Paroxetine Hydrochloride - Lannett Company, LLC

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

Administer Paroxetine once daily in the morning, with or without food [see Clinical Pharmacology (12.3)]. Swallow the extended-release tablets whole and do not chew or crush.

The recommended starting dosage and maximum dosage of Paroxetine in patients with MDD, PD, and SAD are presented in Table 1. In patients with an inadequate response, may increase the Paroxetine dosage by 12.5 mg/day at weekly intervals (e.g., if the starting dosage is 12.5 mg/day may increase the dosage the next week to 25 mg/day), depending on tolerability, up to the maximum recommended dosage.

Table 1: Recommended Daily Dosage of Paroxetine in Patients with MDD, PD, and SAD

The recommended starting dosage of Paroxetine in women with PMDD is 12.5 mg/day. Administer Paroxetine either:

• Continuously (every day throughout the menstrual cycle) or
• Intermittently with each new cycle (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses).

In patients with an inadequate response, may increase the Paroxetine dosage by 12.5 mg/day at weekly intervals (e.g., after 1 week may increase the dosage from 12.5 mg/day to 25 mg/day) to the maximum recommended dosage of 25 mg/day, depending on tolerability.

For the treatment of MDD, PD, SAD, or PMDD in geriatric patients (those 65 years of age or older), patients with severe renal impairment, and patients with severe hepatic impairment [see Use in Specific Populations (8.5, 8.6, 8.7)]:

• The recommended starting dosage of Paroxetine is 12.5 mg/day. If these patients have an inadequate response, may increase the Paroxetine dosage by 12.5 mg/day at weekly intervals (e.g., after 1 week, may increase the dosage from 12.5 mg/day to 25 mg/day) up to the maximum recommended dosage.
• The maximum recommended dosage is 50 mg/day for MDD or PD; 37.5 mg/day for SAD; and 25 mg/day for PMDD.

In these patients with PMDD, may administer Paroxetine intermittently [see Dosage and Administration (2.3)].

At least 14 days must elapse between discontinuation of an monoamine oxidase inhibitor (MAOI) antidepressant and initiation of Paroxetine. In addition, at least 14 days must elapse after stopping Paroxetine before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)].

When discontinuing Paroxetine treatment, gradually reduce the dosage rather than stopping Paroxetine abruptly whenever possible [see Warnings and Precautions (5.7) and Drug Abuse and Dependence (9.3)].

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 were differences in absolute risk of suicidal thoughts and behaviors across the different uses, 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 Pediatric¹ and Adult Patients

¹ Paroxetine is not approved for use in pediatric patients.

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric patients 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 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, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Selective serotonin reuptake inhibitors (SSRIs, including Paroxetine, 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 Paroxetine is 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 Paroxetine with MAOIs is contraindicated. In addition, do not initiate Paroxetine 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 of administration (such as orally or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Paroxetine, discontinue Paroxetine before initiating treatment with the MAOI [see Contraindications (4) and Drug Interactions (7.1)].

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

Cases of QTc interval prolongation have been reported with the use of paroxetine, although a causal relationship with Paroxetine has not been established.

Paroxetine is a CYP2D6 inhibitor. Concomitant use of Paroxetine with CYP2D6 substrates that prolong the QTc interval can increase the concentration of those CYP2D6 substrates and may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden death.

The concomitant use of Paroxetine is contraindicated with CYP2D6 substrates that prolong the QTc interval [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Paroxetine can cause fetal harm when administered to a pregnant woman. 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, 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 Paroxetine, 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 and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio when initiating, titrating, or discontinuing Paroxetine.

In patients with bipolar disorder, treating a depressive episode with Paroxetine or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of immediate-release paroxetine tablets for unipolar depression, hypomania or mania occurred in approximately 1% of immediate-release paroxetine tablets-treated patients compared to 1.1% of active-control-treated patients and 0.3% of placebo-treated patients.

Prior to initiating treatment with Paroxetine, 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, included 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. When discontinuing Paroxetine, a gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.7 )] .

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

Paroxetine has not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. During clinical studies with immediate-release paroxetine, seizures occurred in 0.1% of patients treated with immediate-release paroxetine.

Paroxetine should be prescribed with caution in patients with a seizure disorder. Discontinue Paroxetine in patients who develop a seizure.

The pupillary dilation that occurs following use of many antidepressant drugs including Paroxetine 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 immediate-release paroxetine have been reported.

Avoid use of antidepressants, including Paroxetine, in patients with untreated anatomically narrow angles.

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

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

In patients with symptomatic hyponatremia, discontinue Paroxetine and institute appropriate medical intervention.

Use of SSRIs, including Paroxetine, 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.

Recommend prescribers inquire about sexual function prior to initiation of Paroxetine and to inquire specifically about changes in sexual function during Paroxetine treatment because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtain a detailed history (including timing of symptom onset) 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 for sexual dysfunction.

Some studies have shown that the efficacy of tamoxifen, as measured by breast cancer relapse and mortality, may be reduced with concomitant use of paroxetine as a result of paroxetine’s irreversible CYP2D6 inhibition and lower concentration of the active metabolite of tamoxifen [see Drug Interactions (7.1)]. One study suggested that the risk may increase with longer duration of concomitant use of paroxetine and tamoxifen. However, other studies have failed to demonstrate such a risk.

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 rather than Paroxetine.

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

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.

Safety data for Paroxetine are from 11 short-term, placebo-controlled clinical trials including 3 studies in patients with major depressive disorder (MDD) (Studies 1, 2, and 3), 3 studies in patients with panic disorder (PD) (Studies 4, 5, and 6), 1 study in patients with social anxiety disorder (SAD) (Study 7), and 4 studies in female patients with premenstrual dysphoric disorder (PMDD) (Studies 8, 9, 10, and 11) [see Clinical Studies (14)]. These 11 trials included 1,627 patients treated with Paroxetine.

• Studies 1 and 2 were 12-week studies that enrolled patients 18 to 65 years old with MDD.Patients in the Paroxetine group received Paroxetine at a dosage that ranged from 25 mg to 62.5 mg once daily. Study 3 was a 12-week study in patients 60 to 88 years old with MDD. Patients in the Paroxetine group received Paroxetine at a dosage that ranged from 12.5 mg to 50 mg once daily.  
• Studies 4, 5, and 6 were 10-week studies in patients 19 to 72 years old with PD. Patients in the Paroxetine group received Paroxetine at a dosage that ranged from 12.5 mg to 75 mg once daily.
• Study 7 was a 12-week study that enrolled adult patients. Patients in the Paroxetine group received Paroxetine with SAD at a dosage that ranged from 12.5 mg to 37.5 mg once daily.
• Studies 8, 9, and 10 were 12-week, placebo-controlled trials in female patients 18 to 46 years old with PMDD. Patients in the Paroxetine group received Paroxetine at a dosage of 12.5 mg or 25 mg once daily.
• Study 11 was a 12-week placebo-controlled trial in patients 18 to 46 years old with PMDD. Patients in the Paroxetine group received Paroxetine two weeks prior to the onset of each menses (luteal phase dosing) at a dosage of 12.5 mg or 25 mg once daily.

Adverse Reactions that Led to Discontinuation in Patients with MDD, PD, SAD, and PMDD

In pooled studies in patients with MDD, PD and SAD, the most common adverse reactions that led to study withdrawal in the Paroxetine-treated patients were nausea (up to 4% of patients), asthenia, headache, depression, insomnia, and abnormal liver function tests (each occurred in up to 2% of patients), and dizziness, somnolence, and diarrhea (each occurred up to 1% of patients).

In pooled studies for PMDD, the most common adverse reactions that led to study withdrawal in the Paroxetine-treated patients were nausea (occurred in up to 6% of patients), asthenia (occurred in up to 5% of patients), somnolence (occurred in up to 4% of patients), insomnia (occurred in approximately 2% of patients); and impaired concentration, dry mouth, dizziness, decreased appetite, sweating, tremor, yawn and diarrhea (occurred in less than or equal to 2% of patients).

Common Adverse Reactions in MDD, PD, and SAD

Table 3 presents the most common adverse reactions (incidence ≥5% in Paroxetine-treated patients and greater than in placebo-treated within at least one of the patient populations) in controlled trials in patients with MDD, PD, and SAD. 

Table 3. Most Common Adverse Reactions¹ in 10 to 12 Week Studies of MDD, PD, and SAD 

¹ ≥5% of patients treated with Paroxetine and greater than in patients treated with placebo.

Hyphen = the reaction listed occurred in <5% of patients treated with Paroxetine

NA = the adverse reaction listed did not occur in this group of patients

^a Mostly blurred vision

^b Based on the number of males or females

^c Mostly anorgasmia or delayed ejaculation

^d Mostly anorgasmia or delayed orgasm

Other Adverse Reactions Observed in Studies of MDD, PD, and SAD 

Adverse reactions from studies in MDD (not including Study 3 in patients 60 years of age and older), PD, and SAD that occurred in 1% to 5% of Paroxetine-treated patients and at an incidence greater than in placebo-treated patients included allergic reaction, tachycardia, vasodilatation, hypertension, migraine, vomiting, weight loss, weight gain, hypertonia, paresthesia, agitation, confusion, myoclonus, concentration impaired, depression, rhinitis, cough increased, bronchitis, photosensitivity, eczema, taste perversion, UTI, menstrual disorder, urinary frequency, urination impaired, and vaginitis.

Adverse Reactions in Patients with PMDD

Table 4 displays common adverse reactions (incidence of 5% or more and greater in Paroxetine-treated patients and greater than placebo-treated patients within at least one of the studies) in female patients with PMDD (Studies 8, 9, 10, and 11).

The following adverse reactions in the PMDD studies with continuous dosing (Studies 8, 9, and 10 were dose-related: nausea, somnolence, sweating, dry mouth, dizziness, decreased appetite, tremor, impaired concentration, yawn, paresthesia, hyperkinesia, and vaginitis.

Table 4. Common Adverse Reactions¹ in Pooled Studies in Female Patients with PMDD (Studies 8, 9, 11), and in Study 10^a,b,c

¹ ≥5% of patients treated with Paroxetine and greater than in placebo-treated patients.

NA= the adverse reaction information is not available in this population.

^a <1% means greater than zero and less than 1%.

^b The luteal phase and continuous dosing PMDD trials were not designed for making direct comparisons between the two dosing regimens.

 ^c Mostly anorgasmia or difficulty achieving orgasm.

Male and Female Sexual Dysfunction

The percentage of patients who reported symptoms of sexual dysfunction in patients with MDD, PD, SAD, and PMDD (Studies 1, 2, 4, 5, 6, 7, 8, 9, 10, and 11) are presented in Table 5. 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 labeling may underestimate their actual incidence.

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

Table 5. Adverse Reactions Related to Sexual Dysfunction in Pooled 10-12 Week Studies of MDD, PD, SAD, and PMDD

NA = male patients were not included in these studies.

Less Common Adverse Reactions

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

Reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those that occurred on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those that occurred in 1/100 to 1/1,000 patients; rare reactions are those that occurred in fewer than 1/1,000 patients.

• Cardiovascular System: Infrequent was postural hypotension.
•  Hemic and Lymphatic System: Rare was thrombocytopenia.
•  Metabolic and Nutritional Disorders: Infrequent were generalized edema and hypercholesteremia.
•  Nervous System: Infrequent were convulsion, akathisia, and manic reaction.
•  Psychiatric: Infrequent were hallucinations.
•  Skin and Appendages: Frequent was rash; infrequent was urticaria; rare was  angioedema and erythema multiforme.
•  Urogenital System: Infrequent was urinary retention; rare was urinary incontinence.

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.

• Blood disorders: events related to impaired hematopoiesis (including agranulocytosis, aplastic anemia, bone marrow aplasia and pancytopenia), haemolytic anaemia
• Cardiac disorders: torsade de pointes, ventricular fibrillation, ventricular tachycardia
•  Endocrine disorders: hyperprolactinemia, syndrome of inappropriate antidiuretic hormone (SIADH) secretion
• Gastrointestinal disorders: acute pancreatitis
• Hepatobiliary disorders: elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction)
• Immune system disorders: anaphylactic reaction, vasculitis syndromes (such as Henoch-Schönlein purpura)
• Metabolism and nutrition disorders: porphyria
• Musculoskeletal and connective tissue disorders: hypertonia 
•  Nervous system disorders: extrapyramidal symptoms (i.e. akathisia, bradykinesia, cogwheel rigidity, dystonia, trismus), Guillain-Barré Syndrome, anosmia, hyposmia, optic neuritis, restless legs syndrome (RLS), status epilepticus
• Pregnancy, puerperium and perinatal conditions: eclampsia, premature birth
• Renal and urinary disorders: acute renal failure
• Reproductive system and breast disorders: galactorrhea, priapism
• Respiratory, thoracic and mediastinal disorders: allergic alveolitis, laryngospasm, pulmonary hypertension
• Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN)
• Vascular disorders: severe hypotension

Table 6 includes clinically significant drug interactions with Paroxetine.

Table 6: Clinically Significant Drug Interactions with Paroxetine

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-researchprograms/pregnancyregistry/antidepressants.

Risk Summary

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.

• There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to SSRIs, including Paroxetine, during pregnancy.
• 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 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).

Also, consider the risks of untreated depression when discontinuing or changing treatment with antidepressants during pregnancy and the postpartum period (see Clinical Considerations).

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 in rats are approximately 6 times the maximum recommended human dose (MRHD – 75 mg) of Paroxetine and in rabbits less than 2 times the MRHD 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 pregnant adults with MDD, PD, SAD, or PMDD 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 MDD who were euthymic and taking antidepressants at the beginning of pregnancy.

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 (5.5)].

Fetal/Neonatal Adverse Reactions: Neonates of mothers 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. In some cases, the clinical picture was consistent with serotonin syndrome [see Warnings and Precautions (5.4)].

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 6 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 75 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 Paroxetine and any potential adverse effects on the breastfed infant from Paroxetine or the underlying maternal condition.

Clinical Considerations

Infants exposed to Paroxetine through breastfeeding 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 of paroxetine were detected in the plasma of infants after breastfeeding.

Infertility

Males: 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 Paroxetine in pediatric patients have not been established. Safety and effectiveness of paroxetine for the treatment of MDD in pediatric patients was not demonstrated in three placebo-controlled trials in 752 pediatric patients with MDD treated with immediate-release paroxetine tablets.

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings and Precautions (5.1)]. Decreased appetite and weight loss have been observed in association with the use of SSRIs in pediatric patients.

In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of pediatric patients treated with immediate-release paroxetine tablets and at a rate at least twice that for pediatric patients treated with 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 immediate-release paroxetine tablet treatment (occurred in at least 2% of paroxetine-treated patients and at a rate at least twice that of placebo-treated patients) in the pediatric clinical trials that included a taper phase regimen, were emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain.

SSRIs and SNRIs, including Paroxetine, 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 ( 5.9)].

In premarketing clinical trials with immediate release paroxetine tablets, 17% of paroxetine-treated patients (approximately 700) were 65 years or older. Clinical studies of Paroxetine did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. The minimum plasma concentration (C_min) of paroxetine was higher in immediate release paroxetine-treated patients 65 years of age and older compared to younger adult patients [see Clinical Pharmacology (12.3 )]; therefore, the recommended starting Paroxetine dosage is lower in patients 65 years of age and older for the treatment of MDD and the maximum recommended is lower in patients 65 years of age and older with MDD and PD [see Dosage and Administration (2)].

Compared to those with normal renal function, paroxetine plasma concentrations in patients with renal impairment (RI) were increased, which may increase the risk of paroxetine-associated adverse reactions. Paroxetine plasma concentrations were higher in patients with greater degrees of RI.

The recommended starting and maximum dosage of Paroxetine is lower in patients with severe RI compared to those with normal renal function [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. The recommended Paroxetine dosage in patients with mild RI or moderate RI is the same as in those with normal renal function.

Compared to those with normal hepatic function, paroxetine plasma concentrations in patients with severe hepatic impairment (HI) (Child‑Pugh Class C) were increased, which may increase the risk of paroxetine-associated adverse reactions.

The recommended starting and maximum dosage of Paroxetine is lower in patients with severe HI compared to those with normal hepatic function [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. The recommended dosage in patients with mild HI (Child‑Pugh Class A) or moderate HI (Child‑Pugh Class B) is the same as in those with normal hepatic function.

Paroxetine contains paroxetine, which is not a controlled substance.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, included 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 [see Warnings and Precautions (5.7)].

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

Studies at clinically relevant paroxetine dosage 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 (SSRI) and has only very weak effects on norepinephrine and dopamine neuronal reuptake.

Cardiac Electrophysiology

At the maximum recommended paroxetine dose, a mean increase in the QTc interval >20 milliseconds is unlikely.

During repeated administration of Paroxetine (25 mg once daily), steady state was reached within 2 weeks (i.e., comparable to immediate-release dosage forms). In a repeat-dose study in which healthy male and female subjects (n = 23) received Paroxetine (25 mg daily), mean steady state C_max, C_min, and AUC_0-24 values were 30 ng/mL, 20 ng/mL, and 550 ng•hr./mL, respectively.

Based on studies using immediate-release paroxetine, steady-state paroxetine exposure based on AUC_0-24h was several-fold greater than that of the single-dose data.

In steady-state dose proportionality studies with elderly and nonelderly adult patients, at doses of the immediate-release paroxetine of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, reflecting a saturable metabolic pathway (Figure 3).

Absorption

Following administration of single oral doses of Paroxetine (i.e., 12.5 mg, 25 mg, 37.5 mg, or 50 mg) in healthy subjects, paroxetine C_max and AUC_0-inf increased disproportionately with dose (as seen also with immediate-release dosage forms). Mean C_max and AUC_0-inf values at these doses were 2, 5.5, 9, and 12.5 ng/mL, and 121, 261, 338, and 540 ng•hr. /mL, respectively. T_max was observed typically between 6- and-10 hours post-dose, reflecting a reduction in absorption rate compared with immediate-release dosage forms.

Food Effect: Food did not appreciably affect the bioavailability of Paroxetine 25 mg

Distribution

Paroxetine distributes throughout the body, including the central nervous system (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

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

Metabolism: Paroxetine is extensively metabolized after oral Paroxetine 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 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 (7.1)].

Excretion: Approximately 64% of 30-mg dose of paroxetine oral solution 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.

Drug Interaction Studies

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

See Figure 1 for the impact of paroxetine on the pharmacokinetics of concomitantly administered drugs and Figure 2 for the impact of other drugs on paroxetine pharmacokinetics.

Figure 1. Impact of Paroxetine on the Pharmacokinetics of Concomitantly Administered Drugs (log scale)

Figure 1

Pimozide is a moderately sensitive CYP3A4 substrate and is a CYP2D6 substrate; desipramine is a sensitive 2D6 substrate; propranolol is a moderately sensitive 2D6 substrate, digoxin is P-gp substrate, and phenytoin is a strong 3A4 inhibitor.

Figure 2. Impact of Concomitantly Administered Drugs on the Pharmacokinetics of Paroxetine

Figure 2

Cimetidine is a OCT2, MATE1, and MATE2-K inhibitor, phenobarbital is a 3A4 moderate inducer, phenytoin is a 3A4 strong inhibitor, digoxin is P-gp substrate, and diazepam is a 2C19 moderate sensitive substrate. Increased paroxetine exposure after concomitant use of Paroxetine with cimetidine is not expected to be clinically significant.

Theophylline: Reports of elevated theophylline levels with concomitant use with immediate-release paroxetine treatment have been reported.

Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving the concomitant use of steady-state paroxetine and a CYP3A4 substrate, revealed no effect of paroxetine on the pharmacokinetics of the CYP3A4 substrate. In addition, in vitro studies have shown ketoconazole, a severe CYP3A4 inhibitor, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for CYP3A4, including triazolam and cyclosporine. Paroxetine’s extent of CYP3A4 inhibition is not expected to be of clinical significance.

Specific Populations

The impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3. Although the AUC and C_max was higher in patients with mild renal impairment (RI) or moderate RI compared to those with normal renal function, there was a lot of variability in the exposure and the clinical significance of these findings are unknown. For recommendations for use of Paroxetine in geriatric patients, patients with severe hepatic impairment, or severe hepatic impairment [see Use in Specific Populations (8.5, 8.6, and 8.7)], respectively.

Figure 3. Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale)

Figure 3

Carcinogenesis

Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day in mice and 1, 5, and 20 mg/kg/day in rats. In mice, these doses were up to approximately 1.6 (mouse) and 2.5 (rat) times the MRHD of Paroxetine on an 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 dose 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 [see Use in Specific Populations (8.3)].

A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is approximately twice the MRHD of Paroxetine on an 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 (approximately 6 and 3 times the MRHD of Paroxetine on an mg/m² basis).

The efficacy of Paroxetine for the treatment for major depressive disorder (MDD) was established in: 

• Two 12-week, multicenter, randomized, double-blind, placebo-controlled, flexible-dose studies with Paroxetine (Studies 1 and 2) in adult patients who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for MDD. Studies 1 and 2 included patients 18 to 65 years old who received a Paroxetine dosage of 25 mg to 62.5 mg (N=212) or placebo (N=211) once daily compared to immediate-release paroxetine tablets 20 mg/day to 50 mg/day (N=217).
• One 12-week, multicenter, randomized, double-blind, placebo-controlled, flexible dose study with Paroxetine (Study 3) in elderly patients, with an age range from 60 to 88 years old, with MDD. Patients received a Paroxetine dosage of 12.5 mg to 50 mg (N=104) or placebo (N=109) once daily compared to immediate-release paroxetine tablets 10 mg/day to 40 mg/day (N=106).

In these three studies, the Paroxetine group was statistically superior to the placebo group in improvement of depressive symptoms as measured by the following:

• Mean change from baseline in the Hamilton Depression Rating Scale (HDRS) total score at Week 12,
• Mean change from baseline in the Hamilton Depressed Mood item score at Week 12, and
• Mean change from baseline in the Clinical Global Impression (CGI)–Severity of Illness score.

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

The effectiveness of Paroxetine in the treatment of panic disorder (PD) was evaluated in three 10-week, multicenter, flexible-dose studies (Studies 4, 5, and 6) that compared Paroxetine (12.5 to 75 mg once daily) to placebo in adult outpatients 19 to 72 years of age who met panic disorder (with or without agoraphobia) criteria according to DSM-IV. The key endpoints in these trials were:

1. Proportions of patients free of full panic attacks at Week 10;

2. Change from baseline to Week 10 in the median number of full panic attacks; and

3. Change from baseline to Week 10 in the median Clinical Global Impression Severity score.

For all three studies, the mean dosage of Paroxetine for completers at Week 10 was approximately 50 mg once daily.

For Studies 4 and 5, the Paroxetine group was superior to the placebo group on 2 of these 3 endpoints. Study 6 failed to consistently demonstrate a statistically significant difference between the Paroxetine and placebo groups in the three endpoints. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

Long-term maintenance effects of Paroxetine in patients with PD were demonstrated in a randomized-withdrawal study with immediate-release paroxetine tablets. Below are efficacy results from immediate-release paroxetine tablets. Patients who were responders during a 10-week, double-blind trial (followed by a 3-month double-blind maintenance phase) of immediate-release paroxetine tablets were re-randomized to continue immediate-release paroxetine tablets or placebo in a 3-month, double-blind withdrawal phase. Patients treated with immediate-release paroxetine tablets were statistically significantly less likely to relapse than patients treated with placebo.

The efficacy of Paroxetine as a treatment for social anxiety disorder (SAD) was based on:

• Extrapolation from the effectiveness of immediate-release paroxetine tablets in the treatment of SAD.
• Effectiveness of Paroxetine in the treatment of SAD in one 12-week, multicenter, double-blind, flexible-dose, placebo-controlled study of adult outpatients with a primary diagnosis of SAD by DSM-IV criteria (Study 7).

In Study 7, the effectiveness of Paroxetine (12.5 to 37.5 mg once daily) compared to placebo was evaluated on the basis of (1) change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score at Week 12 and (2) the proportion of responders who scored 1 or 2 (very much improved or much improved) on the CGI Global Improvement score at Week 12.

In Study 7, the Paroxetine group demonstrated statistically significant superiority over the placebo group on both the change on LSAS total score at Week 12 and the CGI Improvement responder criterion at Week 12. For patients who completed the trial, 64% of patients treated with Paroxetine compared to 35% of patients treated with placebo were CGI Improvement responders at Week 12.

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

The effectiveness of Paroxetine for the treatment of Premenstrual Dysphoric Disorder (PMDD) utilizing a continuous dosing regimen has been established in two placebo-controlled trials in female patients ages 18 to 46 (Studies 8 and 9 [N=672]) who met the DSM-IV criteria for PMDD. Another trial was conducted in female patients 18 to 46 years old with PMDD who received continuous dosing of Paroxetine at a dosage of 12.5 mg or 25 mg once daily or placebo (Study 10). Of 1,030 patients including Study 10, who were treated with daily doses of Paroxetine 12.5 or 25 mg/day, or placebo continuously throughout the menstrual cycle for a period of 3 menstrual cycles, the mean duration of the PMDD symptoms was approximately 11 ± 7 years. Patients who were taking systemic hormonal contraceptives were excluded from these trials. Therefore, the efficacy of Paroxetine in combination with systemic (including oral) hormonal contraceptives for the continuous daily treatment of PMDD is unknown.

A key efficacy endpoint in Studies 8 and 9 was the change from baseline to Month 3 on the luteal phase VAS score. The VAS score is a patient-rated instrument that mirrors the diagnostic criteria of PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms associated with PMDD. In Studies 8 and 9, the Paroxetine 12.5 mg/day and 25 mg/day groups were statistically significantly more effective than the placebo group as measured by change from baseline to Month 3 on the luteal phase VAS score.

In an additional study with luteal phase dosing (Study 11), female patients (N = 366) were treated for the two weeks prior to the onset of each menses for a period of 3 months with 12.5 or 25 mg/day of Paroxetine or placebo. In this trial, the Paroxetine 12.5 mg/day and 25 mg/day groups, as luteal phase dosing, was statistically significantly more effective than placebo as measured by change from baseline to luteal phase VAS score at Month 3.

There is insufficient information to determine the effect of race or age on efficacy outcomes in Studies 8, 9, and 11.