Paroxetine Mesylate (paroxetine mesylate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Paroxetine, a selective serotonin-reuptake inhibitor (SSRI), is an antidepressant agent.
Paroxetine is a potent and highly selective reuptake inhibitor of serotonin and has little or no effect on other neurotransmitters. At therapeutic dosages in humans, paroxetine has been shown to inhibit the reuptake of serotonin into platelets.
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 selective serotonin-reuptake inhibitor (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 (alpha1, alpha2, beta) blocking activity at usual therapeutic dosages.
The precise mechanism of action that is responsible for the efficacy of paroxetine in the treatment of obsessive-compulsive disorder is unclear. However, because of the potency of clomipramine and SSRIs (e.g., citalopram, fluoxetine, fluvoxamine, sertraline) in inhibiting serotonin reuptake and their efficacy in the treatment of obsessive-compulsive disorder, a serotonin hypothesis has been developed to explain the pathogenesis of the condition. The hypothesis postulates that a dysregulation of serotonin is responsible for obsessive-compulsive disorder and that paroxetine and these other agents are effective because they correct this imbalance.
Although the available evidence supports the serotonergic hypothesis of obsessive-compulsive disorder, additional studies are necessary to confirm this hypothesis.
The exact mechanism of action of paroxetine in panic disorder, social phobia, or generalized anxiety disorder has not been fully elucidated but appears to involve inhibition of reuptake of serotonin at the presynaptic membrane.
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The conventional oral tablets and suspension of paroxetine hydrochloride are bioequivalent. In healthy males receiving one 30-mg tablet of paroxetine (administered as paroxetine hydrochloride) once daily for 30 days, steady-state plasma paroxetine concentrations were achieved after approximately 10 days in most patients, although achievement of steady-state concentrations may take substantially longer in some patients.
At steady-state, mean peak plasma paroxetine concentrations of 61.7 ng/mL occurred after an average of 5.2 hours following oral administration; corresponding mean trough concentrations of 30.7 ng/mL were reported.
Paroxetine hydrochloride extended-release tablets consist of 2 layers: one layer of the tablet consists of a degradable barrier layer and the other contains the active material in a hydrophilic matrix. The absorption rate of paroxetine extended-release tablets is reduced compared with immediate-release formulations. The degradable polymeric matrix is designed to control the dissolution rate of paroxetine over a period of approximately 4--5 hours.
An enteric coating delays the start of drug release until the tablets have left the stomach. The time to maximum concentrations was observed between 6--10 hours post-dose. Steady state was achieved after 2 weeks of dosing.
Paroxetine mesylate is completely absorbed following oral administration of the capsules. The time to maximum plasma paroxetine concentration following paroxetine mesylate capsules was reached at a median of 6 hours. Steady state concentration of paroxetine mesylate capsules was achieved by 12 days.
Paroxetine can be administered with or without food. Administration of a single dose of paroxetine hydrochloride with food resulted in a 6% increase in the AUC, a 29% increase in peak plasma concentrations of the drug, and a decrease in the time to peak plasma concentrations from 6.4 to 4.9 hours.
Paroxetine distributes throughout the body, including the CNS and into human milk, with only 1% remaining in the plasma. Approximately 95 and 93% of paroxetine is bound to plasma proteins at plasma concentrations of 100 and 400 ng/mL, respectively. Under usual clinical conditions, plasma paroxetine concentrations would be less than 400 ng/mL.
In vitro, paroxetine does not alter the plasma protein binding of 2 other highly protein-bound drugs, phenytoin and warfarin.
The elimination half-life of paroxetine when administered as paroxetine hydrochloride is approximately 21 hours with the immediate-release formulation and between 15--20 hours with the extended-release formulation. Paroxetine is extensively metabolized. 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 partially metabolized by the drug metabolizing isoenzyme cytochrome P-450 (CYP) 2D6. Saturation of this enzyme at dosages used clinically appears to account for the nonlinearity of paroxetine kinetics observed with increasing dosage and duration of treatment. The role of the CYP2D6 enzyme in paroxetine metabolism also suggests potential drug-drug interactions.
In steady-state, dose-proportionality studies involving elderly and nonelderly patients receiving 20-40 and 20-50 mg daily of paroxetine (administered as paroxetine hydrochloride), respectively, some nonlinearity was observed in both groups, which suggests a saturable metabolic pathway. When compared with trough paroxetine concentrations after 20 mg of the drug daily, trough concentrations after 40 mg daily were approximately 2-3 times higher than doubled.
Following oral administration, paroxetine and its metabolites are excreted in both urine and feces. Following oral administration of a single, 30-mg dose of paroxetine (administered as paroxetine hydrochloride) as an oral solution approximately 64% of the dose was excreted in the urine within 10 days; unchanged paroxetine accounted for 2% of the dose and metabolites accounted for the remaining 62% of the dose. During the same period, approximately 36% of the dose was eliminated in feces (probably via the bile), mostly as metabolites and less than 1% as the parent drug.
Paroxetine is commercially available in the US as paroxetine hydrochloride and paroxetine mesylate.
Generic name: paroxetine mesylate
Pronunciation: (pa-ROX-e-teen)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Paroxetine Mesylate
Indications
The following indications are listed for Paroxetine Mesylate:
- Vasomotor Symptoms Associated With Menopause
Dosing
Dosages of paroxetine hydrochloride and paroxetine mesylate are expressed in terms of paroxetine.
When discontinuing paroxetine hydrochloride, gradually reduce the dosage rather than stopping the drug abruptly whenever possible. Adverse reactions may occur upon discontinuation of paroxetine.
Paroxetine is commercially available in the US as paroxetine hydrochloride conventional, film-coated tablets (e.g., Paxil(R)), extended-release tablets (e.g., Paxil CR(R)), and oral suspension and as paroxetine mesylate capsules. Conventional tablets of Paxil(R) and paroxetine mesylate capsules are not bioequivalent.
Paroxetine hydrochloride and paroxetine mesylate are administered orally.
Paroxetine hydrochloride conventional film-coated tablets, extended-release tablets, and suspension usually are administered once daily in the morning with or without food. Paroxetine hydrochloride oral suspension should be shaken well just prior to administration of each dose. Extended-release tablets of paroxetine hydrochloride should be swallowed whole and should not be chewed or crushed.
Paroxetine mesylate capsules are administered once daily at bedtime with or without food.
Paroxetine hydrochloride conventional tablets should be stored at 15-30degreesC. The oral suspension and extended-release tablets of paroxetine hydrochloride should be stored at or below 25degreesC. Paroxetine hydrochloride extended-release tablets may be exposed to temperatures ranging between 15degrees to 30degreesC.
Paroxetine mesylate conventional capsules should be stored at 20-25degreesC but may be exposed to temperatures ranging from 15-30degreesC; the capsules should be protected from light and humidity.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Paroxetine undergoes extensive hepatic metabolism via the cytochrome P-450 (CYP) 2D6 enzyme. Paroxetine is a strong CYP2D6 inhibitor.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Concomitant use of monoamine oxidase inhibitors (MAOIs) (including linezolid and IV methylene blue) or use within 14 days of discontinuing an MAOI, due to an increased risk of serotonin syndrome.
*Concomitant use of thioridazine, due to the risk of QT prolongation.
*Concomitant use of pimozide, due to the risk of QT prolongation.
*Known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients of the formulation.
*Paroxetine mesylate only: Pregnancy; vasomotor symptoms do not occur during pregnancy and paroxetine can cause fetal harm.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects with paroxetine hydrochloride conventional tablets and suspension (>=5% and at least twice placebo) are abnormal ejaculation, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, infection, insomnia, libido decreased, male genital disorder, nausea, nervousness, somnolence, sweating, tremor, and yawn.
The most common adverse effects with paroxetine hydrochloride extended-release tablets (>=5% and at least twice placebo) are abnormal ejaculation, abnormal vision, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, insomnia, libido decreased, nausea, somnolence, sweating, and tremor.
The most common adverse effects with paroxetine mesylate capsules (>=2% and at a higher incidence that placebo) are headache, fatigue, malaise, lethargy, nausea, and vomiting.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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The safety and effectiveness of paroxetine in pediatric patients have not been established. Effectiveness was not established in 3 studies comparing paroxetine to placebo in pediatric patients with MDD. The main safety concern is the increased risk of suicidal thoughts and behaviors.
Paroxetine mesylate capsules are not indicated for use in the pediatric population.
Paroxetine mesylate capsules are contraindicated for use in pregnant women because menopausal vasomotor symptoms do not occur during pregnancy and paroxetine can cause fetal harm.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including paroxetine, during pregnancy. Advise patients to register by calling the National Pregnancy Registry for Antidepressants 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi stry/antidepressants/.
Paroxetine is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. There are risks of persistent pulmonary hypertension of the newborn (PPHN) and/or poor neonatal adaptation with exposure during pregnancy. Use of paroxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. There also are risks associated with untreated depression in pregnancy. Additionally, women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. For women who intend to become pregnant or who are in their first trimester of pregnancy, initiate paroxetine only after consideration of the other available treatment options.
Data from the published literature report the presence of paroxetine in human milk. There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to paroxetine through breast milk. Monitor for these symptoms in infants exposed to paroxetine. There are no data on the effect of paroxetine on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for paroxetine and any potential adverse effects on the breast-fed child from paroxetine or from the underlying maternal condition.
Paroxetine hydrochloride conventional tablets or suspension: For elderly patients, the recommended initial dosage is 10 mg daily. Do not exceed 40 mg daily.
Paroxetine hydrochloride extended-release tablets: In elderly patients, the recommended initial dosage is 12.5 mg daily; if necessary, reduce the initial dose and increase the intervals between upward titration of the dosage. Do not exceed 50 mg daily for MDD or PD treatment. Do not exceed 37.5 mg daily for SAD treatment.
Paroxetine mesylate capsules: No dosage adjustment is necessary.
In premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose of paroxetine hydrochloride is recommended; however, no overall differences in safety or effectiveness were observed between elderly and younger patients. SSRIs including paroxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction.
Clinical studies of paroxetine mesylate capsules did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger subjects. Elderly patients may have elevated paroxetine plasma concentrations compared to younger patients. However, no dosage adjustment of paroxetine mesylate capsules is considered necessary in elderly patients.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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