PEXEVA® (paroxetine mesylate) tablets
PEXEVA contains paroxetine mesylate, an SSRI. It is the mesylate salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4′- fluorophenyl)-3S-[(3′,4′-methylenedioxyphenoxy) methyl] piperidine mesylate and has the empirical formula of C19H20FNO3•CH3SO3H. The molecular weight is 425.5 (329.4 as free base).
PEXEVA tablets are intended for oral administration. Each oval, film-coated tablet contains 10 mg, 20 mg, 30 mg, or 40 mg paroxetine equivalent to 12.9 mg, 25.8 mg, 38.8 mg, or 51.7 mg paroxetine mesylate, respectively. Inactive ingredients consist of dibasic calcium phosphate, hydroxypropyl methylcellulose, hydroxypropylcellulose, magnesium stearate, sodium starch glycolate, titanium dioxide, ferric oxide red (C.I. 77491) (20 mg and 40 mg only) and ferric oxide yellow (C.I. 77492) (20 mg, 30 mg, and 40 mg only).
INDICATIONS AND USAGE
PEXEVA is indicated in adults for the treatment of:
- Major depressive disorder (MDD)
- Obsessive-compulsive disorder (OCD)
- Panic disorder (PD)
- Generalized anxiety disorder (GAD)
Mechanism of Action
The mechanism of action of paroxetine in the treatment of major depressive disorder (MDD), obsessive compulsive disorder (OCD), panic disorder (PD), and general anxiety disorder (GAD) 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
Administer PEXEVA as a single daily dose in the morning, with or without food.
The recommended initial dosage and maximum dosage of PEXEVA in patients with MDD, OCD, PD, and GAD are presented in Table 1.
In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability.
|Indication||Starting Dose||Maximum Dose|
|MDD||20 mg||50 mg|
|OCD||20 mg||60 mg|
|PD||10 mg||60 mg|
|GAD||20 mg||50 mg|
Screen for Bipolar Disorder Prior to Starting PEXEVA
Prior to initiating treatment with PEXEVA or other antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania
Recommended Dosage Modifications for Elderly Patients, Patients with Severe Renal Impairment and Patients with Severe Hepatic Impairment
The recommended initial dose is 10 mg/day for elderly patients, patients with severe renal impairment and patients with severe hepatic impairment. Dosage should not exceed 40 mg/day.
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 PEXEVA. In addition, at least 14 days must elapse after stopping PEXEVA before starting an MAOI antidepressant.
Discontinuation of Treatment with PEXEVA
Adverse reactions may occur upon discontinuation of PEXEVA. Gradually reduce the dosage rather than stopping PEXEVA abruptly whenever possible.
PEXEVA is 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 PEXEVA
WARNINGS AND PRECAUTIONS
- Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. PEXEVA is not approved for use in pediatric patients.
- Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If occurs, discontinue PEXEVA 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 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
- Sexual Dysfunction: Pexeva may cause symptoms of sexual dysfunction
Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion (SIADH), prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura) and premature births in pregnant women. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.
|Monoamine Oxidase Inhibitors (MAOIs)|
|Clinical Impact||The concomitant use of SSRIs, including PEXEVA, and MAOIs increases the risk of serotonin syndrome|
|Intervention||PEXEVA is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue.|
|Examples||selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue|
|Pimozide and Thioridazine|
|Clinical Impact||Increased plasma concentrations of pimozide and thioridazine, drugs with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias.|
|Intervention||PEXEVA is contraindicated in patients taking pimozide or thioridazine.|
|Other Serotonergic Drugs|
|Clinical Impact||The concomitant use of serotonergic drugs with PEXEVA increases the risk of serotonin syndrome.|
|Intervention||Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of PEXEVA and/or concomitant serotonergic drugs.|
|Examples||other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort|
|Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)|
|Clinical Impact||The concurrent use of an antiplatelet agent or anticoagulant with PEXEVA may potentiate the risk of bleeding.|
|Intervention||Inform patients of the increased risk of bleeding associated with the concomitant use of PEXEVA and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.|
|Examples||aspirin, clopidogrel, heparin, warfarin|
|Drugs Highly Bound to Plasma Protein|
|Clinical Impact||PEXEVA is highly bound to plasma protein. The concomitant use of PEXEVA with another drug that is highly bound to plasma protein may increase free concentrations of PEXEVA or other tightly-bound drugs in plasma.|
|Intervention||Monitor for adverse reactions and reduce dosage of PEXEVA or other protein-bound drugs as warranted.|
|Drugs Metabolized by CYP2D6|
|Clinical Impact||PEXEVA is a CYP2D6 inhibitor. The concomitant use of PEXEVA with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.|
|Intervention||Decrease the dosage of a CYP2D6 substrate if needed with concomitant PEXEVA use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if PEXEVA is discontinued.|
|Examples||propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone.|
|Clinical Impact||Concomitant use of tamoxifen with PEXEVA may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen|
|Intervention||Consider use of an alternative antidepressant with little or no CYP2D6 inhibition.|
|Clinical Impact||Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine.|
|Intervention||Any dose adjustment should be guided by clinical effect (tolerability and efficacy).|
USE IN SPECIFIC POPULATIONS
Pregnancy Category D: Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy may have an increased risk of congenital malformations, particularly cardiovascular malformations.
Treatment of Pregnant Women During Their Third Trimester: Neonates exposed to PEXEVA® and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), 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.
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from PEXEVA, a decision should be made whether to discontinue nursing infants or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: The safety and effectiveness of PEXEVA in pediatric patients have not been established. Effectiveness was not demonstrated in three placebo-controlled trials in 752 paroxetine-treated pediatric patients with MDD.
Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients. Decreased appetite and weight loss have been observed in association with the use of SSRIs.
Geriatric Use: In premarketing clinical trials with immediate-release paroxetine, 17% of paroxetine-treated patients (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; however, no overall differences in safety or effectiveness were observed between these subjects and younger subjects.
SSRIs, including PEXEVA, 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 of PEXEVA should be reduced in patients with severe renal impairment and patients with severe hepatic impairment.
The following have been reported with paroxetine tablet overdosage:
Seizures, which may be delayed, and altered mental status including coma.
Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.
Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk).
Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a paroxetine overdose.