receptors. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Both also do not have any monoamine oxidase (MAO) inhibitory activity.
- Mechanism of action
The exact mechanism of action of venlafaxine is unknown, but appears to be associated with the its potentiation of neurotransmitter activity in the CNS. Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), inhibit the reuptake of both serotonin and norepinephrine with a potency greater for the 5-HT than for the NE reuptake process. Both venlafaxine and the ODV metabolite have weak inhibitory effects on the reuptake of dopamine but, unlike the tricyclics and similar to SSRIs, they are not active at histaminergic, muscarinic, or alpha(1)-adrenergic receptors.
Target Actions Organism ASodium-dependent serotonin transporter inhibitorHuman ASodium-dependent noradrenaline transporter inhibitorHuman USodium-dependent dopamine transporter inhibitorHuman - Absorption
Venlafaxine is well absorbed. Food does not effect the absorption of venlafaxine or its subsequent metabolism into ODV. Bioavailability is 45% following oral administration. Time to steady state = 3 days.
- Volume of distribution
- 7.5 ± 3.7 L/kg Venlafaxine
- 5.7 ± 1.8 L/kg [O-desmethylvenlafaxine(active metabolite)]
- Protein binding
The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected.
- Metabolism
Undergoes extensive first pass metabolism in the liver to its major, active metabolite, ODV, and two minor, less active metabolites, N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. Formation of ODV is catalyzed by cytochrome P450 (CYP) 2D6, whereas N-demethylation is catalyzed by CYP3A4, 2C19 and 2C9. ODV possesses antidepressant activity that is comparable to that of venlfaxine.
- Route of elimination
Renal elimination of venlafaxine and its metabolites is the primary route of excretion. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%).
- Half life
5 hours
- Clearance
Steady state plasma clearance, venlafaxine = 1.3 ± 0.6 L/h/kg; Steady state plasma clearance, ODV = 0.4 ± 0.2 L/h/kg.
- Toxicity
Most patients overdosing with venlafaxine develop only mild symptoms. However, severe toxicity is reported with the most common symptoms being CNS depression, serotonin toxicity, seizure, or cardiac conduction abnormalities. Venlafaxine's toxicity appears to be higher than other SSRIs, with a fatal toxic dose closer to that of the tricyclic antidepressants than the SSRIs. Doses of 900 mg or more are likely to cause moderate toxicity. Deaths have been reported following large doses.
- Affected organisms
- Humans and other mammals
- Pathways
Pathway Category Venlafaxine Metabolism Pathway Drug metabolism - Pharmacogenomic Effects/ADRs
Interacting Gene/Enzyme Allele name Genotype(s) Defining Change(s) Type(s) Description Details Cytochrome P450 2D6 CYP2D6*4 (A;A) / (A;A) A Allele / A Allele Effect Directly Studied Patients with this genotype have reduced metabolism of venlafaxine. Details Cytochrome P450 2D6 CYP2D6*6 (-;-) / (-;T) / (-;-) T deletion / T deletion, homozygote Effect Directly Studied Patients with this genotype have reduced metabolism of venlafaxine. Details Cytochrome P450 2D6 CYP2D6*5 Not Available Whole gene deletion, homozygote Effect Directly Studied Patients with this genotype have reduced metabolism of venlafaxine. Details Multidrug resistance protein 1 --- (C;C) / (C;T) C Allele Effect Directly Studied Patients with this genotype have an increased likelihood of remission when using venlafaxine to treat major depressive disorder Details Multidrug resistance protein 1 --- (C;C) / (C;T) T > C Effect Directly Studied Patients with this genotype have increased risk of adverse events with venlafaxine Details Cytochrome P450 2D6 CYP2D6*3 Not Available C allele Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*7 Not Available 2935A>C Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*8 Not Available 1758G>T Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*11 Not Available 883G>C Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*12 Not Available 124G>A Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*13 Not Available CYP2D7/2D6 hybrid gene structure Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*14A Not Available 1758G>A Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*15 Not Available 137insT, 137_138insT Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*19 Not Available 2539_2542delAACT Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*20 Not Available 1973_1974insG Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*21 Not Available 2573insC Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*31 Not Available -1770G>A / -1584C>G … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*36 Not Available 100C>T / -1426C>T … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*38 Not Available 2587_2590delGACT Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*40 Not Available 1863_1864ins(TTT CGC CCC)2 Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*42 Not Available 3259_3260insGT Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*44 Not Available 2950G>C Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*47 Not Available 100C>T / -1426C>T … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*51 Not Available -1584C>G / -1235A>G … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*56 Not Available 3201C>T Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*57 Not Available 100C>T / 310G>T … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*62 Not Available 4044C>T Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*68A Not Available -1426C>T / -1235A>G … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*68B Not Available Similar but not identical switch region compared to CYP2D6*68A. Found in tandem arrangement with CYP2D6*4. Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*69 Not Available 2988G>A / -1426C>T … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*92 Not Available 1995delC Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*100 Not Available -1426C>T / -1235A>G … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Cytochrome P450 2D6 CYP2D6*101 Not Available -1426C>T / -1235A>G … show all Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details
Interactions
- Drug Interactions
Drug Interaction (R)-warfarin The risk or severity of adverse effects can be increased when Venlafaxine is combined with (R)-warfarin. (S)-Warfarin The risk or severity of adverse effects can be increased when Venlafaxine is combined with (S)-Warfarin. 2,4-thiazolidinedione Venlafaxine may increase the hypoglycemic activities of 2,4-thiazolidinedione. 3,4-Methylenedioxyamphetamine The risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Venlafaxine. 4-Bromo-2,5-dimethoxyamphetamine The risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Venlafaxine. 4-hydroxycoumarin The risk or severity of adverse effects can be increased when Venlafaxine is combined with 4-hydroxycoumarin. 4-Methoxyamphetamine The risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Venlafaxine. 7-Nitroindazole The risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Venlafaxine. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline The risk or severity of adverse effects can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Venlafaxine. Abciximab Venlafaxine may increase the antiplatelet activities of Abciximab. - Food Interactions
- Avoid alcohol.
- Avoid St.John's Wort.
- Take with food.
References
- Synthesis Reference
Thomas P. Jerussi, Chrisantha H. Senanayake, "Derivatives of (+)-venlafaxine and methods of preparing and using the same." U.S. Patent US6197828, issued June, 1994.
US6197828- General References
- Golden RN, Nicholas L: Antidepressant efficacy of venlafaxine. Depress Anxiety. 2000;12 Suppl 1:45-9. [PubMed:11098413]
- Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA: A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability. J Clin Psychopharmacol. 2006 Oct;26(5):482-8. [PubMed:16974189]
- Bielski RJ, Ventura D, Chang CC: A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. J Clin Psychiatry. 2004 Sep;65(9):1190-6. [PubMed:15367045]
- Rowbotham MC, Goli V, Kunz NR, Lei D: Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004 Aug;110(3):697-706. [PubMed:15288411]
- Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R: The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005 Feb;45(2):144-52. [PubMed:15705120]
- Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE: Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012 Oct;92(4):414-7. doi: 10.1038/clpt.2012.96. [PubMed:22992668]
- Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
- External Links
- Human Metabolome Database
- HMDB0061166
- KEGG Drug
- D08670
- KEGG Compound
- C07187
- PubChem Compound
- 5656
- PubChem Substance
- 46504593
- ChemSpider
- 5454
- BindingDB
- 82071
- ChEBI
- 9943
- ChEMBL
- CHEMBL637
- Therapeutic Targets Database
- DAP000054
- PharmGKB
- PA451866
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- PDRhealth
- PDRhealth Drug Page
- Wikipedia
- Venlafaxine
- ATC Codes
- N06AX16 — Venlafaxine
- AHFS Codes
- 28:16.04.16 — Selective Serotonin and Norepinephrine-reuptake Inhibitors
- FDA label
- Download (3.38 MB)
- MSDS
- Download (36.5 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Wyeth pharmaceuticals inc
- Teva pharmaceuticals usa inc
- Osmotica pharmaceutical corp
- Actavis totowa llc
- Amneal pharmaceuticals
- Aurobindo pharma ltd
- Caraco pharmaceutical laboratories ltd
- Dr reddys laboratories ltd
- Mylan pharmaceuticals inc
- Pliva hrvatska doo
- Sandoz inc
- Vintage pharmaceuticals llc
- Zydus pharmaceuticals usa inc
- Wyeth
- Packagers
- Advanced Pharmaceutical Services Inc.
- Amerisource Health Services Corp.
- AQ Pharmaceuticals Inc.
- A-S Medication Solutions LLC
- Bryant Ranch Prepack
- Cadila Healthcare Ltd.
- Caraco Pharmaceutical Labs
- Cardinal Health
- Caremark LLC
- Direct Pharmaceuticals Inc.
- Dispensing Solutions
- Diversified Healthcare Services Inc.
- Doctor Reddys Laboratories Ltd.
- Heartland Repack Services LLC
- Innoviant Pharmacy Inc.
- Kaiser Foundation Hospital
- Lake Erie Medical and Surgical Supply
- Murfreesboro Pharmaceutical Nursing Supply
- Mylan
- Nucare Pharmaceuticals Inc.
- Palmetto Pharmaceuticals Inc.
- PD-Rx Pharmaceuticals Inc.
- Physicians Total Care Inc.
- Prepackage Specialists
- Prepak Systems Inc.
- Rebel Distributors Corp.
- Remedy Repack
- Resource Optimization and Innovation LLC
- Schwarz Pharma Inc.
- Southwood Pharmaceuticals
- Stat Rx Usa
- Teva Pharmaceutical Industries Ltd.
- Tya Pharmaceuticals
- UDL Laboratories
- Upstate Pharma LLC
- Vangard Labs Inc.
- Wyeth Pharmaceuticals
- Zydus Pharmaceuticals
- Dosage forms
Form Route Strength Capsule, extended release Oral 150.0 mg Capsule, extended release Oral 75.0 mg Tablet Oral 75 mg/1 Tablet Oral 37.5 mg Tablet Oral 50 mg Tablet Oral 75 mg Capsule, extended release Oral 150 mg Capsule, extended release Oral 37.5 mg Capsule, extended release Oral 75 mg Capsule, extended release Oral 150 mg/1 Capsule, extended release Oral 37.5 mg/1 Capsule, extended release Oral 75 mg/1 Tablet, extended release Oral 150 mg/1 Tablet, extended release Oral 225 mg/1 Tablet, extended release Oral 37.5 mg/1 Tablet, extended release Oral 75 mg/1 Capsule, coated, extended release Oral 75 mg/1 Capsule, delayed release Oral 75 mg/1 Tablet Oral 100 mg/1 Tablet Oral 25 mg/1 Tablet Oral 37.5 mg/1 Tablet Oral 50 mg/1 Tablet, film coated Oral 100 mg/1 Tablet, film coated Oral 25 mg/1 Tablet, film coated Oral 37.5 mg/1 Tablet, film coated Oral 50 mg/1 Tablet, film coated Oral 75 mg/1 Tablet, film coated, extended release Oral 150 mg/1 Tablet, film coated, extended release Oral 225 mg/1 Tablet, film coated, extended release Oral 37.5 mg/1 Tablet, film coated, extended release Oral 75 mg/1 - Prices
Unit description Cost Unit Venlafaxine HCl 30 225 mg 24 Hour tablet Bottle 276.98USD bottle Effexor XR 30 37.5 mg 24 Hour Capsule Bottle 144.33USD bottle Venlafaxine HCl 30 37.5 mg 24 Hour tablet Bottle 114.46USD bottle Effexor 30 75 mg tablet Bottle 87.83USD bottle Effexor 30 25 mg tablet Bottle 74.82USD bottle Effexor XR 150 mg 24 Hour Capsule 5.87USD capsule Effexor xr 150 mg capsule 5.65USD capsule Effexor XR 75 mg 24 Hour Capsule 5.39USD capsule Effexor xr 75 mg capsule 4.76USD capsule Venlafaxine HCl 150 mg 24 Hour tablet 4.72USD tablet Effexor xr 37.5 mg capsule 4.63USD capsule Venlafaxine HCl 75 mg 24 Hour tablet 4.42USD tablet Effexor 100 mg tablet 2.92USD tablet Effexor 75 mg tablet 2.7USD tablet Effexor 50 mg tablet 2.6USD tablet Effexor 37.5 mg tablet 2.5USD tablet Effexor 25 mg tablet 2.4USD tablet Venlafaxine hcl 100 mg tablet 2.36USD tablet Venlafaxine hcl 75 mg tablet 2.23USD tablet Effexor Xr 150 mg Extended-Release Capsule 2.16USD capsule Venlafaxine hcl 50 mg tablet 2.1USD tablet Effexor Xr 75 mg Extended-Release Capsule 2.05USD capsule Venlafaxine hcl 37.5 mg tablet 2.04USD tablet Venlafaxine hcl 25 mg tablet 1.98USD tablet Apo-Venlafaxine Xr 150 mg Extended-Release Capsule 1.2USD capsule Co Venlafaxine Xr 150 mg Extended-Release Capsule 1.2USD capsule Mylan-Venlafaxine Xr 150 mg Extended-Release Capsule 1.2USD capsule Novo-Venlafaxine Xr 150 mg Extended-Release Capsule 1.2USD capsule Pms-Venlafaxine Xr 150 mg Extended-Release Capsule 1.2USD capsule Ratio-Venlafaxine Xr 150 mg Extended-Release Capsule 1.2USD capsule Sandoz Venlafaxine Xr 150 mg Extended-Release Capsule 1.2USD capsule Apo-Venlafaxine Xr 75 mg Extended-Release Capsule 1.14USD capsule Co Venlafaxine Xr 75 mg Extended-Release Capsule 1.14USD capsule Mylan-Venlafaxine Xr 75 mg Extended-Release Capsule 1.14USD capsule Novo-Venlafaxine Xr 75 mg Extended-Release Capsule 1.14USD capsule Pms-Venlafaxine Xr 75 mg Extended-Release Capsule 1.14USD capsule Ratio-Venlafaxine Xr 75 mg Extended-Release Capsule 1.14USD capsule Sandoz Venlafaxine Xr 75 mg Extended-Release Capsule 1.14USD capsule Effexor Xr 37.5 mg Extended-Release Capsule 1.02USD capsule Apo-Venlafaxine Xr 37.5 mg Extended-Release Capsule 0.57USD capsule Co Venlafaxine Xr 37.5 mg Extended-Release Capsule 0.57USD capsule Mylan-Venlafaxine Xr 37.5 mg Extended-Release Capsule 0.57USD capsule Novo-Venlafaxine Xr 37.5 mg Extended-Release Capsule 0.57USD capsule Pms-Venlafaxine Xr 37.5 mg Extended-Release Capsule 0.57USD capsule Ratio-Venlafaxine Xr 37.5 mg Extended-Release Capsule 0.57USD capsule Sandoz Venlafaxine Xr 37.5 mg Extended-Release Capsule 0.57USD capsule DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) US5916923 No 1993-06-28 2013-06-28 US CA2126305 No 2006-10-17 2014-06-20 Canada CA2199778 No 2005-12-20 2017-03-12 Canada US6403120 Yes 1997-09-20 2017-09-20 US US6419958 Yes 1997-09-20 2017-09-20 US US6274171 Yes 1997-09-20 2017-09-20 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 215-217 °C (Hydrochloride salt) Not Available water solubility 572 mg/ml (Hydrochloride salt) Not Available - Predicted Properties
Property Value Source Water Solubility 0.23 mg/mL ALOGPS logP 2.69 ALOGPS logP 2.74 ChemAxon logS -3.1 ALOGPS pKa (Strongest Acidic) 14.42 ChemAxon pKa (Strongest Basic) 8.91 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 32.7 Å2 ChemAxon Rotatable Bond Count 5 ChemAxon Refractivity 83.02 m3·mol-1 ChemAxon Polarizability 32.33 Å3 ChemAxon Number of Rings 2 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule Yes ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 0.9782 Blood Brain Barrier + 0.9382 Caco-2 permeable + 0.852 P-glycoprotein substrate Substrate 0.6534 P-glycoprotein inhibitor I Inhibitor 0.7031 P-glycoprotein inhibitor II Inhibitor 0.8031 Renal organic cation transporter Non-inhibitor 0.5792 CYP450 2C9 substrate Non-substrate 0.7583 CYP450 2D6 substrate Substrate 0.8919 CYP450 3A4 substrate Substrate 0.7407 CYP450 1A2 substrate Non-inhibitor 0.7664 CYP450 2C9 inhibitor Non-inhibitor 0.6876 CYP450 2D6 inhibitor Inhibitor 0.7287 CYP450 2C19 inhibitor Non-inhibitor 0.7199 CYP450 3A4 inhibitor Non-inhibitor 0.8308 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8666 Ames test Non AMES toxic 0.8 Carcinogenicity Non-carcinogens 0.6762 Biodegradation Not ready biodegradable 0.9941 Rat acute toxicity 2.5404 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.5486 hERG inhibition (predictor II) Inhibitor 0.6627
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as anisoles. These are organic compounds containing a methoxybenzene or a derivative thereof.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Phenol ethers
- Sub Class
- Anisoles
- Direct Parent
- Anisoles
- Alternative Parents
- Phenoxy compounds / Methoxybenzenes / Cyclohexanols / Aralkylamines / Alkyl aryl ethers / Tertiary alcohols / 1,3-aminoalcohols / Trialkylamines / Cyclic alcohols and derivatives / Organopnictogen compounds show 1 more
- Substituents
- Phenoxy compound / Anisole / Methoxybenzene / Alkyl aryl ether / Aralkylamine / Cyclohexanol / Monocyclic benzene moiety / 1,3-aminoalcohol / Tertiary alcohol / Cyclic alcohol show 12 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- tertiary alcohol, tertiary amino compound, monomethoxybenzene, cyclohexanols (CHEBI:9943)
Targets
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Serotonin:sodium symporter activity
- Specific Function
- Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
- Gene Name
- SLC6A4
- Uniprot ID
- P31645
- Uniprot Name
- Sodium-dependent serotonin transporter
- Molecular Weight
- 70324.165 Da
References
- Chen F, Larsen MB, Sanchez C, Wiborg O: The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. Eur Neuropsychopharmacol. 2005 Mar;15(2):193-8. [PubMed:15695064]
- Gould GG, Altamirano AV, Javors MA, Frazer A: A comparison of the chronic treatment effects of venlafaxine and other antidepressants on serotonin and norepinephrine transporters. Biol Psychiatry. 2006 Mar 1;59(5):408-14. Epub 2005 Sep 2. [PubMed:16140280]
- Shang Y, Gibbs MA, Marek GJ, Stiger T, Burstein AH, Marek K, Seibyl JP, Rogers JF: Displacement of serotonin and dopamine transporters by venlafaxine extended release capsule at steady state: a [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single photon emission computed tomography imaging study. J Clin Psychopharmacol. 2007 Feb;27(1):71-5. [PubMed:17224717]
- Malizia AL, Melichar JM, Brown DJ, Gunn RN, Reynolds A, Jones T, Nutt DJ: Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo. J Psychopharmacol. 1997;11(3):279-81. [PubMed:9305421]
- Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
- Van Ameringen M, Mancini C, Patterson B, Simpson W: Pharmacotherapy for social anxiety disorder: an update. Isr J Psychiatry Relat Sci. 2009;46(1):53-61. [PubMed:19728573]
- Beique J, de Montigny C, Blier P, Debonnel G: Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: I. in vivo electrophysiological studies in the rat. Neuropharmacology. 2000 Jul 24;39(10):1800-12. [PubMed:10884561]
- Westenberg HG: Recent advances in understanding and treating social anxiety disorder. CNS Spectr. 2009 Feb;14(2 Suppl 3):24-33. [PubMed:19238127]
- Sindrup SH, Otto M, Finnerup NB, Jensen TS: Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol. 2005 Jun;96(6):399-409. [PubMed:15910402]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Norepinephrine:sodium symporter activity
- Specific Function
- Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
- Gene Name
- SLC6A2
- Uniprot ID
- P23975
- Uniprot Name
- Sodium-dependent noradrenaline transporter
- Molecular Weight
- 69331.42 Da
References
- Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJ: Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity. Biol Psychiatry. 2004 Feb 1;55(3):320-2. [PubMed:14744476]
- Mitchell HA, Ahern TH, Liles LC, Javors MA, Weinshenker D: The effects of norepinephrine transporter inactivation on locomotor activity in mice. Biol Psychiatry. 2006 Nov 15;60(10):1046-52. Epub 2006 Aug 7. [PubMed:16893531]
- Beique JC, Lavoie N, de Montigny C, Debonnel G: Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters. Eur J Pharmacol. 1998 May 15;349(1):129-32. [PubMed:9669506]
- Van Ameringen M, Mancini C, Patterson B, Simpson W: Pharmacotherapy for social anxiety disorder: an update. Isr J Psychiatry Relat Sci. 2009;46(1):53-61. [PubMed:19728573]
- Beique J, de Montigny C, Blier P, Debonnel G: Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: I. in vivo electrophysiological studies in the rat. Neuropharmacology. 2000 Jul 24;39(10):1800-12. [PubMed:10884561]
- Westenberg HG: Recent advances in understanding and treating social anxiety disorder. CNS Spectr. 2009 Feb;14(2 Suppl 3):24-33. [PubMed:19238127]
- Sindrup SH, Otto M, Finnerup NB, Jensen TS: Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol. 2005 Jun;96(6):399-409. [PubMed:15910402]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Monoamine transmembrane transporter activity
- Specific Function
- Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
- Gene Name
- SLC6A3
- Uniprot ID
- Q01959
- Uniprot Name
- Sodium-dependent dopamine transporter
- Molecular Weight
- 68494.255 Da
References
- Dawson LA, Nguyen HQ, Geiger A: Effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline in the rat frontal cortex: augmentation via 5-HT1A receptor antagonism. Neuropharmacology. 1999 Aug;38(8):1153-63. [PubMed:10462128]
- Bourin M: [Psychopharmacological profile of venlafaxine]. Encephale. 1999 Jun;25 Spec No 2:21-2; discussion 23-5. [PubMed:10434156]
- Barkin RL, Fawcett J: The management challenges of chronic pain: the role of antidepressants. Am J Ther. 2000 Jan;7(1):31-47. [PubMed:11319571]
- Lemke MR: [Antidepressant effects of dopamine agonists. Experimental and clinical findings]. Nervenarzt. 2007 Jan;78(1):31-8. [PubMed:17187269]
Enzymes
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
- Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
- Fogelman SM, Schmider J, Venkatakrishnan K, von Moltke LL, Harmatz JS, Shader RI, Greenblatt DJ: O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology. 1999 May;20(5):480-90. [PubMed:10192828]
- Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
- Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
- Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, Sellers EM: Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol. 1996 Feb;41(2):149-56. [PubMed:8838442]
- Ciusani E, Zullino DF, Eap CB, Brawand-Amey M, Brocard M, Baumann P: Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine: pharmacokinetic and clinical aspects. J Psychopharmacol. 2004 Dec;18(4):559-66. doi: 10.1177/026988110401800414. [PubMed:15582923]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
- Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
- Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Transporters
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE: Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther. 2003 Apr;305(1):197-204. [PubMed:12649369]
- Uhr M, Grauer MT, Holsboer F: Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol Psychiatry. 2003 Oct 15;54(8):840-6. [PubMed:14550684]
- Karlsson L, Schmitt U, Josefsson M, Carlsson B, Ahlner J, Bengtsson F, Kugelberg FC, Hiemke C: Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein. Eur Neuropsychopharmacol. 2010 Sep;20(9):632-40. doi: 10.1016/j.euroneuro.2010.04.004. Epub 2010 May 13. [PubMed:20466523]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inducer
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- Bachmeier CJ, Beaulieu-Abdelahad D, Ganey NJ, Mullan MJ, Levin GM: Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine. Biopharm Drug Dispos. 2011 May;32(4):233-44. doi: 10.1002/bdd.753. Epub 2011 Mar 28. [PubMed:21446053]
Drug created on June 13, 2005 07:24 / Updated on September 24, 2018 02:40