데스벤라팍신

Pharmaceutical -> transformation product

Pharmaceuticals -> Metabolite of Venlafaxine

Pharmaceuticals -> SNRIs (Serotonin-Norepinephrine Reuptake inhibitors)

Antidepressants -> Serotonin-noradrenaline reuptake inhibitors (SNRI)

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Serotonin-Norepinephrine Reuptake Inhibitors

FDA approved drugs -> Active ingredient

166.2 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: Antidepressants]

163.78 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

166.7 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

166.9 Ų [M+H]+

This chemical does not meet GHS hazard criteria for 4.3% (2 of 46) of reports.

Warning

H319 (91.3%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

P264+P265, P280, P305+P351+P338, and P337+P317 (click each P-code to see the statement)

Aggregated GHS information provided per 46 reports by companies from 8 notifications to the ECHA C&L Inventory.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including desvenlafaxine succinate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Desvenlafaxine succinate/

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.

Desvenlafaxine does not inhibit or induce the CYP3A4 isoenzyme in vitro. Concurrent administration of desvenlafaxine (400 mg daily; 8 times the recommended dosage) and midazolam (single 4-mg dose), a CYP3A4 substrate, decreased the AUC and peak plasma concentrations of midazolam by approximately 31 and 16%, respectively. The manufacturer states that concurrent use of desvenlafaxine with a drug metabolized by CYP3A4 can result in lower exposures to that drug.

Selective serotonin-reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitor (SNRIs), including desvenlafaxine, may increase the risk of bleeding events. Concurrent administration of aspirin, nonsteroidal anti-inflammatory agents, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. The manufacturer recommends that patients be advised of the risk of bleeding associated with the concomitant use of desvenlafaxine and aspirin or other nonsteroidal anti-inflammatory agents, warfarin, or other drugs that affect coagulation or bleeding.

Desvenlafaxine minimally inhibits the cytochrome P-450 (CYP) 2D6 isoenzyme. In a study in healthy adults, concurrent administration of desvenlafaxine (100 mg daily) and desipramine (single 50-mg dose), a CYP2D6 substrate, increased peak plasma concentrations and AUCs of desipramine by approximately 25 and 17%, respectively. The manufacturer states that concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 can result in higher plasma concentrations of that drug.

In a clinical study, desvenlafaxine did not increase impairment of mental and motor skills caused by alcohol. However, the manufacturer recommends avoiding concomitant alcohol consumption during desvenlafaxine therapy.

For more Interactions (Complete) data for Desvenlafaxine (11 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1700(SRC), determined from a structure estimation method(2), indicates that desvenlafaxine is expected to have low mobility in soil(SRC). Estimated values for pKa1 of 9.45 (amine) and pKa2 of 10.66 (phenol)(3) indicate 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(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Desvenlafaxine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.8X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Biodegradation data in soil were not available(SRC, 2012).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1700(SRC), determined from a structure estimation method(2), indicates that desvenlafaxine is expected to adsorb to suspended solids and sediment(SRC). Estimated values for pKa1 of 9.45 (amine) and pKa2 of 10.66 (phenol)(3) indicate desvenlafaxine 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(4), an estimated BCF of 24(SRC), from an estimated log Kow of 2.72(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2012).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), desvenlafaxine, which has an estimated vapor pressure of 6.8X10-8 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 desvenlafaxine 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 1.4X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase desvenlafaxine may be removed from the air by wet or dry deposition(SRC). Desvenlafaxine does not contain chromophores that absorb at wavelengths >290 nm(4), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

There is a broad range of general adverse effects that patients can experience with the usage of desvenlafaxine. A study comparing desvenlafaxine to a placebo in treating major depressive disorder in adolescents noted the most common side effects to be abdominal pain, decreased appetite, headache, and nausea. Less commonly noted were diarrhea, dizziness, and cough. As with most selective serotonin reuptake inhibitors (SSRIs), it is necessary to monitor for increased suicidal ideation. Abruptly stopping the use of desvenlafaxine can cause irritability, nausea, and headaches. Gradually tapering the medication is recommended to avoid such side effects.

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 < 0.02), desvenlafaxine (R = 0.48, F = 4.41, P < 0.009), and combined venlafaxine/desvenlafaxine (R = 0.51, F = 5.16, P < 0.004), 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.

This study characterizes the extent of desvenlafaxine transfer into milk and provides data on infant exposure to desvenlafaxine via breast milk in ten women with postnatal depression and their breastfed infants. Desvenlafaxine concentration in milk and plasma was measured chromatographically in milk and in maternal and infant plasma collected at steady state. Theoretic and relative infant doses via milk were estimated and the per cent drug in infant versus mother's plasma was calculated. Theoretic infant dose via milk was 85 (53-117) ug kg(-1) day(-1) (mean and 95% confidence interval) and relative infant dose was 6.8% (5.5-8.1%). The ratio of drug in infant/maternal plasma also gave an infant exposure estimate of 4.8% (3.5-6.2%) for all ten infants and 5.3% (4.2-5.7%) in the eight infants who were exclusively breastfed. ... The relative infant dose was similar to that for previous studies using venlafaxine and was supported by a separate exposure measure using the ratio of drug in the infant's plasma relative to that in the mother's plasma. The theoretic infant dose of desvenlafaxine was 41-45% of that for venlafaxine and its metabolite desvenlafaxine in previous studies, reflecting the lower recommended maternal dose for desvenlafaxine. ...

Desvenlafaxine is rarely lethal when used as a standalone agent. There is a risk of serotonin syndrome when combined with other serotonin augmenting medications, triptans, tricyclic antidepressants, over-the-counter agents, and monoamine oxidase inhibitors. The treatment for overdose is symptomatic and supportive. There is no specific treatment for desvenlafaxine toxicity.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of desvenlafaxine can be estimated to be 1700(SRC). According to a classification scheme(2), this estimated Koc value suggests that desvenlafaxine is expected to have low mobility in soil. Estimated values for pKa1 of 9.45 (amine) and pKa2 of 10.66 (phenol)(3) indicate 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(4).

/SIGNS AND SYMPTOMS/ Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions) if used concurrently with antipsychotic agents or other dopamine antagonists. If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue treatment with desvenlafaxine and any concurrently administered antidopaminergic or serotonergic agents and initiate supportive and symptomatic treatment.

/CASE REPORTS/ A case is presented of the occurrence of an episode of mania apparently induced by desvenlafaxine, in a patient with a history of major depressive disorder and no apparent history of previous mania or hypo-mania. ...

/CASE REPORTS/ A 70-year-old Caucasian male with alcohol and opioid dependence in remission, was started on 50 mg of desvenlafaxine for a moderate depressive episode. After 10 weeks, he developed an ecchymosis of the right upper extremity, in the absence of past or family history of bleeding disorder. He had a prolonged activated partial thromboplastin time (74.5 s) not corrected on performing mixing study, decreased Factor VIII activity (< 1%) and detectable Factor VIII inhibitor (30 Bethesda units) confirming a diagnosis of AHA /acquired hemophilia A/. After all other causes were ruled out, desvenlafaxine was discontinued and the patient was infused with Factor VIIa followed by a 6-week prednisone taper with which he achieved remission.

/OTHER TOXICITY INFORMATION/ Potential pharmacologic interaction (increased risk of bleeding) if used concurrently with aspirin or other nonsteroidal anti-inflammatory agents, warfarin, or other drugs that affect coagulation or bleeding; use with caution. Altered anticoagulant effects, including increased bleeding, have been reported when selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitor (SNRIs) were concurrently administered with warfarin or other anticoagulants. The manufacturer recommends carefully monitoring patients receiving warfarin during initiation and discontinuance of desvenlafaxine therapy.

Desvenlafaxine's production and use in pharmaceutical formulations(1) may result in its release to the environment through various waste streams(SRC). Desvenlafaxine is the major active metabolite of venlafaxine, a prescribed antidepressant(2).

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

desvenlafaxine

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 24 was calculated in fish for desvenlafaxine(SRC), using an estimated log Kow of 2.72(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

Estimated values for pKa1 of 9.45 (amine) and pKa2 of 10.66 (phenol) indicate desvenlafaxine will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water and moist soil surfaces is not expected to be an important fate process. Desvenlafaxine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.8X10-8 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Acute Exposure/ The aim of this study was to investigate the effects of desvenlafaxine succinate on gastric slow waves (GSW), antral contractions, and gastric accommodation in dogs. Fifteen healthy dogs implanted with gastric serosal electrodes and a gastric cannula were studied in four separate sessions: control, desvenlafaxine succinate (50 mg), propranolol (1 mg/kg(-1)/hr(-1)), and propranolol + desvenlafaxine succinate. Gastric slow waves were measured via the gastric serosal electrodes. Antral contractions were assessed via an intraluminal manometric catheter inserted via the gastric cannula. The sympathovagal activity was assessed from the spectral analysis of the heart rate variability signal. Gastric tone was measured by barostat via an intragastric balloon inserted into the fundus via the gastric cannula. In the postprandial period, in comparison with the control, desvenlafaxine succinate reduced the percentage of normal gastric slow waves (P=0.001) and increased the percentage of tachygastria (P=0.005) and bradygastria (P=0.002). Simultaneously, desvenlafaxine succinate increased the sympathetic activity (P=0.006) and the sympathovagal ratio (low frequency/high frequency; P=0.044). These effects were blocked by propranolol. Desvenlafaxine succinate attenuated postprandial antral contractions and gastric accommodation. The postprandial antral contractile index (area under the curve) was decreased by 26% with desvenlafaxine succinate (P=0.013), and gastric accommodation was decreased by about 50% with desvenlafaxine succinate (P < 0.001). The inhibitory effect of desvenlafaxine succinate on gastric accommodation was blocked by propranolol. desvenlafaxine succinate inhibits gastric contractions, slow waves, and accommodation in the fed state. These inhibitory effects are associated with an increased sympathetic modulation in the gastrointestinal system. Cautions should be made when desvenlafaxine succinate is used for treating patients with depression and gastric motility disorders. /Desvenlafaxine succinate/

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reduced fertility was observed in a study in which both male and female rats received desvenlafaxine succinate. This effect was noted at oral doses approximately 10 times a human dose of 100 mg/day on a mg/sq m basis. There was no effect on fertility at oral doses approximately 3 times a human dose of 100 mg/day on a mg/sq m basis.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ When desvenlafaxine succinate was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity in rats at any doses tested, up to 10 times a human dose of 100 mg/day (on a mg/sq m basis) in rats, and up to 15 times a human dose of 100 mg/day (on a mg/sq basis) in rabbits. However, fetal weights were decreased in rats, with a no-effect dose 10 times a human dose of 100 mg/day (on a mg/sq basis).

/GENOTOXICITY/ Desvenlafaxine was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vitro chromosome aberration assay in cultured CHO cells, an in vivo mouse micronucleus assay, or an in vivo chromosome aberration assay in rats. Additionally, desvenlafaxine was not genotoxic in the in vitro CHO mammalian cell forward mutation assay and was negative in the in vitro BALB/c-3T3 mouse embryo cell transformation assay.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including desvenlafaxine succinate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Desvenlafaxine succinate/

N06AX23

N - Nervous system

QN - Nervous system

Desvenlafaxine is a selective serotonin and norepinephrine reuptake inhibitor. It lacks significant activity on muscarinic-cholinergic, H₁-histaminergic, or &alpha;₁-adrenergic receptors <i>in vitro</i>, or inhibitory activity against monoamine oxidase. Desvenlafaxine does not appear to exert activity against calcium, chloride, potassium and sodium ion channels and also lacks monoamine oxidase (MAO) inhibitory activity. It was also shown to lack significant activity against the cardiac potassium channel, hERG, <i>in vitro</i>. Electrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between desvenlafaxine treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval.

The exact mechanism of the antidepressant action of desvenlafaxine is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Particularly, desvenlafaxine has been found to inhibit the serotonin, norepinephrine, and dopamine transporters with varying degrees of affinity. Desvenlafaxine inhibits serotonin transporters with 10 times the affinity of norepinephrine transporters, and dopamine transporters with the lowest affinity.

The exact mechanism of antidepressant action of desvenlafaxine has not been fully elucidated but appears to be associated with the drug's potentiation of serotonergic and noradrenergic activity in the CNS. Like venlafaxine and duloxetine, desvenlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake; however, inhibition of dopamine reuptake at concentrations that inhibit serotonin and norepinephrine reuptake appears unlikely in most patients. The drug does not inhibit monoamine oxidase (MAO) and has not demonstrated significant affinity for muscarinic cholinergic, H1-histaminergic, alpha1-adrenergic, dopaminergic, gamma-aminobutyric acid (GABA), glutamate, and opiate receptors in vitro.

The mean terminal half-life is 11.1 hours and may be prolonged in patients with renal and/or moderate to severe hepatic impairment.

The mean half life changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively.

The mean terminal half-life, is approximately 11 hours.

Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. O-glucuronide conjugation is likely be catalyzed by UGT1A1, UGT1A3, UGT2B4, UGT2B15, and UGT2B17. CYP3A4 and potentially CYP2C19 mediates the oxidative metabolism (N-demethylation) of desvenlafaxine to N,O-didesmethyl venlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype.

Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. CYP3A4 is the cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved, and after administration of 100 mg, the pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. ... Approximately 19% of the administered dose is excreted as the glucuronide metabolite and < 5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine

NG99554ANW

DESVENLAFAXINE

Mechanisms of Action [MoA] - Norepinephrine Uptake Inhibitors

Established Pharmacologic Class [EPC] - Serotonin and Norepinephrine Reuptake Inhibitor

Mechanisms of Action [MoA] - Serotonin Uptake Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 2D6 Inhibitors

Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems.

Drugs that selectively block or suppress the plasma membrane transport of SEROTONIN and NORADRENALINE into axon terminals and are used as ANTIDEPRESSIVE AGENTS.

The absolute oral bioavailability of desvenlafaxine after oral administration is about 80%. The time to reach maximal concentration (Tmax) is estimated to be 7.5 hours after oral administration. The AUC in a 24 h dosing interval at steady state with a 100 mg dose was also calculated to be 6747 ng*h/mL, and the Cmax 376 ng/mL. Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine Cmax about 16% and had no effect on AUC.

Desvenlafaxine is mainly excreted in the urine. Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-didesmethyl venlafaxine) in urine.

The steady-state volume of distribution of desvenlafaxine is 3.4 L/kg.

Following the administration of 100 mg of desvenlafaxine in healthy subjects from 18 to 45 years of age, the renal clearance was calculated to be 222 ± 82 mL/min.

The plasma protein binding of desvenlafaxine is low (30%) and is independent of drug concentration. The desvenlafaxine volume of distribution at steady-state following intravenous administration is 3.4 L/kg, indicating distribution into nonvascular compartments.

The absolute oral bioavailability of Pristiq after oral administration is about 80%. Mean time to peak plasma concentrations (Tmax) is about 7.5 hours after oral administration.