Paroxetine Hydrochloride Hemihydrate

Paroxetine tablets are indicated in adults for the treatment of:

• Major depressive disorder (MDD)
• Obsessive compulsive disorder (OCD)
• Panic disorder (PD)
• Social anxiety disorder (SAD)
• Generalized anxiety disorder (GAD)
• Posttraumatic stress disorder (PTSD) Paroxetine tablets are a selective serotonin reuptake inhibitor (SSRI) indicated in adults for the treatment of ( 1 ):
• Major Depressive Disorder (MDD)
• Obsessive Compulsive Disorder (OCD)
• Panic Disorder (PD)
• Social Anxiety Disorder (SAD)
• Generalized Anxiety Disorder (GAD)
• Posttraumatic Stress Disorder (PTSD)

Paroxetine Tablets, USP are available containing paroxetine hydrochloride, USP (hemihydrate) equivalent to 10 mg, 20 mg, 30 mg or 40 mg of paroxetine.

• The 10 mg tablets are blue, film-coated, modified capsule-shaped, scored tablets debossed with M on one side of the tablet and N to the left of the score and 1 to the right of the score on the other side.
• The 20 mg tablets are blue, film-coated, modified capsule-shaped, scored tablets debossed with M on one side of the tablet and N to the left of the score and 2 to the right of the score on the other side.
• The 30 mg tablets are blue, film-coated, round, unscored tablets debossed with M over N3 on one side of the tablet and blank on the other side.
• The 40 mg tablets are blue, film-coated, round, unscored tablets debossed with M over N4 on one side of the tablet and blank on the other side.
• Tablets: 10 mg, scored; 20 mg, scored; 30 mg; and 40 mg tablets. ( 3 )

Paroxetine 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 [see Warnings and Precautions (5.2) , Drug Interactions (7) ] .
• Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5.3) , Drug Interactions (7) ] .
• Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3) , Drug Interactions (7) ] .
• With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients in paroxetine tablets [see Adverse Reactions (6.1) , (6.2) ] .
• Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOI. ( 4 , 5.3 , 7 )
• Concomitant use of pimozide or thioridazine. ( 4 , 5.3 , 7 )
• Known hypersensitivity to paroxetine or to any of the inactive ingredients in paroxetine tablets. ( 4 )

• Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If occurs, discontinue paroxetine tablets and serotonergic agents and initiate supportive measures. ( 5.2 )
• Embryofetal Toxicity: May cause fetal harm. Meta-analyses of epidemiological studies have shown increased risk (less than 2-fold) of cardiovascular malformations with exposure during the first trimester. ( 5.4 , 8.1 )
• Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. ( 5.5 )
• Activation of Mania/Hypomania: Screen patients for bipolar disorder. ( 5.6 )
• Seizures: Use with caution in patients with seizure disorders. ( 5.8 )
• Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.9 )
• Sexual Dysfunction: Paroxetine tablets may cause symptoms of sexual dysfunction. ( 5.13 )

5.1 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. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2. Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional cases 18-24 years old 5 additional cases Decreases Compared to Placebo 25-64 years old 1 fewer case ≥ 65 years old 6 fewer cases Paroxetine tablets are not approved for use in pediatric patients. 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 four 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 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 tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome SSRIs, including paroxetine tablets, 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 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of paroxetine tablets with MAOIs is contraindicated. In addition, do not initiate paroxetine tablets 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) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine tablets discontinue paroxetine tablets before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7) ] . Monitor all patients taking paroxetine tablets for the emergence of serotonin syndrome. Discontinue treatment with paroxetine tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of paroxetine tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

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

5.4 Embryofetal Toxicity 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, paroxetine tablets, should be initiated only after consideration of the other available treatment options [see Use in Specific Populations (8.1) ] .

5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including paroxetine tablets, 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 use of 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 paroxetine tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with paroxetine tablets or another antidepressant may precipitate a mixed/manic episode. […]

The following adverse reactions are included in more detail in other sections of the prescribing information:

• Hypersensitivity reactions to paroxetine [see Contraindications (4) ]
• Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1) ]
• Serotonin Syndrome [see Warnings and Precautions (5.2) ]
• Embryofetal Toxicity [see Warnings and Precautions (5.4) ]
• Increased Risk of Bleeding [see Warnings and Precautions (5.5) ]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.6) ]
• Discontinuation Syndrome [see Warnings and Precautions (5.7) ]
• Seizures [see Warnings and Precautions (5.8) ]
• Angle-closure Glaucoma [see Warnings and Precautions (5.9) ]
• Hyponatremia [see Warnings and Precautions (5.10) ]
• Bone Fracture [see Warnings and Precautions (5.12) ]
• Sexual Dysfunction [see Warnings and Precautions (5.13) ] Most common adverse reactions (≥ 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, yawn. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data for paroxetine tablets are from:

• 6-week clinical trials in MDD patients who received paroxetine tablets 20 mg to 50 mg once daily
• 12-week clinical trials in OCD patients who received paroxetine tablets 20 mg to 60 mg once daily
• 10- to 12-week clinical trials in PD patients who received paroxetine tablets 10 mg to 60 mg once daily
• 12-week clinical trials in SAD patients who received paroxetine tablets 20 mg to 50 mg once daily
• 8-week clinical trials in GAD patients who received paroxetine tablets 10 mg to 50 mg once daily
• 12-week clinical trials in PTSD patients who received paroxetine tablets 20 mg to 50 mg once daily Adverse Reactions Leading to Discontinuation Twenty percent (1,199/6,145) of patients treated with paroxetine tablets in clinical trials in MDD and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with paroxetine tablets in clinical trials in SAD, OCD, PD, GAD, and PTSD, respectively, discontinued treatment due to an adverse reaction. The most common adverse reactions (≥ 1%) associated with discontinuation (i.e., those adverse reactions associated with dropout at a rate approximately twice or greater for paroxetine tablets compared to placebo) are presented in Table 3: Table 3: Adverse Reactions Reported as Leading to Discontinuation (≥ 1% of Paroxetine Tablets Treated Patients and Greater than Placebo) in MDD, OCD, PD, SAD, GAD, and PTSD Trials Where numbers are not provided the incidence of the adverse reactions in patients treated with paroxetine tablets was not > 1% or was not greater than or equal to 2 times the incidence of placebo. MDD OCD PD SAD GAD PTSD Paroxetine Tablets % Placebo % Paroxetine Tablets % Placebo % Paroxetine Tablets % Placebo % Paroxetine Tablets % Placebo % Paroxetine Tablets % Placebo % Paroxetine Tablets % Placebo % CNS Somnolence 2.3 0.7 – 1.9 0.3 3.4 0.3 2.0 0.2 2.8

0.6 Insomnia – – 1.7 0 1.3 0.3 3.1 0 – – Agitation 1.1 0.5 – – – Tremor 1.1 0.3 – 1.7 0 1.0

0.2 Anxiety – – – 1.1 0 – – Dizziness – – 1.5 0 1.9 0 1.0 0.2 – – Gastrointestinal Constipation – 1.1 0 – – Nausea 3.2 1.1 1.9 0 3.2 1.2 4.0 0.3 2.0 0.2 2.2

0.6 Diarrhea 1.0 0.3 – Dry mouth 1.0 0.3 – – – Vomiting 1.0 0.3 – 1.0 0 – – Flatulence 1.0 0.3 – – Other Asthenia 1.6 0.4 1.9 0.4 2.5 0.6 1.8 0.2 1.6

0.2 Abnormal Ejaculation Incidence corrected for gender. 1.6 0 2.1 0 4.9 0.6 2.5 0.5 – – Sweating 1.0 0.3 – 1.1 0 1.1 0.2 – – Impotence – 1.5 0 – – Libido Decreased 1.0 0 – – Most Common Adverse Reactions The most commonly observed adverse reactions associated with the use of paroxetine tablets (incidence of 5% or greater and at least twice that for placebo) were: MDD: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. OCD: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. PD: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. SAD: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. GAD: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. PTSD: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence. Adverse Reactions in Patients with MDD Table 4 presents the adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of paroxetine tablets-treated patients with MDD. Table 4: Adverse Reactions (≥ 1% of Paroxetine Tablets-Treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDD Body System/ Adverse Reaction Paroxetine Tablets (n = 421) % Placebo (n = 421) % Body as a Whole Headache 18 17 Asthenia 15 6 Cardiovascular Palpitation 3 1 Vasodilation 3 1 Dermatologic Sweating 11 2 Rash 2 1 Gastrointestinal Nausea 26 9 Dry Mouth 18 12 Constipation 14 9 Diarrhea 12 8 Decreased Appetite 6 2 Flatulence 4 2 Oropharynx Disorder Includes mostly “lump in throat” and “tightness in throat.” 2 0 Dyspepsia 2 1 Musculoskeletal Myopathy 2 1 Myalgia 2 1 Myasthenia 1 0 Nervous System Somnolence 23 9 Dizziness 13 6 Insomnia 13 6 Tremor 8 2 Nervousness 5 3 Anxiety 5 3 Paresthesia 4 2 Libido Decreased 3 0 Drugged Feeling 2 1 Confusion 1 0 Respiration Yawn 4 0 Special Senses Blurred Vision 4 1 Taste Perversion 2 0 Urogenital System Ejaculatory Disturbance Percentage corrected for gender. Mostly “ejaculatory delay.” 13 0 Other Male Genital Disorders Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.” 10 0 Urinary Frequency 3 1 Urination Disorder Includes mostly “difficulty with micturition” and “urinary hesitancy.” 3 0 Female Genital Disorders Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” 2 0 Adverse Reactions in Patients with OCD, PD, and SAD Table 5 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD, PD, and SAD. Table 5. […]

Table 9 presents clinically significant drug interactions with paroxetine tablets. Table 9: Clinically Significant Drug Interactions with Paroxetine Tablets Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs, including paroxetine tablets, and MAOIs increases the risk of serotonin syndrome. Intervention Paroxetine tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.5) , Contraindications (4) , Warnings and Precautions (5.2) ] . 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 Paroxetine tablets are contraindicated in patients taking pimozide or thioridazine [see Contraindications (4) ]. Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with paroxetine tablets 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 paroxetine tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2) ] . Examples other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and 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 paroxetine tablets may potentiate the risk of bleeding. Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of paroxetine tablets and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions (5.5) ] . Examples aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact Paroxetine tablets are highly bound to plasma protein. The concomitant use of paroxetine tablets with another drug that is highly bound to plasma protein may increase free concentrations of paroxetine tablets or other tightly-bound drugs in plasma . Intervention Monitor for adverse reactions and reduce dosage of paroxetine tablets or other protein-bound drugs as warranted. Examples Warfarin Drugs Metabolized by CYP2D6 Clinical Impact Paroxetine tablets are a CYP2D6 inhibitor [see Clinical Pharmacology (12.3) ] . The concomitant use of paroxetine tablets with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention Decrease the dosage of a CYP2D6 substrate if needed with concomitant paroxetine tablets use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if paroxetine tablets are discontinued. Examples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone. Tamoxifen Clinical Impact Concomitant use of tamoxifen with paroxetine tablets 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 [see Warnings and Precautions (5.11) ]. Fosamprenavir/Ritonavir Clinical Impact Co-administration of fosamprenavir/ritonavir with paroxetine tablets significantly decreased plasma levels of paroxetine. Intervention Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

• Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of paroxetine tablets or other protein-bound drugs (e.g., warfarin) as warranted. ( 7 )
• Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. ( 7 )
• Concomitant use with tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. ( 5.11 , 7 )

• Pregnancy: SSRI use, particularly later in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability) in the neonate. ( 8.1 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including paroxetine tablets, during pregnancy. Healthcare providers are encouraged to 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/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 ] . Paroxetine tablets are 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 cardiac 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 paroxetine tablets 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 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 U.S. 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 embryofetal 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 risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum. Maternal Adverse Reactions Use of paroxetine tablets 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 paroxetine 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 an 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 defect (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 the maximum recommended human dose (MRHD – 60 mg) on an mg/m 2 basis. These studies have revealed no evidence of developmental effects. 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/m 2 basis. The no effect dose for rat pup mortality was not determined. The cause of these deaths is not known.

8.2 Lactation 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 effect of paroxetine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for paroxetine tablets and any potential adverse effects on the breastfed child from paroxetine tablets or from underlying maternal condition. Clinical Considerations Infants exposed to paroxetine 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 infants after breastfeeding.

8.3 Females and Males of Reproductive Potential 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) ] .

8.4 Pediatric Use The safety and effectiveness of paroxetine tablets in pediatric patients have not been established [see Box Warning ] . Effectiveness was not demonstrated in three placebo-controlled trials in 752 paroxetine tablets-treated pediatric patients with MDD. […]

The mechanism of action of paroxetine tablets in the treatment of MDD, SAD, OCD, PD, GAD, and PTSD 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-hydroxy-tryptamine, 5-HT).