Paroxetine Hydrochloride

Check Drug InteractionsCheck known drug interactions.

Paroxetine Hydrochloride Prescribing Information

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors

[see Warnings and Precautions (

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 1000 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 patients
18 to 24 years old	5 additional patients
	Decreases Compared to Placebo
25 to 64 years old	1 fewer patient
≥ 65 years old	6 fewer patients

Paroxetine is 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, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

)]

. Paroxetine tablets, USP is not approved for use in pediatric patients

[see Use in Specific Populations (

8.4 Pediatric Use

The safety and effectiveness of paroxetine in pediatric patients have not been established

[see Box 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 ]

. 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 occurred 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.

)]

Warnings and Precautions (

5.2 Serotonin Syndrome

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 , Drug Interactions ]

. 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 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 (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 discontinue paroxetine before initiating treatment with the MAOI

[see Contraindications , Drug Interactions ]

Monitor all patients taking paroxetine for the emergence of serotonin syndrome. Discontinue treatment with paroxetine and any concomitant serotonergic agents 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.

5.5 Increased Risk of Bleeding

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 ].

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.

) 8/2023

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 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 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
)

Table 1: Recommended Daily Dosage of Paroxetine 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

Indication	Starting Daily Dose	Maximum Daily 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 was demonstrated in patients dosed in a range of 20 mg to 60 mg daily. While the safety of paroxetine 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 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
Prior to initiating treatment with paroxetine or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania
[see Warnings and Precautions ].
)
When discontinuing paroxetine, 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. 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 orange, modified capsule shape, film-coated scored tablets debossed with "671" on one side and "O" on the other side with bisect.
20 mg yellow, modified capsule shape, film-coated scored tablets debossed with "672" on one side and "O" on the other side with bisect.
30 mg white to off-white, modified capsule shape, film-coated tablets debossed with "673" on one side and "O" on the other.
40 mg blue, modified capsule shape, film-coated tablets debossed with "674" on one side and "O" on the other.

Pregnancy
: Can cause fetal and neonatal harm. Advise women of potential risk to the fetus. (
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].
Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. If paroxetine is used during pregnancy, or if the patient becomes pregnant while taking paroxetine, advise the patient of the potential hazard to the fetus.
Clinical Considerations

Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant
[see Warnings and Precautions ]
. For
- A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery.
- A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8).
- Two large case-control studies using separate databases, each with >9,000 birth defect cases and >4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the OR was 2.5 (95% confidence interval, 1.0 to 6.0, 7 exposed infants) and in the other study the OR was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants).
Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations.
Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant
[see Warnings and Precautions ]
. For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options
[see Warnings and Precautions ]
.
Treatment of Pregnant Women During Their Third Trimester
: Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), including paroxetine, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome
[see Warnings and Precautions ].
Exposure to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20^thweek of gestation compared to infants who had not been exposed to antidepressants during pregnancy.
There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs.
When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment
.
A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy. The women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
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 ].
Animal Findings

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/m²basis. 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 than the MRHD on an mg/m²basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.
)
Nursing Mothers
: Discontinue drug or nursing, taking into consideration importance of drug to mother. (
8.3 Nursing Mothers
Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from paroxetine, a decision should be made whether to discontinue nursing infants or to discontinue the drug, taking into account the importance of the drug to the mother.
)

Paroxetine is contraindicated in patients:

Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome

[see Warnings and Precautions (

5.2 Serotonin Syndrome

[see Contraindications , Drug Interactions ]

. Serotonin syndrome can also occur when these drugs are used alone.

[see Contraindications , Drug Interactions ]

), Drug Interactions (

7 DRUG INTERACTIONS

Table 9presents clinically significant drug interactions with paroxetine.

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

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

)].

Taking thioridazine because of risk of QT prolongation

[see Warnings and Precautions (

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 is contraindicated in combination with thioridazine and pimozide

[see Contraindications , Drug Interactions , Clinical Pharmacology ].

) and Drug Interactions (

7 DRUG INTERACTIONS

Table 9presents clinically significant drug interactions with paroxetine.

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

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

)].

aking pimozide because of risk of QT prolongation

[see Warnings and Precautions (

5.3 Drug Interactions Leading to QT Prolongation

[see Contraindications , Drug Interactions , Clinical Pharmacology ].

), Drug Interactions (

7 DRUG INTERACTIONS

Table 9presents clinically significant drug interactions with paroxetine.

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

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

)].

With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients in paroxetine tablets, USP

[see Adverse Reactions (

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 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
12-week clinical trials in SAD patients who received paroxetine 20 mg to 50 mg once daily
8-week clinical trials in GAD patients who received paroxetine 10 mg to 50 mg once daily
12-week clinical trials in PTSD patients who received paroxetine 20 mg to 50 mg once daily

Adverse Reactions Leading to Discontinuation

Twenty percent (1,199/6,145) of patients treated with paroxetine 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 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 compared to placebo) are presented in Table 3:

Table 3: Adverse Reactions Reported as Leading to Discontinuation (≥1% of Paroxetine - 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 was not >1% or was not greater than or equal to 2 times the incidence of placebo. ^a.Incidence corrected for gender.
	MDD		OCD		PD			SAD			GAD			PTSD
	Paroxetine %	Placebo %	Paroxetine %	Placebo %	Paroxetine %	Placebo %	Paroxetine %		Placebo %	Paroxetine %		Placebo %	Paroxetine %		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^a	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^a	—		1.5	0									—		—
Libido Decreased							1.0		0				—		—

Most Common Adverse Reactions

The most commonly observed adverse reactions associated with the use of paroxetine (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 4presents the adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of paroxetine -treated patients with MDD.

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6.2 Postmarketing Experience

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), syndrome of inappropriate ADH secretion, prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, oculogyric crisis which has been associated with concomitant use of pimozide; 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.

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