Duloxetine

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Antidepressant

Pharmaceuticals -> Listed in ZINC15

Antidepressants -> Serotonin-noradrenaline reuptake inhibitors (SNRI)

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

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

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

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

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

Warning

H351 (100%): Suspected of causing cancer [Warning Carcinogenicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 9 reports by companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H225: Highly Flammable liquid and vapor [Danger Flammable liquids]

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

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Recommended storage temperature -20 °C

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low areas.; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.; Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations.

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.

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.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapour or mist. Use explosion-proof equipment.Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Body Protection: Complete suit protecting against chemicals, Flame retardant antistatic protective clothing., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Skin protection: Handle with gloves.

Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

There is no specific antidote to Duloxetine, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. 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 may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. (L1712)

Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCt,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued.

Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.

Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).

When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin.

Liver test abnormalities with ALT elevations above 3 times the upper limit of normal have been reported to occur in ~1% of patients on duloxetine, but elevations were usually self-limited and did 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 duloxetine. The onset of injury is usually within 1 to 6 months and the pattern of serum enzyme elevations is usually hepatocellular, but mixed and cholestatic forms have also been described. Fatal cases have been described but their relatedness to duloxetine has been quesitoned. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8.1X10+4(SRC), determined from a structure estimation method(2), indicates that duloxetine is expected to be immobile in soil(SRC). The estimated pKa of duloxetine is 9.70(3), 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(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Duloxetine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8.1X10+4(SRC), determined from a structure estimation method(2), indicates that duloxetine is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.70(3) indicates duloxetine will exist almost entirely in the cation or anion 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 370(SRC), from an estimated log Kow of 4.68(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data in water were not available(SRC, 2015).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), duloxetine, which has an estimated vapor pressure of 1.2X10-7 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 duloxetine 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 25 min(SRC), calculated from its rate constant of 3.13X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase duloxetine may be removed from the air by wet and dry deposition(SRC). Duloxetine contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Duloxetine hydrochloride is used for the acute management of generalized anxiety disorder in adults, the management of neuropathic pain associated with diabetic peripheral neuropathy in adults, the management of fibromyalgia in adults, the management of moderate to severe stress urinary incontinence (SUI) in women, and the acute and maintenance treatment of major depressive disorder in adults. HUMAN EXPOSURE AND TOXICITY: Possible risk of severe hepatic toxicity; elevated serum transaminase concentrations, sometimes requiring discontinuance of duloxetine, have been reported. In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. A higher proportion of patients reporting discontinuation-emergent adverse events were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one discontinuation-emergent adverse event differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of discontinuation-emergent adverse events. Abrupt discontinuation of duloxetine is associated with a discontinuation-emergent adverse event profile similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants ANIMAL STUDIES: Duloxetine was administered in the diet to mice for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (6 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/ sq m basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (2 times the MRHD). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (4 times the MRHD). Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (4 times the MRHD) did not alter mating or fertility. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/sq m basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. Duloxetine was not mutagenic in the bacterial reverse mutation assay (Ames test), and not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, it was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA assay in rat hepatocytes, and did not induce in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

Fatal outcomes have occurred with overdoses at as low as 1000 mg. Signs and symptoms of overdose include serotonin syndrome, seizures, coma, somnolence, syncope, tachycardia, autonomic instability, diarrhea, and vomiting. Signs of serotonin syndrome include agitation, restlessness, disorientation, diaphoresis, hyperthermia, tachycardia, nausea, vomiting, tremor, muscle rigidity, hyperreflexia, myoclonus, dilated pupils, dry mucous membranes, and increased bowel sounds. Clonus and hyperreflexia are particularly common in serotonin syndrome.

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. The antidepressant and pain inhibitory actions of duloxetine are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. The mechanism of action of duloxetine in SUI has not been determined, but is thought to be associated with the potentiation of serotonin and norepinephrine activity in the spinal cord, which increases urethral closure forces and thereby reduces involuntary urine loss.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of duloxetine can be estimated to be 8.1X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that duloxetine is expected to be immobile in soil. The estimated pKa of duloxetine is 9.70(3), 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(4). Duloxetine, present at 0.08 ug/L, exhibited Kd values of 1.3X10+4, 3.2X10+3 and 2.9X10+3 in primary, secondary sludge (short age) and secondary sludge (long age), respectively(5).

/SIGNS AND SYMPTOMS/ In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

/SIGNS AND SYMPTOMS/ Possible risk of severe hepatic toxicity; elevated serum transaminase concentrations, sometimes requiring discontinuance of duloxetine, have been reported. Laboratory findings suggestive of severe liver injury (e.g., increased serum transaminase, bilirubin, and alkaline phosphatase concentrations) with evidence of obstruction were reported in 3 patients who received duloxetine in clinical studies. Because there was evidence of substantial alcohol use in these patients that may have contributed to the abnormalities, duloxetine should not ordinarily be prescribed to patients with a history of excessive alcohol consumption.

/EPIDEMIOLOGY STUDIES/ Data were obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder (MDD). In a pooled analysis of 6 short-term treatment trials, in which treatment was stopped abruptly, discontinuation-emergent adverse events (DEAEs) were reported by 44.3% and 22.9% of duloxetine- and placebo-treated patients, respectively (p<0.05). Among duloxetine-treated patients reporting at least 1 discontinuation-emergent adverse event, the mean number of symptoms was 2.4. discontinuation-emergent adverse events reported significantly more frequently on abrupt discontinuation of duloxetine compared with placebo were dizziness (12.4%), nausea (5.9%), headache (5.3%), paresthesia (2.9%), vomiting (2.4%), irritability (2.4%), and nightmares (2.0%). Dizziness was also the most frequently reported discontinuation-emergent adverse event in the analyses of 3 long-term duloxetine studies. Across the short- and long-term data sets, 45.1% of discontinuation-emergent adverse events had resolved in the duloxetine-treated populations by the end of the respective studies, and the majority of these (65.0%) resolved within 7 days. Most patients rated the severity of their symptoms as mild or moderate. A higher proportion of patients reporting discontinuation-emergent adverse events were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one discontinuation-emergent adverse event differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of discontinuation-emergent adverse events. Abrupt discontinuation of duloxetine is associated with a discontinuation-emergent adverse event profile similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. It is recommended that, whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment.

/SIGNS AND SYMPTOMS/ The most frequently observed adverse reactions in the clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as CYMBALTA.

For more Human Toxicity Excerpts (Complete) data for DULOXETINE (8 total), please visit the HSDB record page.

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

N06AX21

N - Nervous system

QN - Nervous system

Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling.

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT₂, 5-HT₃, and α₁ adrenergic receptors. 5-HT₂ and α₁ are both G_q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP₃/PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT₃ functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT₂, 5-HT₃, α₁-adrenergic, and α₂-adrenergic receptors. 5-HT₂, 5-HT₃, and α₁-adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT₁ and α₂ receptors are G_i/G_o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α₁ receptors predominates, vasoconstriction results as the G_q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction.

Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). CYMBALTA is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with CYMBALTA, consideration should be given to the possibility that they might be drug-related.

Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

Mean of 12 h with a range of 8-17.

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range.

Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor. 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.

Biotransformation and disposition of duloxetine in humans have been determined following oral administration of (14C)-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate.

Duloxetine has known human metabolites that include 4-Hydroxyduloxetine, 5-((S)-3-Methylamino-1-thiophen-2-yl-propoxy)-naphthalen-2-ol, and 5-Hydroxyduloxetine.

The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. The major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Route of Elimination: Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Half Life: 12 hours (range 8-17 hours)

O5TNM5N07U

DULOXETINE

Mechanisms of Action [MoA] - Norepinephrine Uptake Inhibitors

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

Mechanisms of Action [MoA] - Serotonin Uptake Inhibitors

Duloxetine is a Serotonin and Norepinephrine Reuptake Inhibitor. The mechanism of action of duloxetine is as a Norepinephrine Uptake Inhibitor and Serotonin Uptake Inhibitor.

Compounds capable of relieving pain without the loss of CONSCIOUSNESS.

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.

Any drugs that are used for their effects on dopamine receptors, on the life cycle of dopamine, or on the survival of dopaminergic neurons.

Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. 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. 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. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree.

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

Apparent Vd of 1620-1800 L. Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma.

There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. 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.

Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.

MEDICATION

Adrenergic Uptake Inhibitors; Analgesics; Antidepressive Agents; Dopamine Uptake Inhibitors; Serotonin Uptake Inhibitors

Use (kg; approx.) in Germany (2009): >2500

For the acute and maintenance treatment of major depressive disorder (MDD), as well as acute management of generalized anxiety disorder. Also used for the management of neuropathic pain associated with diabetic peripheral neuropathy, and fibromyalgia. Has been used in the management of moderate to severe stress urinary incontinence (SUI) in women.

Reaction of 2-acetylthiophene with paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-1-propanone, which is enantioselectively reduced with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol and LiAlH4 in toluene to yield (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol. The condensation of (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol with 1-fluoronaphthalene catalyzed by NaH in DMSO affords the corresponding naphthyl ether (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine, which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and zinc in toluene and treated with oxalic acid.

Preparation: D. W. Robertson et al., European Patent Office patent 273658; eidem, United States of America patent 5023269 (1988, 1991 both to Lilly) ... Improved process: R. A. Berglund, United States of America patent 5362886 (1994 to Lilly).