Venlafaxine

VENLAFAXINE HCL · EFFEXOR · VENLAFAXIN · D,L-VENLAFAXINE, HYDROCHLORIDE · Velafax · Trevilor · Wy-45030 · Wy-45651

Identifikatoren & physikalische Daten

CAS No.	93413-69-5
Summenformel	C17H27NO2
Durchschnittliche Molmasse	277,4 g/mol
Monoisotopische Masse	277,2041791 g/mol
SMILES	COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
InChIKey	PNVNVHUZROJLTJ-UHFFFAOYSA-N
PubChem CID	5656
ChEMBL	CHEMBL637
ChEBI	CHEBI:9943
EC No.	618-944-2
DTXSID	DTXSID6023737

Chemische & physikalische Eigenschaften

XLogP	2,9
Polarare Oberfläche (TPSA)	32,7
H-Brücken-Donoren	1
H-Brücken-Akzeptoren	3
Frei drehbare Bindungen	5
Schwere Atome	20
Formalladung	0
Komplexität	279
LogP (Verteilungskoeffizient)	log Kow = 3.20
Löslichkeit	572Molecular weight: 313.86. White to off-white crystalline solid from methanol/ethyl acetate, mp 215-217 °C. SOlubility (mg/mL): 572 water. Partition coefficient (octanol/water): 0.43 /Venlafaxine hydrochloride/soluble in Dichloromethane, Ethyl Acetate<0.1g/L(room temperature)
Schmelzpunkt	Crystals from ethyl acetatemelting point 102-104 °Cspecific optical rotation: +27.6 deg (c = 1.07 in 95% ethanol) /Venlafaxine (+)form/specific optical rotation: -27.1 deg (c = 1.04 in 95% ethanol) /Venlafaxine (-)form/Crystals from methanol/ethermelting point 240-240.5 °Cspecific optical rotation: -4.7 deg (c = 0.945 in ethanol) /Venlafaxine (+)form hydrochloride/specific optical rotation: +4.6 deg (c = 1.0 in ethanol) /Venlafaxine (-)form hydrochloride/74 - 76 °C72-74°C
Physical Description	Solid
Dissociation Constants	9.5
Kovats Retention Index	2080.32056.92133.1
Collision Cross Section	170.7 Å² [M+H]+ [CCS Type: DTBuffer gas: N2Ionization: ESI+Dataset: TOXCASTSource Identifier: DTXSID8047397]170.8 Å² [M+H]+ [CCS Type: DTIonization: APCI+Dataset: Antidepressants]177.7 Å² [M+Na]+ [CCS Type: DT171.6 Å² [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]169.9 Å² [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]175.6 Å² [M+Na]+ [CCS Type: TW166.8 Å² [M+H-H2O]+ [CCS Type: TW168.8 Å² [M+H]+ [CCS Type: TW170.2 Å² [M+H]+ [CCS Type: DTMethod: single field calibrated]171.86 Å² [M+H]+179.64 Å² [M+Na]+
Siedepunkt	397.6±27.0 °C(Predicted)
Dichte	1.060±0.06 g/cm3(Predicted)
Lagerbedingungen	Keep in dark place,Inert atmosphere,2-8°C
pKa (Säurekonstante)	pKa 9.5 (Uncertain)
Aggregatzustand	Crystalline
Farbe	White to off-white
LogP (Verteilungskoeffizient)	0.4-600
CAS Datenbank	93413-69-5(CAS DataBase Reference)

Sicherheit & Vorschriften

GHS-Einstufung	DangerH302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]H319 (33.3%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]H360 (33.3%): May damage fertility or the unborn child [Danger Reproductive toxicity]H362 (33.3%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]H411 (33.3%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]P203, P260, P263, P264, P264+P265, P270, P273, P280, P301+P317, P305+P351+P338, P318, P330, P337+P317, P391, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.
Regulatorische Informationen	Status: Active Update: 16-04-2013 https://echa.europa.eu/registration-dossier/-/registered-dossier/1218
FDA-Anforderungen	The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including venlafaxine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Venlafaxine hydrochloride/
Hazard Classes and Categories	Acute Tox. 4 (100%)Eye Irrit. 2 (33.3%)Repr. 1A (33.3%)Lact. (33.3%)Aquatic Chronic 2 (33.3%)
Entsorgungsverfahren	SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.
Körperbelastung	Blood concentrations of venlafaxine in the two overdose cases were 53 mg/L and 78 mg/L. Comparison of venlafaxine concentrations in blood samples taken at different times after death revealed increases in concentrations over time, suggesting the possible postmortem redistribution of venlafaxine. /Salt not specified/
Treatment	Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. (L1712)
Wechselwirkungen	Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.A 25-year-old white woman with chronic depression was treated with venlafaxine 150 mg/day and trimipramine 50 mg/day. Eleven days after increase of the trimipramine dosage to 100 mg/d, she was hospitalized because of seizures suggesting a secondary generalized grand-mal episode. The electroencephalogram showed a pathologic pattern with several generalized epileptiform discharges. Because of suspected drug-induced seizures, both antidepressants were stopped. After antidepressant drug cessation, the patient was symptom free and had no further seizure episodes within the following 12 months of follow-up. No other potential cause for the seizure episode could be identified. Both venlafaxine and trimipramine have been associated with seizures, mainly after overdose. Venlafaxine-associated seizures at therapeutic doses have not been reported in the literature. /It was/ hypothesize that a pharmacodynamic or pharmacokinetic drug interaction between venlafaxine and trimipramine involving the CYP2D6 isoenzyme may have played a role in inducing the seizures.A patient developed neuroleptic malignant syndrome after a single dose of venlafaxine with trifluoperazine treatment. A dopamine-inhibition effect induced by one dose of venlafaxine may have augmented dopamine-receptor inhibition by trifluoperazine.Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of O-desmethylvenlafaxine, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus O-desmethylvenlafaxine is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.For more Interactions (Complete) data for Venlafaxine (24 total), please visit the HSDB record page.
Hepatotoxicity	Liver test abnormalities have been reported to occur in less than 1% of patients on venlafaxine or desvenlafaxine, and elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on both venlafaxine but not desvenlafaxine, perhaps because of less overall use of the more recently approved agent. The onset of injury is usually within 1 to 3 months. The patterns of serum enzyme elevation have varied from cholestatic to hepatocellular. All cases have been self-limiting and resolved within a few months. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon or mild. The estimated frequency is 1 per 5000 patients years of exposure.Likelihood score (venlafaxine): B (highly likely rare causes of clinically apparent liver injury).Likelihood score (desvenlafaxine): E* (suspected but unproven cause of clinically apparent liver injury).
Umweltverhalten	TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 190(SRC), determined from a log Kow of 3.20(2) and a regression-derived equation(3), indicates that Venlafaxine is expected to have moderate mobility in soil(SRC). The estimated pKa of Venlafaxine is 10.09(4), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Venlafaxine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.5X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(SRC, 2011).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 190(SRC), determined from a log Kow of 3.20(2) and a regression-derived equation(3), indicates that venlafaxine is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 10.09(4) indicates venlafaxine will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(5), an estimated BCF of 60(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2010)however its detection in wastewater treatment plant effluent(6) would indicate that biodegradation may not be an important environmental fate process in water(SRC).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), venlafaxine, which has an estimated vapor pressure of 2.5X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase venlafaxine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC)the half-life for this reaction in air is estimated to be 1 hour(SRC), calculated from its rate constant of 1.28X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase venlafaxine may be removed from the air by wet or dry deposition(SRC).
Unerwünschte Wirkungen	Venlafaxine causes a lower frequency of anticholinergic, sedating, and cardiovascular adverse effects but a higher incidence of gastrointestinal complaints, sleep impairment, and sexual dysfunction than TCAs. Additionally, venlafaxine may impair sexual function, resulting in diminished libido, impotence, or difficulty achieving orgasm. Sexual dysfunction frequently results in noncompliance. Sexual dysfunction can sometimes be alleviated by lowering the dose or instituting drug-free weekends and holidays in appropriate patients.Venlafaxine is prescribed for the long term, and it carries severe risks if not taken as directed or stopped abruptly. Abrupt cessation of venlafaxine can lead to severe adverse effects such as irritability, tiredness, restlessness, anxiety, insomnia, trouble sleeping, nightmares, headache, sweating, dizziness, tingling, or "pins and needles" feeling, shaking, confusion, nausea, vomiting, or diarrhea. Some patients find withdrawal symptoms uncomfortable. Common adverse effects of venlafaxine include headache, nausea, insomnia, dizziness, somnolence, xerostomia, asthenia, hypertension, impotence, decreased libido, anorgasmia, constipation, weight loss, abnormal dreams, diarrhea, abdominal pain, blurred vision, anxiety, tremor, hypercholesterolemia, and hyponatremia. Severe adverse effects include serotonin syndrome and seizures.Venlafaxine can cause depression exacerbation and hypomania/mania. Venlafaxine can also cause abnormal bleeding, altered platelet function, and anaphylaxis/anaphylactoid reaction. Venlafaxine can cause fatal skin conditions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. Venlafaxine can also cause deterioration of glaucoma angle closure and seizures. Venlafaxine has implications linking it to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypertension, arrhythmia, interstitial lung disease, eosinophilic pneumonia, pancreatitis, and hepatotoxicity.Drug-Drug Interactions* Venlafaxine can interact with many other medications or herbs.* Concomitant administration of desvenlafaxine with other serotonergic drugs should be avoided due to the risk of serotonin syndrome resulting from hyperstimulation of brainstem 5HT-1A receptors. Concurrent use of venlafaxine with SNRIs, SSRIs, triptans, TCAs, opioids, lithium, buspirone, amphetamines, tramadol, tryptophan, and St John's wort is not recommended. Vigilant monitoring for symptoms indicative of serotonin syndrome is imperative when venlafaxine is administered alongside these medications. If serotonin syndrome is suspected, prompt evaluation and consideration for discontinuation of venlafaxine and the other serotonergic agents involved are warranted to mitigate potential adverse effects and ensure patient safety.* Venlafaxine should be used cautiously with sedating medications, such as central nervous system depressants and alcohol.* The coadministration of venlafaxine with antiplatelet or anticoagulant medications may increase the risk of bleeding. This risk is attributed to venlafaxine's potential impact on serotonin release by platelets. Close monitoring for signs of bleeding is essential when initiating or discontinuing venlafaxine in patients receiving antiplatelet or anticoagulant therapy. Clinicians should be vigilant for bleeding complications and consider appropriate interventions as necessary.* Patients should not take venlafaxine with MAOIs, linezolid, and methylene blue.* Venlafaxine should not be ingested with drugs for weight loss, such as phentermine. Concurrent use of venlafaxine phentermine may cause excessive weight loss, serotonin syndrome, tachycardia, and psychosis.* The risk of bleeding may increase when taking venlafaxine with warfarin and NSAIDs such as aspirin, ibuprofen, and naproxen.* Clarithromycin, ritonavir, and ketoconazole can inhibit the breakdown of venlafaxine, leading to its accumulation in the body.* Concurrent use of venlafaxine with lorazepam zolpidem or diphenhydramine can result in increased sedation.* The efficacy of metoprolol is reduced when administered with venlafaxine.* The risk of QT prolongation increases when venlafaxine and haloperidol are administered concurrently.
Expositionspfade	Oral. 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.
Milk Concentrations	Women participating in a prospective investigation of perinatal pharmacokinetics from January 2001 through July 2006 who were treated with venlafaxine and who chose to continue venlafaxine during lactation were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient, and serial samples were collected over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Venlafaxine and desvenlafaxine concentrations were determined using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted. Thirteen women and their nursing infants participated, providing 106 breast milk samples. The mean milk/plasma ratio was 275.3% (95% CI = 144.8% to 405.7%). There were statistically significant time courses of excretion for venlafaxine (R = 0.36, F = 6.82, P < .02), desvenlafaxine (R = 0.48, F = 4.41, P < .009), and combined venlafaxine/desvenlafaxine (R = 0.51, F = 5.16, P < .004), with the highest venlafaxine and desvenlafaxine concentrations in the breast milk occurring 8 hours after maternal ingestion. Infant plasma concentrations for combined venlafaxine/desvenlafaxine were 37.1% of maternal plasma concentrations. The theoretical infant venlafaxine/desvenlafaxine dose was 0.208 mg/kg/d, and the relative infant venlafaxine/desvenlafaxine dose was 8.1%. The theoretical and relative infant doses for desvenlafaxine were 197% and 224% higher, respectively, than those for venlafaxine.
Toxizitätsübersicht	Signs and Symptoms of OverdoseSymptoms of an overdose of venlafaxine can include tachycardia, unusual sleepiness, dilated pupils, seizures, vomiting, cardiac arrhythmias, hypotension, muscle aches or pains, or dizziness. Severe toxicity of venlafaxine, especially when combined with other antidepressants such as SSRI, SNRI, or MAOI, can lead to serotonin syndrome. Serotonin syndrome is a possibly life-threatening condition associated with increased serotonergic activity in the central nervous system.Serotonin syndrome may present with a spectrum of clinical findings, including autonomic hyperactivity, mental status changes, and neuromuscular abnormalities. Serotonin syndrome characteristically presents with myoclonus, agitation, abdominal cramping, hyperpyrexia, hypertension, and potentially death. No laboratory tests exist to confirm the diagnosis, as serotonin concentrations do not correlate clinically with symptoms. Hunter Toxicity Criteria Decision Rules can be used to form the diagnosis.To meet the criteria, the patient must be taking a serotonergic agent and fulfill 1 of the following conditions:* Spontaneous clonus* Inducible clonus with agitation or diaphoresis* The presence of ocular clonus plus agitation or diaphoresis* Tremor with hyperreflexia* Hypertonia with a temperature above 38 °C plus ocular clonus or inducible clonusManagement of OverdoseManagement of serotonin syndrome involves promptly discontinuing all serotonergic agents with supportive care to normalize hemodynamics. Patient sedation with benzodiazepines and serotonin antagonists may also be an option. Cyproheptadine can be an option in the event of a failure with benzodiazepines and supportive care. Cyproheptadine is a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties. Treatment with propranolol, bromocriptine, or dantrolene is not recommended. Serotonin syndrome symptoms usually resolve within 24 hours of discontinuation of the offending agent.The exact mechanism of action of venlafaxine is unknown, but appears to be associated with the its potentiation of neurotrasmitter 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.
Ökotoxizitätsauszüge	/AQUATIC SPECIES/ The effects of embryonic and larval exposure to environmentally relevant (ng/L) concentrations of common antidepressants, fluoxetine, sertraline, venlafaxine, and bupropion (singularly and in mixture) on C-start escape behavior were evaluated in fathead minnows (Pimephales promelas). Embryos (postfertilization until hatching) were exposed for 5 days and, after hatching, were allowed to grow in control well water until 12 days old. Similarly, posthatch fathead minnows were exposed for 12 days to these compounds. High-speed (1,000 frames/s) video recordings of escape behavior were collected and transferred to National Institutes of Health Image for frame-by-frame analysis of latency periods, escape velocities, and total escape response (combination of latency period and escape velocity). When tested 12 days posthatch, fluoxetine and venlafaxine adversely affected C-start performance of larvae exposed as embryos. Conversely, larvae exposed for 12 days posthatch did not exhibit altered escape responses when exposed to fluoxetine but were affected by venlafaxine and bupropion exposure. Mixtures of these four antidepressant pharmaceuticals slowed predator avoidance behaviors in larval fathead minnows regardless of the exposure window. The direct impact of reduced C-start performance on survival and, ultimately, reproductive fitness provides an avenue to assess the ecological relevance of exposure in an assay of relatively short duration.
Signs and Symptoms	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.
Effluent Concentrations	Venlafaxine was detected downstream from a single source wastewater treatment plant on Boulder Creek (Colorado) and Fourmile Creek (Iowa) at ranges of 140 to 220 ng/L and 102 to 210 ng/L, respectivelydetection limit = 0.5 ng/L. Sampling was conducted in April and March of 2005, respectively. Concentration ranges in July and April of 2006 ranged from 99.5 to 672 ng/L and 146 to 690 ng/L(1).
Gefahrstoffdaten	93413-69-5(Hazardous Substances Data)

Anwendungen & Verwendung

History

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) with a history dating back to the 1980s, developed by a research team at Wyeth Pharmaceuticals. The discovery of this compound was based on ongoing research into novel antidepressants, aiming to provide a drug with a dual mechanism of action to improve efficacy in patients who do not respond well to traditional selective serotonin reuptake inhibitors (SSRIs). Key chemists and pharmacologists involved in the synthesis and bioactivity evaluation of the compound included John P. Yardley, G. E. Morris Husbands, and Eric A. Muth, among others. Their research ultimately led to the development of venlafaxine, a compound that demonstrated effective inhibition of serotonin and norepinephrine transporters in in vitro experiments.An immediate-release formulation of venlafaxine (IR), marketed as Effexor, was approved by the U.S. Food and Drug Administration (FDA) in 1993 for the treatment of major depressive disorder. This marked the first clinical application of an SNRI antidepressant. Subsequently, in order to improve patient compliance and reduce the side effects caused by peak drug concentration, Wyeth continued to develop an extended-release formulation (ER), marketed as Effexor XR, which was approved by the FDA in 1997. The launch of Effexor XR further solidified venlafaxine's position in the treatment of depression. Over time, the indications for venlafaxine have also expanded to include generalized anxiety disorder, social anxiety disorder, and panic disorder.

Verwenden

A optically active version of Venlafaxine, a selective serotonin noradrenaline reuptake inhibitor. Used as an antidepressant