Paxil Drug Information

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

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. 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). 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 MDD 18 to 65 year olds MDD ≥60 years old Panic Disorder Social Anxiety Disorder Body System/ Adverse Reaction PAXIL CR (N=212) % Placebo (N=211) % PAXIL CR (N=104) % Placebo (N=109) % PAXIL CR (N=444) % Placebo (N=445) % PAXIL CR (N=186) % Placebo (N=184) % Body as a Whole Headache 27 20 17 13 NA NA 23 17 Asthenia 14 9 15 14 15 10 18 7 Abdominal Pain 7 4 - - 6 4 5 4 Back Pain 5 3 - - NA NA 4 1 Digestive System Nausea 22 10 - - 23 17 22 6 Diarrhea 18 7 15 9 12 9 9 8 Dry Mouth 15 8 18 7 13 9 3 2 Constipation 10 4 13 5 9 6 5 2 Flatulence 6 4 - - NA NA NA NA Decreased Appetite 2 12 5 8 6 1 <1 Dyspepsia NA NA 13 10 NA NA 2 <1 Musculoskeletal System Myalgia NA NA - - 5 3 NA NA Nervous System Somnolence 22 8 21 12 20 9 9 4 Insomnia 17 9 10 8 20 11 9 4 Dizziness 14 4 9 5 NA NA 7 4 Libido Decreased 7 3 8 <1 9 4 1 Nervousness NA NA - - 8 7 NA NA Tremor 7 1 7 0 8 2 4 2 Anxiety NA NA - - 5 4 2 1 Respiratory System Sinusitis NA NA - - 8 5 NA NA Yawn 0 - - 3 0 2 0 Skin and Appendages Sweating 6 2 10 <1 7 2 14 3 Special Senses Abnormal Vision a 5 1 - - 3 <1 2 0 Urogenital System Abnormal Ejaculation b,c 26 1 17 3 27 3 15 1 Female Genital Disorder b,d 10 <1 - - 7 1 3 0 Impotence b 5 3 9 3 10 1 9 0 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 Body System/ Adverse Reaction % Reporting Adverse Reaction Continuous Dosing Luteal Phase Dosing PAXIL CR (n = 681) % Placebo (n = 349)% PAXIL CR (n = 246)% Placebo (n = 120)%% Body as a Whole Asthenia 17 6 15 4 Headache 15 12 NA NA Infection 6 4 NA NA Digestive System Nausea 17 7 18 2 Diarrhea 6 2 6 0 Constipation 5 1 2 <1 Nervous System Libido Decreased 12 5 9 6 Somnolence 9 2 3 <1 Insomnia 8 2 7 3 Dizziness 7 3 6 3 Tremor 4 <1 5 0 Skin and Appendages Sweating 7 <1 6 <1 Urogenital System Female Genital Disorders c 8 1 2 0 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 Studies 1 and 2 % Studies 4, 5 and 6 % Study 7 % Studies 8, 9 and 11 (Continuous Dosing) % Study 10 (Luteal Phase Dosing) % PAXIL CR Placebo PAXIL CR Placebo PAXIL CR Placebo PAXIL CR Placebo PAXIL CR Placebo n (males) 78 78 162 194 88 97 NA NA NA NA Decreased Libido 10 5 9 6 13 1 NA NA NA NA Abnormal ejaculation 26 1 27 3 15 1 NA NA NA NA Impotence 5 3 10 1 9 0 NA NA NA NA n (females) 134 133 282 251 98 87 681 349 246 120 Decreased Libido 4 2 8 2 4 1 12 5 9 6 Orgasmic Disturbance 10 <1 7 1 3 0 8 1 2 0 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.

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), 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).

Clinically Significant Drug Interactions Table 6 includes clinically significant drug interactions with

PAXIL CR. Table 6: Clinically Significant Drug Interactions with PAXIL CR Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs, including PAXIL CR, and MAOIs increases the risk of serotonin syndrome. Intervention PAXIL CR is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue . 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 PAXIL CR is contraindicated in patients taking pimozide or thioridazine . Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with PAXIL CR 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 PAXIL CR and/or concomitant serotonergic drugs . Examples Other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, 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 PAXIL CR may potentiate the risk of bleeding.

Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of PAXIL CR and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio. Examples aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact PAXIL CR is highly bound to plasma protein.

The concomitant use of PAXIL CR with another drug that is highly bound to plasma protein may increase free concentrations of PAXIL CR or other tightly-bound drugs in plasma. Intervention Monitor for adverse reactions and reduce dosage of PAXIL CR or other protein-bound drugs as warranted. Examples warfarin Drugs Metabolized by CYP2D6 Clinical Impact PAXIL CR is a CYP2D6 inhibitor.

The concomitant use of PAXIL CR with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention Decrease the dosage of a CYP2D6 substrate if needed with concomitant PAXIL CR use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if PAXIL CR is discontinued.

Examples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone. Tamoxifen Clinical Impact Concomitant use of tamoxifen with PAXIL CR may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen Intervention Consider use of an alternative antidepressant little or no CYP2D6 inhibition. 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).

Pregnancy 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 https://womensmentalhealth.org/clinical-and-researchprograms/ pregnancyregistry/antidepressants/. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage . PAXIL CR 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). There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including PAXIL CR, during pregnancy.

There also are risks associated with untreated depression in pregnancy (see Clinical Considerations). For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options. No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits. These doses are approximately 6 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 75 mg) on an mg/m 2 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/m 2 basis (see Data). The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or 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 major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy.

Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of PAXIL CR in the month before delivery may be associated with an increased risk of postpartum hemorrhage . Fetal/Neonatal adverse reactions Neonates exposed to PAXIL CR and other SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome . 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. PPHNoccurs in 1-2 per 1000 live births in the general population and is associated with substantialneonatal 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/m 2 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/m 2 basis. The no‑effect dose for rat pup mortality was not determined.

The cause of these deaths is not known.

Pediatric Use The safety and effectiveness of PAXIL CR in pediatric patients have not been established. Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with immediate-release paroxetine, and effectiveness was not established in pediatric patients. 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 immediate-release paroxetine hydrochloride and 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 immediate-release paroxetine hydrochloride 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.

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. Taking thioridazine because of risk of QT prolongation . Taking pimozide because of risk of QT prolongation. With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in PAXIL CR. Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOIs.

Concomitant use of pimozide or thioridazine. Known hypersensitivity to paroxetine or to any of the inactive ingredients in PAXIL CR.

The following have been reported with paroxetine tablet overdosage: Seizures, which may be delayed, and altered mental status including coma. Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.

Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a paroxetine overdose. Consider contacting a Poison Center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.