Paroxetine hydrochloride

Paroxetine hydrochloride

Paroxetine hydrochloride

Paroxetine extended-release tablets contain paroxetine hydrochloride, an SSRI. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4′-fluorophenyl)-3S-[(3′,4’­ methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base).

Paroxetine hydrochloride hemihydrate, USP is an odorless, off-white powder, having a melting point range of 120° to 138°C and a solubility of 5.4 mg/mL in water.

Paroxetine extended-release tablets are intended for oral administration. Each extended-release tablet contains 12.5 mg, or 25 mg paroxetine equivalent to 14.25 mg, or 28.51 mg of paroxetine hydrochloride, respectively. One layer of the tablet consists of a degradable barrier layer and the other contains the active material in a hydrophilic matrix.

Inactive ingredients consist of hypromellose, povidone, lactose monohydrate, magnesium stearate, silicon dioxide, glyceryl behenate, methacrylic acid ethyl acrylate copolymer (1:1) type A (contains copolymer substance based on methacrylic acid and ethyl acrylate, sodium lauryl sulfate and polysorbate 80), polysorbate 80, talc, triethyl citrate, titanium dioxide and polyethylene glycol. In addition, 12.5 mg tablets contain yellow ferric oxide and red ferric oxide, while 25 mg tablets contain red ferric oxide.

In addition, the tablets are printed with black ink comprising of shellac glaze (modified) in SD-45, isopropyl alcohol, black iron oxide non-irradiated, n-butyl alcohol, propylene glycol and ammonium hydroxide.

FDA approved dissolution specifications differ from the USP dissolution specifications.

FDA approved dissolution test method differs from the USP dissolution test method.

INDICATIONS AND USAGE

Paroxetine extended-release tablets are indicated in adults for the treatment of:

  • Major depressive disorder (MDD)
  • Panic disorder (PD)
  • Social anxiety disorder (SAD)
  • Premenstrual dysphoric disorder (PMDD)

Mechanism of Action

The mechanism of action of paroxetine in the treatment of major depressive disorder (MDD), panic disorder (PD), social anxiety disorder (SAD), and premenstrual dysphoric disorder (PMDD) is unknown, but is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-HT)

DOSAGE AND ADMINISTRATION

Important Administration Instructions

Administer paroxetine extended-release tablets as a single daily dose in the morning, with or without food. Swallow tablets whole and do not chew or crush.

Dosage in Patients with Major Depressive Disorder, Panic Disorder, and Social Anxiety Disorder

In patients with an inadequate response, dosage may be increased in increments of 12.5 mg per day at intervals of at least 1 week, depending on tolerability.

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Dosage in Patients with Premenstrual Dysphoric Disorder

The recommended starting dosage in women with PMDD is 12.5 mg per day. Paroxetine extended-release tablets may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing is repeated with each new cycle.

In patients with an inadequate response, the dosage may be increased to the maximum recommended dosage of 25 mg per day, depending on tolerability. Institute dosage adjustments at intervals of at least 1 week.

Screen for Bipolar Disorder Prior to Starting Paroxetine Extended-Release Tablets

Prior to initiating treatment with paroxetine extended-release tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania

Dosage Modifications for Elderly Patients, Patients with Severe Renal Impairment and Patients with Severe Hepatic Impairment

The recommended initial dose of paroxetine extended-release tablets is 12.5 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment. Reduce initial dose and increase up-titration intervals if necessary. Dosage should not exceed 50 mg per day for MDD or PD and should not exceed 37.5 mg per day for SAD

Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of paroxetine extended-release tablets. In addition, at least 14 days must elapse after stopping paroxetine extended-release tablets before starting an MAOI antidepressant

Discontinuation of Treatment with Paroxetine Extended-Release Tablets

Adverse reactions may occur upon discontinuation of paroxetine extended-release tablets. Gradually reduce the dosage rather than stopping paroxetine extended-release tablets abruptly whenever possible.

CONTRAINDICATIONS

Paroxetine extended-release tablets are contraindicated in patients:

  • Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome
  • Taking thioridazine because of risk of QT prolongation
  • Taking pimozide because of risk of QT prolongation
  • With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in paroxetine extended-release tablets

WARNINGS AND PRECAUTIONS

Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If occurs, discontinue paroxetine extended-release tablets and initiate supportive measures.

Embryofetal and Neonatal Toxicity: Can cause fetal and neonatal harm. Increased risk of cardiovascular malformations for exposure during the first trimester. Exposure in late pregnancy may lead to an increased risk for persistent pulmonary hypertension (PPNH) of the newborn.

Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk.

Activation of Mania/Hypomania: Screen patients for bipolar disorder.

Seizures: Use with caution in patients with seizure disorders.

Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

Suicidal Thoughts and Behaviors in Adolescents and Young Adults: In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing paroxetine extended-release tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Drug Interactions Leading to QT Prolongation: The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of paroxetine extended-release tablets is contraindicated in combination with thioridazine and pimozide

Discontinuation Syndrome: Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible

Hyponatremia: Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including paroxetine extended-release tablets. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Reduction of Efficacy of Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced with concomitant use of paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen

Bone Fracture: Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment.

ADVERSE REACTIONS

Most common adverse reactions (≥5% and at least twice placebo) in placebo-controlled MDD, PD, SAD, and PMDD clinical trials: abnormal ejaculation, abnormal vision, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, insomnia, libido decreased, nausea, somnolence, sweating, tremor.

To report SUSPECTED ADVERSE REACTIONS, contact Sinotherapeutics Inc. at 1-877-382-6787 and/or at [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Pregnancy Category D: 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. If paroxetine is used during pregnancy, or if the patient becomes pregnant while taking paroxetine, advise the patient of the potential hazard to the fetus.

Treatment of Pregnant Women During Their Third Trimester: Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), including paroxetine extended-release tablets, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

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Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from paroxetine extended-release tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of paroxetine extended-release tablets in pediatric patients have not been established

Geriatric Use: SSRIs and SNRIs, including paroxetine extended-release tablets, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction

Renal and/or Hepatic Impairment: Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage should be reduced in patients with severe renal impairment and patients with severe hepatic impairment

OVERDOSAGE

Since the introduction of immediate-release paroxetine hydrochloride in the United States, spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide. These include overdoses with paroxetine alone and in combination with other substances. There are reports of fatalities that appear 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 torsade de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.

Overdose Management

No specific antidotes for paroxetine are known. If over-exposure occurs, all your poison control center at 1-800-222-1222 for latest recommendations.

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