Paroxetine

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)

• Recommended starting and maximum daily dosage for MDD, OCD, PD, and PTSD: (
  2.2 Recommended Dosage for MDD, OCD, PD, and PTSD

  The recommended starting dosages and maximum dosages of paroxetine tablets in patients with MDD, OCD, PD, and PTSD 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.

  Table 1 Recommended Daily Dosage of Paroxetine Tablets in Patients with MDD, OCD, PD, and PTSD

  Indication	Starting Dose	Maximum Dose
  MDD	20 mg	50 mg
  OCD	20 mg	60 mg
  PD	10 mg	60 mg
  PTSD	20 mg	50 mg
  )

• Recommended starting dosage for SAD and GAD is 20 mg daily. (
  2.3 Recommended Dosage for SAD and GAD

  SAD

  The starting and recommended dosage in patients with SAD is 20 mg daily. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 mg to 60 mg daily.

  While the safety of paroxetine tablets has been evaluated in patients with SAD at doses up to 60 mg daily, available information does not suggest any additional benefit for doses above 20 mg daily

  [see Clinical Studies ].

  GAD

  The starting and recommended dosage in patients with GAD is 20 mg daily. In clinical trials the effectiveness of paroxetine tablets in GAD was demonstrated in patients dosed in a range of 20 mg to 50 mg daily. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg daily

  [see Clinical Studies ].

  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.
  )
• Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dosage is 10 mg daily. Maximum dosage is 40 mg daily. (
  2.4 Screen for Bipolar Disorder Prior to Starting Paroxetine Tablets

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

  [see Warnings and Precautions ].
  )
• When discontinuing paroxetine tablets, reduce dosage gradually. (
  2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI)

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

  [see Contraindications , Warnings and Precautions ].
  ,
  5.7 Discontinuation Syndrome

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

  [see Dosage and Administration ].

  During clinical trials of GAD and PTSD, gradual 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 adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric patients. The safety and effectiveness of paroxetine in pediatric patients have not been established

  [see Boxed Warning, Warnings and Precautions , Use in Specific Populations ].
  )

Paroxetine tablets, USP are available as:

• 10 mg: White to off-white, round-shaped, biconvex, film- coated tablets debossed with the logo of 'ZC, 15 and bisect' on one side and plain on other side
• 20 mg: White to off-white, round-shaped, biconvex, film- coated tablets debossed with the logo of 'ZC, 16 and bisect' on one side and plain on other side
• 30 mg: White to off-white, round-shaped, biconvex, film- coated tablets debossed with the logo of 'ZC17' on one side and plain on other side
• 40 mg: White to off-white, round-shaped, biconvex, film- coated tablets debossed with the logo of 'ZC18' on one side and plain on other side

• 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 Pregnancy

  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 and Clinical Considerations].

  Paroxetine 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 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 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 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 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 in the month before delivery may be associated with an increased risk of postpartum hemorrhage

  [see Warnings and Precautions ].

  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 ].

  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/m2 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/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.
  )