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DEA NFLIS-Drug Category -> Antidepressants

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Nervous system -> Psychoanaleptics

Pharmaceuticals -> SSRIs (Selective Serotonin Reuptake Inhibitors)

Pharmaceuticals -> Listed in ZINC15

log Kow = 1.23

3.6

4.07

Odorless, off-white powder, mp 147-150 °C . Solubility in water: >1 g/mL/Paroxetine methanesulfonate/

In water, 1,131 mg/L at 25 °C

8.53e-03 g/L

Antidepressants -> Selective serotonin reuptake inhibitors (SSRI)

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Serotonin Uptake Inhibitors

Pharmaceuticals

120-138

Odorless off-white powder; molecular weight: 374.84; melting point: 120-138 °C /Hydrochloride hemihydrate/

129 - 131 °C

9.51

9.90

pKa1 = 9.6 /secondary amine/

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

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

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

183.61 Ų [M+H]+

Crystals; melting point: 129-131 °C; solubility in water: 5.4 mg/mL /Paroxetine hydrochloride hemihydrate/

Crystals from ethanol-ether; melting point: 136-138 °C; Specific optical rotation for the D (sodium) line: -87 deg (c= 5 in ethanol) /paroxetine maleate/

This chemical does not meet GHS hazard criteria for 16.7% (1 of 6) of reports.

Danger

H302 (66.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P264, P270, P273, P280, P301+P317, P318, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 6 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

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

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

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

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Paroxetine hydrochloride hemihydrate/

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. /Paroxetine hydrochloride hemihydrate/

Store tablets between 15 deg and 30 °C (59 deg and 86 °F). ... Store suspension at or below 25 °C (77 °F).

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Paroxetine hydrochloride hemihydrate/

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.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Contaminated packaging: Dispose of as unused product. /Paroxetine hydrochloride hemihydrate/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Paroxetine hydrochloride hemihydrate/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Paroxetine hydrochloride hemihydrate/

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. /Paroxetine hydrochloride hemihydrate/

Skin protection: Handle with gloves. /Paroxetine hydrochloride hemihydrate/

Eye/face protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Paroxetine hydrochloride hemihydrate/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Paroxetine hydrochloride hemihydrate/

Body Protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Paroxetine hydrochloride hemihydrate/

Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of major depressive disorder. 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 paroxetine are known. (L1712)

Rhodiola rosea (Russian Rhodiola/Golden Root) is a high mountain plant from the arctic regions of Europe and Asia which has the active substance phenylpropanoide. It has sedative, anti-depressive, drive-enhancing and stress-modulated properties stimulating the distribution of dopamine and serotonin; in combination with other drugs, an increase of side effects and risk profile has to be expected. A case report is presented in order to illustrate the interaction between Rhodiola rosea and antidepressants. We report the case of a 68-year-old female patient with recurrent moderate depressive disorder with somatic syndrome (ICD-10 F33.11) who developed vegetative syndrome, restlessness feeling and trembling since she began to ingest Rhodiola rosea in addition to paroxetine. Prescribing Rhodiola rosea with paroxetine, pharmacokinetic and -dynamic interactions have to be assumed. The symptoms of the patient can be interpreted as a serotonergic syndrome. Because of its different effects, the plant is widely used. An increase of clinical relevant risks should be considered in the add-on treatments.

A 74-year-old man with depressive symptoms was admitted to a psychiatric hospital due to insomnia, loss of appetite, exhaustion, and agitation. Medical treatment was initiated at a daily dose of 20 mg paroxetine and 1.2 mg alprazolam. On the 10th day of paroxetine and alprazolam treatment, the patient exhibited marked psychomotor retardation, disorientation, and severe muscle rigidity with tremors. The patient had a fever (38.2 degrees C), fluctuating blood pressure (between 165/90 and 130/70 mg mm Hg), and severe extrapyramidal symptoms. Laboratory tests showed an elevation of creatine phosphokinase (2218 IU/L), aspartate aminotransferase (134 IU/L), alanine aminotransferase (78 IU/L), and BUN (27.9 mg/ml) levels. The patient received bromocriptine and diazepam to treat his symptoms. 7 days later, the fever disappeared and the patient's serum CPK levels were normalized (175 IU/L). This patient presented with symptoms of neuroleptic malignant syndrome (NMS), thus demonstrating that NMS-like symptoms can occur after combined paroxetine and alprazolam treatment. The adverse drug reaction score obtained by the Naranjo algorithm was 6 in our case, indicating a probable relationship between the patient's NMS-like adverse symptoms and the combined treatment used in this case. The involvement of physiologic and environmental aspects specific to this patient was suspected. Several risk factors for NMS should be noted in elderly depressive patients whose symptoms often include dehydration, agitation, malnutrition, and exhaustion. Careful therapeutic intervention is necessary in cases involving elderly patients who suffer from depression.

Serotonin toxicity is an iatrogenic complication of serotonergic drug therapy. It is due to an overstimulation of central and peripheral serotonin receptors that lead to neuromuscular, mental and autonomic changes. Moclobemide is a reversible inhibitor of monoamine oxidase (MAO)-A, selegiline is an irreversible selective inhibitor of MAO-B, and paroxetine is a selective serotonin reuptake inhibitor. Combined use of these agents is known to cause serotonin toxicity. A 53-year-old woman had been treated with paroxetine and selegiline. After moclobemide was prescribed in place of paroxetine without a washout period, she quickly developed confusion, agitation, ataxia, diaphoresis, tremor, mydriasis, ocular clonus, hyperreflexia, tachycardia, moderately elevated blood pressure and high fever, symptoms that were consistent with serotonin toxicity. Discontinuation of the drugs, hydration and supportive care were followed by remarkable improvement of baseline status within 3 days. This case demonstrates that serotonin toxicity may occur even with small doses of paroxetine, selegiline and moclobemide in combination. Physicians managing patients with depression must be aware of the potential for serotonin toxicity and should be able to recognize and treat or, ideally, anticipate and avoid this pharmacodynamically-mediated interaction that may occur between prescribed drugs.

A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 ug/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. ... According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors.

For more Interactions (Complete) data for PAROXETINE (53 total), please visit the HSDB record page.

Liver test abnormalities have been reported to occur in up to 1% of patients on paroxetine, but 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 paroxetine. The onset of injury is usually within 2 to 16 weeks, but can be more delayed, to up to 1 year. The pattern of serum enzyme elevations varies from hepatocellular to mixed or cholestatic. While most cases are mild-to-moderate in severity, severe cases with hepatic failure have been reported. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

EC50; Species: Xenopus laevis (African Clawed Frog) blastula; Conditions: freshwater, renewal, 23 °C, pH 6.5-9.0; Concentration: 4600 ug/L for 96 hr; Effect: development, increased deformation /98% purity/

LC50; Species: Ceriodaphnia dubia (Water Flea) age <24 hr neonate, 3rd or 4th brood; Conditions: freshwater, static, 24-26 °C, pH 8.1-8.35, hardness 78-93 mg/L CaCO3, alkalinity 64-78 mg/L CaCO3, dissolved oxygen 5.6-6.8 mg/L; Concentration: 580 ug/L for 48 hr /99.86% purity/

TERRESTRIAL FATE: Based on a classification scheme(1), a Koc range 8,128 to 2.9X10+5(2) indicates that paroxetine is expected to be immobile in soil(SRC). The pKa of paroxetine is 9.6(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 ation and cations do not volatilize. Paroxetine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.8X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Biodegradation data in soil were not available(SRC, 2015).

AQUATIC FATE: Based on a classification scheme(1), a Koc range of 8,128 to 2.9X10+5(2) indicates that paroxetine is expected to adsorb to suspended solids and sediment(SRC). A pKa of 9.6(3) indicates paroxetine 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 3(SRC), from its log Kow of 1.23(3) and a regression-derived equation(5), suggests the potential for bioconcentration in aquatic organisms is low(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), paroxetine, which has an estimated vapor pressure of 4.8X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase paroxetine may be removed from the air by wet and dry deposition(SRC). Photodegradation first order rate constants of 0.29 and 0.27/hr were reported with half-lives of 2.6 and 2.4 hours, respectively(3).

Many of the side effects of paroxetine are dose-dependent. The most common side effects include drowsiness, dry mouth, loss of appetite, sweating, sleep disturbance, and sexual side effects. Clinicians can address sexual side effects medications like sildenafil). Discontinuation syndrome is more common and more severe with paroxetine than with other SSRIs; this may be due in part to the fact that it inhibits its own metabolism. Withdrawal symptoms from discontinuation include dizziness, lethargy, nausea, vomiting, headache, fever, chills, vivid dreams, electric shock-like-sensation, dyskinesia, anxiety, crying, irritability, and depersonalization.

Paroxetine hydrochloride is slowly, but completely absorbed following oral administration. Paroxetine mesylate salt is also completely absorbed after oral dosing. The oral bioavailability appears to be low due to extensive first-pass metabolism. Paroxetine hydrochloride oral tablets and suspension are reportedly bioequivalent. Absorption of either salt form is not substantially affected by food. Peak concentrations of Brisbelle (mesylate salt) were reached at 6 hours (3 to 8 hours range). Steady state Cmax was 13.10 ng/mL. The steady state AUC (0-last) was 237 hr*ng/mL. Paroxetine mesylate generally follows non-linear pharmacokinetics because CYP2D6, the enzyme that is part responisible for paroxetine metabolism, is readily saturable.

EXPERIMENTAL: The study was carried out to quantify the excretion of the selective serotonin reuptake inhibitor paroxetine in breast milk. In 6 lactating women, the concentrations of paroxetine in breast milk and serum were studied at the times for assumed minimum (24 hours after dose intake) and maximum (4-7 hours after dose intake) drug levels in milk. Moreover, a seventh subject was studied with frequent and regular sampling throughout a dose interval of 24 hours at 2 different dose levels. The mean milk/serum concentration ratios in the first 6 subjects ranged from 0.39 to 1.11 (overall mean +/- SD = 0.69 +/- 0.29), and the mean estimated dose to the infants ranged from 0.7% to 2.9% (overall mean +/- SD = 1.4% +/- 0.79%) of the weight-adjusted maternal dose. Based on area-under-the-curve data from the seventh subject, the milk/serum concentration ratio was 0.69 at a dose of 20 mg/day and 0.72 at a dose of 40 mg/day; the estimated relative doses to the infant were 1.0% and 2.0%, respectively. The mean increase in milk paroxetine concentrations from assumed minimum to assumed maximum was 61% (range, 4%-172%; p < .01). The mean paroxetine concentration in hindmilk was 78% higher than in foremilk (range, 16%-169%; p < .01), an increase that was parallel to the increase in milk triglyceride levels (r = 0.83, p = 0.005). No adverse drug reactions or unusual behaviors were reported in the infants. CONCLUSION: The study indicates that the relative dose to a suckling infant for paroxetine is lower than that reported for fluoxetine and citalopram and higher than that reported for sertraline and fluvoxamine.

IDENTIFICATION AND USE: Paroxetine is an odorless off-white powder formulated into an oral suspension, extended-release film-coated tablets, or film-coated tablets. Paroxetine a second generation selective serotonin-reuptake inhibitor is used for the treatment of major depressive disorder, obsessive and compulsive disorder, panic disorder, social anxiety disorders, general anxiety disorders, and posttraumatic stress disorder. Paroxetine has more recently been approved for use in the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. HUMAN EXPOSURE AND TOXICITY: Spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported; some of these cases were fatal and some of the fatalities appeared to involve paroxetine alone. Commonly reported adverse reactions associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsades de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention. During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine. During premarketing testing, hypomania or mania occurred in approximately 1.0% of paroxetine-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine and 11.6% for the combined active-control groups. Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported in paroxetine-treated patients. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. Perinatal adverse effects, including respiratory distress and neonatal adaptation problems are common in exposed infants, and an increased risk for persistent pulmonary hypertension of the newborn (PPHN) has been observed. Also, some neonates exposed to paroxetine and other selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) late in the third trimester of pregnancy have developed complications that occasionally have been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special care nurseries. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Genotoxicity tests for cytogenetic aberrations in vitro in human lymphocytes were negative. ANIMAL STUDIES: Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Reproduction studies in rats receiving oral paroxetine dosages of 50 mg/kg daily and in rabbits receiving 6 mg/kg daily during organogenesis have been conducted. Although these studies have not revealed evidence of teratogenicity, an increase in pup deaths was observed in rats during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg daily. A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day. Paroxetine produced no genotoxic effects in a battery of in vitro and in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in a dominant lethal test in rats.

Though it is rarely lethal in overdose by itself, patients can develop somnolence, nausea, tremor, heart rhythm disturbances, confusion, vomiting, dizziness, and mydriasis. During toxicity, a patient’s airway, oxygenation, and ventilation require evaluation first. The treatment for overdose includes symptomatic supportive treatment. There is no specific treatment for paroxetine toxicity.

Paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake. Paroxetine likely inhibits the reuptake of serotonin at the neuronal membrane, enhances serotonergic neurotransmission by reducing turnover of the neurotransmitter, therefore it prolongs its activity at synaptic receptor sites and potentiates 5-HT in the CNS; paroxetine is more potent than both sertraline and fluoxetine in its ability to inhibit 5-HT reuptake. Compared to the tricyclic antidepressants, SSRIs have dramatically decreased binding to histamine, acetylcholine, and norepinephrine receptors. The mechanism of action for the treatment of vasomotor symptoms is unknown.

/AQUATIC SPECIES/ Selective serotonin reuptake inhibitors (SSRIs) are neurologically active drugs that can contaminate surface waters and have the potential to negatively affect aquatic organisms. In this investigation, the 48 hr acute toxicity of mixtures (binary and quaternary) of four common SSRIs (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil], and citalopram [Celexa]) were determined in the daphnid Ceriodaphnia dubia. Logistic regression was used to model mortality data and to investigate the applicability of concentration addition and independent action models to explain observed mortality. The concentrations estimated to induce 50% mortality in 48 hr for the individual SSRIs sertraline, fluoxetine, paroxetine, and citalopram were 0.48 to 0.66, 1.23 to 1.84, 2.23 to 3.57, and 10.47 to 14.53 uM, respectively. Concentration addition was a better predictor of mixture effects than independent action and suggested that the tested SSRIs have a similar mechanism of action. Results indicate that environmental hazard assessments should be conservative and consider that acutely toxic effects in aquatic organisms can be additive for each SSRI in a mixture.

/AQUATIC SPECIES/ ...In this investigation, the acute and chronic toxicity of five /selective serotonin reuptake inhibitors/ (SSRIs) (fluoxetine, Prozac; fluvoxamine, Luvox; paroxetine, Paxil; citalopram, Celexa; and sertraline, Zoloft) were evaluated in the daphnid Ceriodaphnia dubia. For each SSRI, the 48 hr median lethal concentration (LC50) was determined in three static tests with neonate C. dubia, and chronic (8 day) tests were conducted to determine no-observable-effect concentrations (NOEC) and lowest-observable-effect concentrations (LOEC) for reproduction endpoints. The 48 hr LC50 for the SSRIs ranged from 0.12 to 3.90 mg/L and the order of toxicity of the compounds was (lowest to highest): Citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline. Mortality data for the 8 day chronic tests were similar to the 48 hr acute data. The SSRIs negatively affected C. dubia reproduction by reducing the number of neonates per female, and for some SSRIs, by reducing the number of broods per female. For sertraline, the most toxic SSRI, the LOEC for the number of neonates per female was 0.045 mg/L and the NOEC was 0.009 mg/L. Results indicate that SSRIs can impact survival and reproduction of C. dubia; however, only at concentrations that are considerably higher than those expected in the environment.

/AQUATIC SPECIES/ ...In the present study, ... the toxicities of five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) as single substances and of citalopram, fluoxetine, and sertraline in binary mixtures /were tested/ in two standardized bioassays. Test organisms were the freshwater algae Pseudokirchneriella subcapitata and the freshwater crustacean Daphnia magna. In algae, test median effect concentrations (EC50s) ranged from 0.027 to 1.6 mg/L, and in daphnids, test EC50s ranged from 0.92 to 20 mg/L, with sertraline being one of the most toxic compounds. ...

Paroxetine was not detected in 84 samples of wastewater from treatment plants at the Spanish Mediterranean area of Valencia. Sampling occurred in June 2008, January 2009, April 2009, and October 2009; detection limit range = 0.17 to 0.27 ug/L(1). Paroxetine was analyzed for but not detected in effluents from 90 European wastewater treatment plants, sampled in 2010(2). The compound was not detected in sewage from Tromso Norway(3).

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

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

N - Nervous system

QN - Nervous system

Paroxetine treats the symptoms of depression, various anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, and the vasomotor symptoms of menopause via the inhibition of serotonin reuptake. The onset of action of paroxetine is reported to be approximately 6 weeks. Due its serotonergic activity, paroxetine, like other SSRI drugs, may potentiate serotonin syndrome. This risk is especially high when monoamine oxidase (MAO) inhibitors are given within 2 weeks of paroxetine administration. Upon cessation of MAO inhibitors, a 2-week interval before paroxetine administration is recommended. Do not coadminister these agents.

Paroxetine enhances serotonergic activity via the inhibition presynaptic reuptake of serotonin by the serotonin (SERT) receptor. This inhibition raises the level of serotonin in the synaptic cleft, relieving various symptoms. This drug has been demonstrated to be a stronger inhibitor of serotonin reuptake than other members of the same drug class, including [Citalopram], [Fluoxetine], and [Fluvoxamine]. The mechanism of action of paroxetine in relieving the vasomotor symptoms of menopause is unknown, according to the Brisdelle prescribing information, but may occur due to its effects on thermoregulation. Paroxetine shows a clinically insignificant affinity for adrenergic alpha-1 and alpha-2 receptors and β-adrenergic receptors, dopamine D1 and D2 receptors, histamine H1 receptors and serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors. This drug shows some affinity for muscarinic cholinergic receptors and 5-H2B receptors. The delayed onset of paroxetine therapeutic effects may be explained by the initial paroxetine actions on the 5-HT neurons. In rats, paroxetine activates 5-HT1A receptors when it is first administered, inhibiting the stimulation of the 5-HT neurons and subsequent release of serotonin at the synaptic cleft.

Functional and structural approaches were used to examine the inhibitory mechanisms and binding site location for fluoxetine and paroxetine, two serotonin selective reuptake inhibitors, on nicotinic acetylcholine receptors (AChRs) in different conformational states. The results establish that: (a) fluoxetine and paroxetine inhibit h alpha1beta1 gammadelta AChR-induced Ca(2+) influx with higher potencies than dizocilpine. The potency of fluoxetine is increased approximately 10-fold after longer pre-incubation periods, which is in agreement with the enhancement of (3)H-cytisine binding to resting but activatable Torpedo AChRs elicited by these antidepressants, (b) fluoxetine and paroxetine inhibit the binding of the phencyclidine analog piperidyl-3,4-(3)H(N)]-(N-(1-(2 thienyl)cyclohexyl)-3,4-piperidine to the desensitized Torpedo AChR with higher affinities compared to the resting AChR, and (c) fluoxetine inhibits (3)H-dizocilpine binding to the desensitized AChR, suggesting a mutually exclusive interaction. This is supported by our molecular docking results where neutral dizocilpine and fluoxetine and the conformer of protonated fluoxetine with the highest LUDI score interact with the domain between the valine (position 13') and leucine (position 9') rings. Molecular mechanics calculations also evidence electrostatic interactions of protonated fluoxetine at positions 20', 21', and 24'. Protonated dizocilpine bridges these two binding domains by interacting with the valine and outer (position 20') rings. The high proportion of protonated fluoxetine and dizocilpine calculated at physiological pH suggests that the protonated drugs can be attracted to the channel mouth before binding deeper within the AChR ion channel between the leucine and valine rings, a domain shared with phencyclidine, finally blocking ion flux and inducing AChR desensitization.

Paroxetine was shown to be a potent (Ki = 1.1 nM) and specific inhibitor of [3H]-5-hydroxytryptamine (5-HT) uptake into rat cortical and hypothalamic synaptosomes in vitro. Lineweaver-Burk kinetic analysis determined that this inhibition was competitive in nature, implying a direct interaction with the 5-HT uptake transporter complex. Oral administration of paroxetine produced a dose-related inhibition of [3H]-5-HT uptake (ED50 = 1.9 mg/kg) into rat hypothalamic synaptosomes ex vivo with little effect on [3H]-l-noradrenaline (NA) uptake (ED50 greater than 30 mg/kg). This selectivity for 5-HT uptake was maintained after oral dosing for 14 days. Paroxetine (ED50 1-3 mg/kg PO) prevented the 5-HT depleting effect of p-chloroamphetamine (PCA) in rat brain, demonstrating 5-HT uptake blockade in vivo. Radioligand binding techniques in rat brain in vitro showed that paroxetine has little affinity for alpha 1, alpha 2 or beta adrenoceptors, dopamine (D2), 5-HT1, 5-HT2 or histamine (H1) receptors at concentrations below 1000 nM. Paroxetine demonstrated weak affinity for muscarinic receptors (Ki = 89 nM) but was at least 15 fold weaker than amitriptyline (Ki = 5.1 nM). Paroxetine, therefore, provides a useful pharmacological tool for investigating 5-HT systems and furthermore should be an antidepressant with reduced tricyclic-like side-effects.

The precise mechanism of antidepressant action of paroxetine is unclear, but the drug has been shown to selectively inhibit the reuptake of serotonin at the presynaptic neuronal membrane. Paroxetine-induced inhibition of serotonin reuptake causes increased synaptic concentrations of serotonin in the CNS, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission. Like other SSRIs (e.g., citalopram, fluoxetine, fluvoxamine, sertraline), paroxetine appears to have only very weak effects on the reuptake of norepinephrine or dopamine and does not exhibit clinically important anticholinergic, antihistaminic, or adrenergic (a1, a2, beta) blocking activity at usual therapeutic dosages. Although the mechanism of antidepressant action of antidepressant agents may involve inhibition of the reuptake of various neurotransmitters (i.e., serotonin, norepinephrine) at the presynaptic neuronal membrane, it has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents. During long-term therapy with most antidepressants (e.g., tricyclic antidepressants, monoamine oxidase (MAO) inhibitors), these adaptive changes mainly consist of subsensitivity of the noradrenergic adenylate cyclase system in association with a decrease in the number of beta-adrenergic receptors; such effects on noradrenergic receptor function are commonly referred to as down regulation. However, in an animal study, long-term administration of paroxetine was not shown to downregulate noradrenergic receptors in the CNS as has been observed with many other clinically effective antidepressants. In addition, some antidepressants (e.g., amitriptyline) reportedly decrease the number of serotonergic (5-HT) binding sites following chronic administration.

Reduced glucose metabolism has been implicated as a pathophysiology of depressive disorder. Normalization of such impaired neurometabolism has been related to the therapeutic actions of antidepressant medication. However, the molecular mechanism underlying the neurometabolic actions of antidepressants has not been fully understood. Given that AMP-activated protein kinase (AMPK) is a master switch for energy homeostasis, we aimed to determine whether selective serotonin reuptake inhibitor paroxetine enhances energy metabolism by activating AMPK in neuroblastoma cells. We found that paroxetine dose dependently increased mitochondrial biogenesis, which involves the AMPK-peroxisome proliferator-activated receptor-gamma coactivator-1a pathway. In addition, paroxetine-induced AMPK activation increases glucose uptake and ATP production. These neurometabolic effects of paroxetine were suppressed by cotreatment with compound C (CC), an AMPK inhibitor. These findings suggest a possibility that modulation of the AMPK pathway might be a previously unrecognized mechanism underlying the neurometabolic action of antidepressants. Further study is warranted to examine the region-specific and time-specific effects of AMPK modulation by antidepressants on mood-related behaviors.

For more Mechanism of Action (Complete) data for PAROXETINE (9 total), please visit the HSDB record page.

The mean elimination half-life of paroxetine is about 21 hours. In healthy young subjects, mean elimination half-life was found to be 17.3 hours.

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean ... half life was ... 21.0 hours (CV 32%) ... .

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of Paxil.

The elimination half-life of paroxetine when administered as paroxetine hydrochloride averages approximately 21-24 hours, although there is wide interpatient variation with half-lives (ranging from 7-65 hours in one study). In healthy males receiving one 30-mg tablet of paroxetine (administered as paroxetine mesylate) once daily for 24 days, the mean paroxetine half-life was 33.2 hours. In geriatric individuals, elimination half-life of paroxetine (administered as paroxetine hydrochloride) may be increased (e.g., to about 36 hours).

Paroxetine metabolism occurs in the liver and is largely mediated by cytochrome CYP2D6 with contributions from CYP3A4 and possibly other cytochrome enzymes. Genetic polymorphisms of the CYP2D6 enzyme may alter the pharmacokinetics of this drug. Poor metabolizers may demonstrate increased adverse effects while rapid metabolizers may experience decreased therapeutic effects. The majority of a paroxetine dose is oxidized to a catechol metabolite that is subsequently converted to both glucuronide and sulfate metabolites via methylation and conjugation. In rat synaptosomes, the glucuronide and sulfate conjugates have been shown to thousands of times less potent than paroxetine itself. The metabolites of paroxetine are considered inactive.

The exact metabolic fate of paroxetine has not been fully elucidated; however, paroxetine is extensively metabolized, probably in the liver. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared by the body. Conjugates with glucuronic acid and sulfate predominate, and the principal metabolites have been isolated and identified. The metabolites of paroxetine have been shown to possess no more than 2% of the potency of the parent compound as inhibitors of serotonin reuptake; therefore, they are essentially inactive.

Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions

Paroxetine has known human metabolites that include 4-[[(3S,4R)-4-(4-Fluorophenyl)piperidin-3-yl]methoxy]benzene-1,2-diol.

Paroxetine is extensively metabolized after oral administration, likely in the liver. The main metabolites are polar and conjugated products of oxidation and methylation, which are readily eliminated by the body. The predominant metabolites are glucuronic acid and sulfate conjugates. Paroxetine metabolites do not possess significant pharmacologic activity (less than 2% that of parent compound). Paroxetine is metabolized by cytochrome P450 (CYP) 2D6. Enzyme saturation appears to account for the nonlinear pharmacokinetics observed with increasing dose and duration of therapy. Route of Elimination: Approximately 64% of a 30 mg oral solution of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites. Approximately 36% of the dose was excreted in the feces (via bile), mostly as metabolites and less than 1% as parent compound. Half Life: 21-24 hours

41VRH5220H

PAROXETINE

Established Pharmacologic Class [EPC] - Serotonin Reuptake Inhibitor

Mechanisms of Action [MoA] - Serotonin Uptake Inhibitors

Paroxetine is a Serotonin Reuptake Inhibitor. The mechanism of action of paroxetine is as a Serotonin Uptake Inhibitor.

PAROXETINE

A structurally and mechanistically diverse group of drugs that are not tricyclics or monoamine oxidase inhibitors. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake.

Compounds that specifically inhibit the reuptake of serotonin in the brain.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2D6.

Paroxetine is readily absorbed from the gastrointestinal tract. Due to the first-pass metabolism, the bioavailability ranges from 30-60%. Cmax is attained 2 to 8 hours after an oral dose. Mean Tmax is 4.3 hours in healthy patients. The steady-state concentration of paroxetine is achieved within 7 to 14 days of oral therapy. In a pharmacokinetic study, AUC in healthy patients was 574 ng·h/mL and 1053 ng·h/mL in those with moderate renal impairment.

About 2/3 of a single paroxetine dose is found to be excreted in the urine and the remainder is found to be excreted in feces. Almost all of the dose is eliminated as metabolites; 3% is found to be excreted as unchanged paroxetine. About 64% of a 30 mg oral dose was found excreted in the urine, with 2% as the parent drug and 62% appearing as metabolites. Approximately 36% of the dose was found to be eliminated in the feces primarily as metabolites and less than 1% as the parent compound.

Paroxetine has a large volume of distribution and is found throughout the body, including in the central nervous system. Only 1% of the drug is found in the plasma. Paroxetine is found in the breast milk at concentrations similar to the concentrations found in plasma.

The apparent oral clearance of paroxetine is 167 L/h. The clearance of paroxetine in patients with renal failure is significantly lower and dose adjustment may be required, despite the fact that it is mainly cleared by the liver. Dose adjustments may be required in hepatic impairment.

Paroxetine hydrochloride appears to be slowly but well absorbed from the GI tract following oral administration. Although the oral bioavailability of paroxetine hydrochloride in humans has not been fully elucidated to date, the manufacturer states that paroxetine is completely absorbed after oral dosing of a solution of the hydrochloride salt. However, the relative proportion of an oral dose that reaches systemic circulation unchanged appears to be relatively small because paroxetine undergoes extensive first-pass metabolism. The oral tablets and suspension of paroxetine hydrochloride reportedly are bioequivalent.

In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.

THERAPEUTIC CATEGORY (VETERINARY): In treatment of canine and feline behavioral disorders

MEDICATION

Antidepressive Agents, Second-Generation; Serotonin Uptake Inhibitors

Use (kg; approx.) in Germany (2009): >1000

Labeled indications include: major depressive disorder (MDD), panic disorder with or without agoraphobia, obsessive-compulsive disorder (OCD), social anxiety disorder (social phobia), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and premenstrual dysphoric disorder (PMDD). Unlabeled indications include: eating disorders, impulse control disorders, vasomotor symptoms of menopause, obsessive-compulsive disorder (OCD) in children, and mild dementia-associated agitation in nonpsychotic individuals. Brisdelle, which consists of paroxetine mesylate is indicated for the treatment of moderate to severe vasomotor symptoms (like hot flashes) associated with menopause.

Grignard reaction of arecoline with 4-fluorophenylmagnesium bromide affords a cis-/trans mixture of methyl 4-(4-fluorophenyl)-N-methyl-nipecotate, which is hydrolyzed, converted into the acid chloride and esterified with (-)-menthol. The distilled methyl ester can be resolved via its hydrobromide salts to afford the (-)-trans form which upon reduction with LiAlH4 gives the desired (-)- trans alcohol. Conversion into the chloro compound with thionyl chloride and reaction with the sodium salt of 3,4-methylenedioxyphenol in refluxing methanol for 16 hr leads to the N-methyl derivative of ... /paroxetine/. N-demethylation is achieved by reaction with phenyl- or ethyl chloroformate and hydrolysis of the urethane with KOH.

Preparation: J. A. Christensen, R. F. Squires, German patent 2404113; eidem, United States of America patent 3912743; United States of America patent 4007196 (1974, 1975, 1977 all to Ferrosan).

Table: Paroxetine Hydrochloride Preparations [Table#6793]

Table: Paroxetine Mesylate Preparations [Table#6794]

Brisdelle is available as 7.5 mg pink capsules printed with black edible ink with "NOVEN" and "7.5 mg" on the capsule. Each capsule contains 9.69 mg paroxetine mesylate equivalent to 7.5 mg paroxetine base.