PEXEVA

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all anti-depressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and  Precautions ( 5.1)] . PEXEVA is not approved for use in pediatric patients [see Use in Specific Populations ( 8.4)] .

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.

Prior to initiating treatment with PEXEVA or other antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.6)] .

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 [see Use in Specific Populations ( 8.5, 8.6)]

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 [see Contraindications ( 4), Warnings and Precautions ( 5.2)] .

Adverse reactions may occur upon discontinuation of PEXEVA [see Warnings and Precaution ( 5.7)] . Gradually reduce the dosage rather than stopping PEXEVA abruptly whenever possible.

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that include 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 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. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond 4 months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication of 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 PEXEVA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts and behaviors.

SSRIs, including PEXEVA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4), Drug Interactions ( 7.1)] . Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of PEXEVA with MAOIs is contraindicated. In addition, do not initiate PEXEVA in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking PEXEVA, discontinue PEXEVA before initiating treatment with the MAOI [see Contraindications ( 4), Drug Interactions ( 7)] .

Monitor all patients taking PEXEVA for the emergence of serotonin syndrome. Discontinue treatment with PEXEVA and any concomitant serotonergic agents immediately if the above symptoms occur and initiate symptomatic treatment. If concomitant use of PEXEVA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

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 PEXEVA is contraindicated in combination with thioridazine and pimozide [see Contraindications ( 4), Drug Interactions ( 7), Clinical Pharmacology ( 12.3)] .

Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants. For women who intend to become pregnant or who are in their first trimester of pregnancy, PEXEVA, should be initiated only after consideration of the other available treatment options [see Use in Specific Populations ( 8.1)] .

Drugs that interfere with serotonin reuptake inhibition, including PEXEVA, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants, may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1)] . Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of PEXEVA and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

In patients with bipolar disorder, treating a depressive episode with PEXEVA or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of immediate-release paroxetine hydrochloride, hypomania or mania occurred in approximately 1% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with PEXEVA, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

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 [see Dosage and Administration ( 2)] .

Adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric patients. The safety and effectiveness of PEXEVA in pediatric patients has not been established. [see Boxed Warning, Warnings and Precautions ( 5.1), Use in Specific Populations ( 8.4)] .

During clinical trials of paroxetine in GAD and another indication, incremental decreases in the daily dose by 10 mg/day at weekly intervals followed by 1 week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness.

During clinical studies, seizure occurred in 0.1% of patients treated with PEXEVA. PEXEVA should be prescribed with caution in patients with a seizure disorder. Discontinue PEXEVA in any patient who develops seizures.

The pupillary dilation that occurs following use of many antidepressant drugs including PEXEVA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Cases of angle-closure glaucoma associated with use of paroxetine hydrochloride tables have been reported. Avoid use of antidepressants, including PEXEVA, in patients with untreated anatomically narrow angles.

Hyponatremia may occur as a result of treatment with SSRIs, including PEXEVA. Cases with serum sodium lower than 110mmol/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 results of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue PEXEVA and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with and SSRIs [see Use in Specific Populations ( 8.5)] .

Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug interactions ( 7.1) . One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such a risk. It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.

Epidemiological studies on bone fracture risk following 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.

Use of SSRIs, including PEXEVA, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1)] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of PEXEVA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot directly be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data for paroxetine are from:

• 6-week clinical trials in MDD patients who received paroxetine 20 mg to 50 mg once daily
• 12-week clinical trials in OCD patients who received paroxetine 20 mg to 60 mg once daily
• 10- to 12-week clinical trials in PD patients who received paroxetine 10 mg to 60 mg once daily
• 8-week clinical trials in GAD patients who received paroxetine 10 mg to 50 mg once daily

Adverse Reactions Leading to Discontinuation

Twenty percent (1199/6145) of patients treated with paroxetine in clinical trials in MDD and 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine in clinical trials in OCD, PD, and GAD, respectively, discontinued treatment due to an adverse reaction. Table 3 shows the most common reactions (≥1%) associated with discontinuation and considered to be drug related (i.e., those reactions associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo).

Most Common Adverse Reactions in MDD, OCD, PD, and GAD

The most commonly observed adverse reactions associated with the use of PEXEVA (incidence of 5% or greater and at least twice that for placebo) were:

Major Depressive Disorder: asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders.

Obsessive Compulsive Disorder:nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.

Panic Disorder:asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.

Generalized Anxiety Disorder:asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.

Adverse Reactions Occurring at an Incidence of 1% or More in Paroxetine Treated Patients

Major Depressive Disorder:Table 4 enumerates adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of paroxetine-treated patients with MDD.

Obsessive Compulsive Disorder and Panic Disorder:Table 5 enumerates adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD and PD.

Generalized Anxiety Disorder:Table 6 enumerates adverse reactions that occurred at a frequency of 2% or more among GAD patients on paroxetine who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day.

Dose Dependency of Adverse Reactions:A comparison of adverse reaction rates in a fixed-dose study comparing paroxetine 10, 20, 30, and 40 mg/day with placebo in the treatment of MDD revealed a clear dose dependency for some of the more common adverse reactions associated with paroxetine use, as shown in Table 7:

In a fixed-dose study comparing placebo and paroxetine 20, 40, and 60 mg in the treatment of OCD, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned. No new adverse reactions were observed in the paroxetine 60 mg dose group compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and paroxetine 10, 20, and 40 mg in the treatment of PD, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse reactions were observed in patients receiving 60 mg of paroxetine compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine in the treatment of GAD, for most of the adverse reactions, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned, except for the following adverse reactions: asthenia, constipation, and abnormal ejaculation.

Male and Female Sexual Dysfunction

Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.

The percentage of patients reporting symptoms of sexual dysfunction in males and females with MDD, OCD, PD, , GAD, and two other indications are displayed in Table 8.

There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine treatment.

Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, healthcare providers should routinely inquire about such possible side effects.

Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 0.2% of paroxetine-treated patients compared to 0.1% of patients receiving placebo.

Less Common Adverse Reactions

The following adverse reactions occurred during the clinical studies of paroxetine and are not included elsewhere in the labeling.

Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole: infrequent: allergic reaction, chills, face edema, malaise, neck pain; rare: adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular System:frequent: hypertension, tachycardia; infrequent: bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare:angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarction, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles. Digestive System: infrequent:bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, abnormal liver function tests , rectal hemorrhage, ulcerative stomatitis; rare:aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, chlolelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries. Endocrine System: rare:diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems: infrequent:anemia, leukopenia, lymphadenopathy, purpura; rare:abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional: frequent: weight gain; infrequent:edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare:alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, nonprotein nitrogen (NPN) increased. Musculoskeletal System: frequent:arthralgia; infrequent:arthritis, arthrosis; rare:bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany. Nervous System:frequent:emotional lability, vertigo; infrequent:abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare:abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome. Respiratory System:  infrequent:asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare:emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages:  frequent:pruritus; infrequent:acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare:angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis, herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses:  frequent:tinnitus; infrequent:abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare:amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect. Urogenital System:  infrequent:amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, pyuria, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare:abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis.

The following reactions have been identified during post approval use of paroxetine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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, drug reaction with eosinophilia and systemic symptoms (DRESS), 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, anosmia, hyposmia, 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.

Table 9: Clinically Significant Drug Interactions with PEXEVA

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants.

Risk Summary

Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.5) and Clinical Considerations] .

PEXEVA is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. While individual epidemiological studies on the association between paroxetine use and cardiovascular malformations have reported inconsistent findings, some meta-analyses of epidemiological studies have identified an increased risk of cardiovascular malformations (see Data). There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data)and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including PEXEVA, during pregnancy. There also are risks associated with untreated depression in pregnancy (see Clinical Considerations). For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options.

No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits. These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD - 60 mg) on an mg/m2 basis. When paroxetine was administered to female rats during the last trimester of gestation and continued through lactation, there was an increase in the number of pup deaths during the first four days of lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis (see Data).

The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Maternal Adverse Reactions

Use of PEXEVA in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions  ( 5.5)] .

Fetal/Neonatal adverse reactions

Neonates exposed to PEXEVA and other SSRIs 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, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see  Warnings and Precautions ( 5.2)] .

Data

Human Data

Published epidemiological studies on the association between first trimester paroxetine use and cardiovascular malformations have reported inconsistent results; however, meta-analyses of population-based cohort studies published between 1996-2017 indicate a less than 2-fold  increased risk for overall cardiovascular malformations. Specific cardiac malformations identified in two meta-analyses include approximately 2 to 2.5-fold increased risk for right ventricular outflow tract defects. One meta-analysis also identified an increased risk (less than 2-fold) for bulbus cordis anomalies and anomalies of cardiac septal closure, and an increased risk for atrial septal defects (pooled OR 2.38, 95% CI 1.14-4.97). Important limitations of the studies included in these meta-analyses include potential confounding by indication, depression severity, and potential exposure misclassification.

Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality.

Animal Data

Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and less than 2 (rabbit) times (MRHD - 60 mg) on an mg/m2 basis. These studies have revealed no evidence of malformations. However, in rats, there was an increase in pup deaths 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/day which is less than the MRHD on an mg/m2 basis. The no effect dose for rat pup mortality was not determined. The cause of these deaths is not known.

Risk Summary

Data from the published literature report the presence of paroxetine in human milk (see Data). There are reports of agitation, irritability, poor  feeding and poor weight gain in infants exposed to paroxetine through breast milk (see Clinical Considerations). There are no data on the effects of paroxetine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PEXEVA and any potential adverse effects on the breastfed infant from PEXEVA or the underlying maternal condition.

Clinical Considerations

Infants exposed to PEXEVA should be monitored for agitation, irritability, poor feeding and poor weight gain.

Data

Published literature suggests the presence of paroxetine in human milk with relative infant doses ranging between 0.4% to 2.2%, and a milk: plasma ratio of <1. No significant amounts were detected in the plasma of an infants after breastfeeding.

Infertility
Male

Based on findings from clinical studies, paroxetine may affect sperm quality which may impair fertility; it is not known if this effect is reversible [see Nonclinical Toxicology ( 13.1)] .

The safety and effectiveness of PEXEVA in pediatric patients have not been established [see Boxed Warning]. 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 [see Boxed Warning, Warnings and Precautions ( 5.1)] . Decreased appetite and weight loss have been observed in association with the use of SSRIs.

In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of pediatric patients treated with paroxetine and at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.

Adverse reactions upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients and at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain.

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 [see Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.3)].

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 [see Warnings and Precautions ( 5.10)] .

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 [see Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.3)].

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).

Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake.

Absorption

Paroxetine mesylate is completely absorbed after oral dosing of the mesylate salt. In a study in which normal male subjects (n=25) received paroxetine 30 mg tablets daily for 24 days, steady-state paroxetine concentrations were achieved by approximately 13 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T1/2 were 81.3 ng/ml (CV 41%), 8.1 hr. (CV 56%), 43.2 ng/ml (CV 52%), and 33.2 hr. (CV 52%), respectively. The steady-state Cmax and Cmin values were about 7 and 10 times what would be predicted from single dose studies. Steady-state drug exposure based on AUC0-24 was about 10 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable.

In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 to 40 mg daily for the elderly and 20 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 were only about 2 to 3 times greater than doubled.

In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than females.

Effect of Food

The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.

Distribution

Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/ml and 400 ng/ml, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/ml. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.

Elimination

Metabolism

The elimination half-life is approximately 15 to 20 hours after a single dose of PEXEVA.

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 cytochrome 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 [see Drug interactions ( 7)] . Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).

Excretion

Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.

Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces.

Drug Interaction Studies:

There are clinically significant drug interactions between paroxetine and other drugs [see Drug Interactions ( 7)].

Potential Effect of PEXEVA on Other Drugs

Drugs Metabolized by CYP3A4

An in vivo drug interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for CYP3A4, including astemizole, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Drugs Metabolized by CYP2D6

Pimozide:Higher doses of paroxetine have been shown to elevate plasma levels of pimozide. In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone [see Drug Interactions ( 7.1)] .

Tamoxifen:It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect on the 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 when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6. However, other studies have failed to demonstrate such a risk [see Warnings and Precautions ( 5.11) and Drug Interactions ( 7.1)] .

Desipramine:In one study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100  mg) Cmax, AUC, and T1/2 by an average of approximately 2-, 5-, and 3-fold, respectively [see Drug Interactions ( 7.1)] .

Risperidone:Daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day), a CYP2D6 substrate, increased mean  plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold [see Drug Interactions ( 7.1)].

Atomoxetine:The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In  healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady-state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone [see Drug Interactions ( 7.1)].

Digoxin:Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine [see Drug Interactions ( 7.1)].

Beta Blockers:In a study in which propranolol (80 mg twice daily) was dosed orally for 18 days, the steady-state plasma concentrations of  propranolol were unaltered during co-administration with paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated.

Potential Effect of Other Drugs on PEXEVA

Concomitant use of paroxetine with other drugs that alter CYP enzymes activities including CYP2D6 may affect the plasma concentrations of paroxetine. Specific studies investigating the effect of other drugs on paroxetine are listed below:

Cimetidine:Cimetidine inhibits many cytochrome P450 enzymes. In a study in which paroxetine (30 mg once daily) was dosed orally for 4  weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during co-administration with oral cimetidine (300 mg three times daily) for the final week [see Drug Interactions (7.2)].

Phenobarbital:Phenobarbital induces many cytochrome P450 enzymes. When a single oral 30 mg dose of paroxetine was administered at  phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T1/2 were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Because paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed [see  Drug Interactions (7.2)].

Phenytoin:When a single oral 30 mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine  AUC and T1/2 were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Because both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed [see Drug Interactions (7.2)].

Digoxin:A clinical drug interaction study showed that concurrent use of digoxin did not affect paroxetine exposure.

Diazepam:A clinical drug interaction study showed that concurrent use of diazepam did not affect paroxetine exposure.

Carcinogenesis: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). These doses are 2.0 (mouse) and 3 (rat) times the maximum recommended human dose (MRHD) of 60 mg on a mg/m2 basis. 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 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.

Mutagenesis:Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 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 vitro in human lymphocytes and in a dominant lethal test in rats.

Impairment of Fertility:Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men. A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2 times the MRHD of 60 mg on a mg/m2 basis. 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 (8 and 4 times the MRHD of 60 mg on a mg/m2 basis).

The efficacy of paroxetine as a treatment for MDD has been established in 6 placebo-controlled studies of patients with MDD (ages 18 to 73). In these studies, paroxetine was shown to be statistically significantly more effective than placebo in treating MDD by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine was statistically significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor.

Long-term efficacy of paroxetine for treatment of MDD in outpatients was demonstrated in a randomized withdrawal study. Patients who responded to paroxetine (HDRS total score <8) during an initial 8-week open-label treatment phase were then randomized to continue paroxetine or placebo, for up to 1 year. Patients treated with paroxetine demonstrated a statistically significant lower relapse rate during the withdrawal phase (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.

The effectiveness of paroxetine in the treatment OCD was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. In study 1, a dose-range finding study, patients received fixed daily doses of paroxetine 20 mg, 40 mg, or 60 mg. Study 1 demonstrated that daily doses of paroxetine 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving paroxetine 40 mg and 60 mg To experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was statistically significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible dose study comparing paroxetine (20 mg to 60 mg daily) with clomipramine (25 mg to 250 mg daily or placebo). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was statistically significantly greater than the mean reduction of approximately 4 points in the placebo-treated patients.

Table 10 provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impressions (CGI) scale for Study 1.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

The long-term efficacy of paroxetine for the treatment of OCD was demonstrated in a long-term extension to Study 1. Patients who responded to paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 mg to 60 mg daily) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were statistically significantly less likely to relapse than comparably treated patients who were randomized to placebo.

The effectiveness of paroxetine in the treatment of panic disorder (PD) was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had PD (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was shown to be statistically significantly more effective than placebo in treating PD by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score.

Study 1 was a 10-week dose-range finding study: patients received fixed doses of paroxetine doses of 10 mg, 20 mg, or 40 mg daily or placebo. A statistically significant difference from placebo was observed only for the paroxetine 40 mg daily group. At endpoint, 76% of patients receiving paroxetine 40 mg daily were free of panic attacks, compared to 44% of placebo-treated patients.

Study 2 was a 12-week flexible-dose study comparing paroxetine 10 mg to 60 mg daily and placebo. At endpoint, 51% of paroxetine-treated patients were free of panic attacks compared to 32% of placebo-treated patients.

Study 3 was a 12-week flexible-dose study comparing paroxetine 10 mg to 60 mg daily to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo-treated patients.

In Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg daily.

Long-term maintenance efficacy of paroxetine in PD was demonstrated in an extension to Study 1. Patients who responded to paroxetine during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine 10 mg, 20 mg, or 40 mg daily or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were statistically significantly less likely to relapse than comparably treated patients who were randomized to placebo.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

The effectiveness of paroxetine in the treatment of generalized anxiety disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with GAD (DSM-IV).

Study 1 was an 8-week study comparing fixed doses of paroxetine 20 mg or 40 mg daily with placebo. Doses of paroxetine 20 mg or 40 mg were both demonstrated to be statistically significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the paroxetine 40 mg daily dose compared to the 20 mg daily dose.

Study 2 was a flexible-dose study comparing paroxetine 20 mg to 50 mg daily and placebo. Paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score.

A third study, a flexible-dose study comparing paroxetine 20 mg to 50 mg daily to placebo, did not demonstrate statistically significant superiority of paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.

Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.

In a long-term trial, 566 patients meeting DSM-IV criteria for GAD, who had responded during a single-blind, 8-week acute treatment phase with paroxetine 20 mg to 50 mg daily , were randomized to continuation of paroxetine at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or withdrawal due to lack of efficacy. Patients continuing to receive paroxetine experienced a statistically significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.