PAXIL CR is indicated in adults for the treatment of:

• Major depressive disorder (MDD)
• Panic disorder (PD)
• Social anxiety disorder (SAD)
• Premenstrual dysphoric disorder (PMDD)

PAXIL CR is a selective serotonin reuptake inhibitor (SSRI) indicated for use in adults for the treatment of (1):

• Major Depressive Disorder (MDD)
• Panic Disorder (PD)
• Social Anxiety Disorder (SAD)
• Premenstrual Dysphoric Disorder (PMDD)

• Swallow tablet whole; do not chew or crush. (2.1)
• Recommended starting and maximum daily dosage: (2.2, 2.3)

• For PMDD, dose continuously or intermittently (luteal phase only). (2.3)
• If inadequate response to starting dosage, titrate in 12.5 mg per day increments once weekly. (2.2, 2.3)
• Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dose is 12.5 mg per day. Do not exceed 50 mg per day for treatment of MDD and PD and 37.5 mg per day for treatment of SAD. (2.5)
• When discontinuing PAXIL CR, reduce dose gradually. (2.7)

Administer PAXIL CR as a single daily dose in the morning, with or without food. Swallow tablets whole and do not chew or crush.

The recommended initial dosage and maximum dosage of PAXIL CR in patients with MDD, PD, and SAD are presented in Table 1.  

In patients with an inadequate response, dosage may be increased in increments of 12.5 mg per day at intervals of at least 1 week, depending on tolerability.

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

The recommended starting dosage in women with PMDD is 12.5 mg per day. PAXIL CR may be administered either continuously (every day throughout the menstrual cycle) or intermittently (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). Intermittent dosing is repeated with each new cycle.

In patients with an inadequate response, the dosage may be increased to the maximum recommended dosage of 25 mg per day, depending on tolerability. Institute dosage adjustments at intervals of at least 1 week.

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

The recommended initial dose of PAXIL CR is 12.5 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment. Reduce initial dose and increase up-titration intervals if necessary. Dosage should not exceed 50 mg per day for MDD or PD and should not exceed 37.5 mg per day for SAD [see Use in Specific Populations (8.5, 8.6)].

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

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

PAXIL CR 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), Drug Interactions (7)].
• Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interactions (7)].
• Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interactions (7)].
• With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in PAXIL CR [see Adverse Reactions (6.1, 6.2)].

• Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOIs. (4, 5.2, 7)
• Concomitant use of pimozide or thioridazine. (4, 5.3, 7)
• Known hypersensitivity to paroxetine or to any of the inactive ingredients in PAXIL CR. (4)

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

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.

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

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

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

The concomitant use of PAXIL CR with MAOIs is contraindicated. In addition, do not initiate PAXIL CR in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking PAXIL CR, discontinue PAXIL CR before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.1)].

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

The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of PAXIL CR is contraindicated in combination with thioridazine and pimozide [see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)].

Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants. For women who intend to become pregnant or who are in their first trimester of pregnancy, PAXIL CR, 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 PAXIL CR, 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 PAXIL CR and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

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

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [See Dosage and Administration (2.7)].

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

PAXIL CR has not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. PAXIL CR should be prescribed with caution in patients with a seizure disorder and should be discontinued in any patient who develops seizures.

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

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including PAXIL CR. 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 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).

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

Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced with concomitant use of paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions ( 7.1)]. One study suggests that the risk may increase with longer duration of coadministration.  However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.

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

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

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

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

• Hypersensitivity reactions to paroxetine [see Contraindications (4)]
• Suicidal Thoughts and Behaviors  [see Warnings and Precautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]
• Embryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)]
• Increased Risk of Bleeding [see Warnings and Precautions (5.5)]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]
• Discontinuation Syndrome [see Warnings and Precautions (5.7)]
• Seizures [see Warnings and Precautions (5.8)]
• Angle-closure Glaucoma [see Warnings and Precautions (5.9)]
• Hyponatremia [see Warnings and Precautions (5.10)]
• Bone Fracture [see Warnings and Precautions (5.12)]
• Sexual Dysfunction [see Warnings and Precautions (5.13)]

Most common adverse reactions (≥5% and at least twice placebo) in placebo-controlled MDD, PD, SAD, and PMDD clinical trials:

abnormal ejaculation, abnormal vision, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, insomnia, libido decreased, nausea, somnolence, sweating, tremor. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp.at 1-800-706-5575  or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 PAXIL CR is 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 1627 patients treated with Paxil CR.

• Studies 1 and 2 were 12-week studies that enrolled patients 18 to 65 years old who received PAXIL CR at doses ranging from 25 mg to 62.5 mg once daily. Study 3 was a 12-week study in patients 60 to 88 years old who received PAXIL CR at doses ranging 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 who received PAXIL CR at doses ranging from 12.5 mg to 75 mg once daily.  
• Study 7 was a 12-week study that enrolled adult patients who received PAXIL CR at doses ranging 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 who received PAXIL CR at doses 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 who received PAXIL CR 2 weeks prior to the onset of menses (luteal phase dosing) at doses of 12.5 mg or 25 mg once daily.

Adverse Reactions Leading 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 leading to study withdrawal were: nausea (up to 4% of patients), asthenia, headache, depression, insomnia, and abnormal liver function tests (each occurring in up to 2% of patients), and dizziness, somnolence, and diarrhea (each occurring in up to 1% of patients).

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

Adverse Reactions in MDD, PD, and SAD

Table 3 presents  the most common adverse reactions in PAXIL CR-treated patients (incidence ≥5% and greater than placebo within at least 1 of the indications) in controlled trials in patients with MDD, PD, and SAD

Table 3. Adverse Reactions (³5% of Patients Treated with PAXIL CR and Greater than Placebo) in 10 to 12 Week Studies of MDD, PD, and SAD

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

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 During the Premarketing Evaluation of PAXIL CR

Adverse reactions from studies in MDD (not including Study 3 in elderly patients), PD, and SAD that occurred between 1% and 5% of patients treated with PAXIL CR and at a rate greater than in placebo-treated patients include:, 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 adverse reactions that occurred (incidence of 5% or more and greater than placebo within at least 1 of the studies) in patients treated with PAXIL CR in Studies 8, 9, 10, and 11.

Table 4. Adverse Reactions (≥5% of Patients Treated with PAXIL CR and Greater than Placebo) in Pooled Studies PMDD (Studies 8, 9, 11), and in Study 10^a,b,c

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 2 dosing regimens.

^c Mostly anorgasmia or difficulty achieving orgasm.  

Dose Dependent Adverse Reactions

Comparison of the incidence of adverse reactions (placebo vs. 12.5 mg PAXIL CR vs. 25 mg PAXIL CR) from studies 8, 9, 10 showed the following adverse reactions to be dose-related: Nausea, somnolence, sweating, dry mouth, dizziness, decreased appetite, tremor, impaired concentration, yawn, paresthesia, hyperkinesia, and vaginitis.

Male and Female Sexual Dysfunction

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

The percentage of patients reporting symptoms of sexual dysfunction in the Studies 1 and 2 (nonelderly patients with MDD), 4, 5, 6, 7, 8, 9, 10, and 11 are presented in Table 5:

Table 5. Adverse Reactions Related To Sexual Dysfunction In Patients Treated With PAXIL CR in Pooled 10-12 Week Studies of MDD, PD, SAD, and PMDD

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

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

Less Common Adverse Reactions

The following adverse reactions occurred during the clinical studies of PAXIL CR 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 occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare reactions are those occurring 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.  

Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain‑Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), priapism, syndrome of inappropriate ADH secretion (SIADH), prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), and vasculitic syndromes (such as Henoch‑Schönlein purpura).