paroxetine

Paroxetine Capsules are indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. Limitation of Use: Paroxetine capsules are not indicated for the treatment of any psychiatric condition. Paroxetine capsules contain a lower dose of paroxetine than that used to treat depression, obsessive compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and post-traumatic stress disorder. The safety and efficacy of this lower dose of paroxetine in paroxetine capsules have not been established for any psychiatric condition. Patients who require paroxetine for treatment of a psychiatric condition should discontinue paroxetine capsules and initiate a paroxetine-containing medication that is indicated for such use.

• Paroxetine capsules are a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause (VMS) Limitation of Use: Paroxetine capsules are not indicated for the treatment of any psychiatric condition

• The recommended dosage of paroxetine capsules is 7.5 mg once daily, at bedtime 2.1 Dosage Information The recommended dosage of paroxetine capsules for the treatment of moderate to severe VMS is 7.5 mg once daily, at bedtime, with or without food. 2.2 Use of Paroxetine Capsules Before or After a Monoamine Oxidase Inhibitor (MAOI) Wait at least 14 days after discontinuation of an MAOI before initiating therapy with paroxetine capsules. Conversely, allow at least 14 days after stopping paroxetine capsules before starting an MAOI [see Contraindications , Warnings and Precautions and Drug Interactions ] .

Paroxetine capsules are not an estrogen, and its mechanism of action for the treatment of VMS is unknown.

The following serious adverse reactions are discussed elsewhere in labeling:

• Suicidality [see Warnings and Precautions ]
• Serotonin syndrome [see Warnings and Precautions ]
• Abnormal bleeding [see Warnings and Precautions ]
• Angle-Closure Glaucoma [see Warnings and Precautions ]
• Hyponatremia [see Warnings and Precautions ]
• Bone Fracture [see Warnings and Precautions ]
• Mania/Hypomania [see Warnings and Precautions ]
• Seizure [see Warnings and Precautions ]
• Akathisia [see Warnings and Precautions ]
• The most common adverse reactions (≥ 2%) reported in clinical trials were: headache, fatigue, and nausea/vomiting To report SUSPECTED ADVERSE REACTIONS, contact Padagis at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 directly be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to paroxetine capsules in the one 8-week Phase 2 randomized, placebo-controlled trial and the two Phase 3 randomized, placebo-controlled, 12-week and 24-week trials for the treatment of moderate to severe VMS [see Clinical Studies ] . In these trials, a total of 635 women were exposed to paroxetine capsules 7.5 mg administered orally once daily and 641 women received placebo. The majority of paroxetine capsule-treated patients were Caucasian (68%) and African American (30%), with a mean age of 55 years (range 40 to 73 years). Women with a history of suicidal ideation or suicidal behavior were excluded from these studies. Adverse Reactions Leading to Study Discontinuation: A total of 4.7% of women taking paroxetine capsules discontinued from the clinical trials due to an adverse reaction, compared to 3.7% of women on placebo; the most frequent adverse reactions leading to discontinuation among paroxetine-treated women were: abdominal pain (0.3%), attention disturbances (0.3%), headache (0.3%), and suicidal ideation (0.3%). Common Adverse Reactions: Overall, based on investigators’ determinations about what events were likely to be drug-related, about 20% of women treated with paroxetine capsules reported at least 1 adverse reaction in the three controlled studies. The most common adverse reactions (≥ 2% and more common among paroxetine capsule-treated women) reported in these studies were headache, fatigue/malaise/lethargy, and nausea/vomiting. Of these commonly reported adverse reactions, nausea occurred primarily within the first 4 weeks of treatment and fatigue occurred primarily within the first week of treatment, and decreased in frequency with continued therapy. The adverse reactions that occurred in at least 2% of patients in the paroxetine capsule group and at a higher incidence than placebo are shown in Table 1 for the pooled Phase 2 and Phase 3 trials. Table 1 Frequency of Adverse Reactions in the Phase 2 and Phase 3 Trials (≥ 2% and at a higher incidence than placebo) Frequency n (%) Paroxetine Capsules (n = 635) Placebo (n = 641) Nervous system disorders Headache 40 31 General disorders and administration site conditions Fatigue, malaise, lethargy 31 18 Gastrointestinal disorders Nausea, vomiting 27 15 Certain symptoms were seen more frequently in women at the time of discontinuation of paroxetine capsules compared to women discontinuing placebo, and have also been reported upon discontinuation of other formulations of paroxetine, particularly when abrupt. These include increased dreaming/nightmares, muscle cramps/spasms/twitching, headache, nervousness/anxiety, fatigue/tiredness, restless feeling in legs, and trouble sleeping/insomnia. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms with other formulations of paroxetine. Serious Adverse Reactions: In the pooled Phase 2 and Phase 3 trials, three paroxetine capsule-treated patients reported a serious adverse reaction of suicidal ideation and one paroxetine capsule-treated patient reported a serious adverse reaction of suicide attempt. There were no serious adverse reactions of suicidal ideation or suicide attempt reported among the placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been identified from clinical studies of paroxetine and during post-approval use of other formulations of paroxetine. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Idiopathic thrombocytopenic purpura, Events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, agranulocytosis). Cardiac Disorders: Atrial fibrillation, Pulmonary edema, Ventricular fibrillation, Ventricular tachycardia (including torsades de pointes). Gastrointestinal Disorders: Pancreatitis, Pancreatitis hemorrhagic, Vomiting. General Disorders and Administration Site Conditions: Death, Drug withdrawal syndrome, Malaise. Hepatobiliary Disorders: Drug-induced liver injury, Hepatic failure, Jaundice. Immune System Disorders: Anaphylactoid reaction, Angioedema, Toxic epidermal necrolysis. Investigations: Elevated liver tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction). Metabolism and Nutrition Disorders: Diabetes mellitus inadequate control, Type 2 diabetes mellitus. Nervous System Disorders: Neuroleptic malignant syndrome, Paresthesia, Somnolence, Tremor, Anosmia, Hyposmia. Psychiatric Disorders: Aggression, Agitation, Anxiety, Confusional state, Depression, Disorientation, Homicidal ideation, Insomnia, Restlessness. Respiratory, Thoracic and Mediastinal Disorders: Pulmonary hypertension. Skin and Subcutaneous Tissue Disorders: Hyperhidrosis, Stevens-Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS).

No drug-drug interaction studies have been conducted with paroxetine capsules. Paroxetine is a strong CYP2D6 inhibitor. Co-administration of paroxetine capsules can alter concentrations of other drugs that are metabolized by CYP2D6. Consider potential drug interactions prior to and during therapy . See Full Prescribing Information for a list of clinically significant drug interactions 7.1 Potential for Paroxetine Capsules to Affect Other Drugs Paroxetine is a strong CYP2D6 inhibitor. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 [see Clinical Pharmacology ] . Table 2 contains examples of drugs with a metabolism that may be affected by co-administration with paroxetine capsules. Table 2 Effects of Paroxetine on Other Drugs Concomitant Drug Name Effect of Paroxetine on Other Drugs Clinical Recommendations Thioridazine Increased plasma concentrations of thioridazine Potential QTc prolongation Concomitant use of thioridazine and paroxetine capsules is contraindicated. Pimozide Increased plasma concentrations of pimozide. Potential QTc prolongation Concomitant use of pimozide and paroxetine capsules is contraindicated. Tamoxifen Reduced plasma concentrations of active tamoxifen metabolite Consider avoiding concomitant use of tamoxifen and paroxetine capsules. Tricyclic Antidepressants (TCA) (e.g., Desipramine) Increased plasma concentrations and elimination half-life Plasma TCA concentrations may need to be monitored and the dose of TCA may need to be reduced if a TCA is co-administered with paroxetine capsules. Monitor tolerability. Risperidone Increased plasma concentrations of risperidone A lower dosage of risperidone may be necessary (see the Full Prescribing Information for risperidone). Monitor tolerability. Atomoxetine Increased exposure of atomoxetine A lower dosage of atomoxetine may be necessary (see Full Prescribing Information for atomoxetine). Monitor tolerability. Drugs Highly Bound to Plasma Protein (e.g., Warfarin) Increased free plasma concentrations The dosage of warfarin may need to be reduced. Monitor tolerability and the International Normalized Ratio. Digoxin Decreased plasma concentrations of digoxin Dosage of digoxin may need to be increased. Monitor digoxin concentrations and clinical effect. Theophylline Increased plasma concentrations of theophylline Dosage of theophylline may need to be decreased. Monitor theophylline concentrations and tolerability. Use caution if co-administering paroxetine capsules with other drugs that are metabolized by CYP2D6, including nortriptyline, amitriptyline, imipramine, desipramine, fluoxetine, phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide). 7.2 Potential for Other Drugs to Affect Paroxetine Capsules The metabolism and pharmacokinetics of paroxetine may be affected by the induction and inhibition of drug metabolizing enzymes such as CYP2D6. Table 3 contains a list of drugs that may affect the pharmacokinetics of paroxetine capsules when administered concomitantly [see Clinical Pharmacology ] . Table 3 Effects of Other Drugs on Paroxetine Concomitant Drug Name Effect of Concomitant Drug on Paroxetine Clinical Recommendations Phenobarbital Decreased paroxetine exposure No dose adjustment for paroxetine capsules. Monitor clinical effect of paroxetine capsules. Phenytoin Decreased paroxetine exposure Fosamprenavir/Ritonavir Decreased plasma concentration of paroxetine Cimetidine Increased plasma concentration of paroxetine Use caution if co-administering paroxetine capsules with other drugs that inhibit CYP2D6 (e.g., quinidine). 7.3 Other Potentially Significant Drug Interactions Monoamine Oxidase Inhibitors (MAOIs) Serious adverse reactions such as serotonin syndrome have been reported in patients receiving a concomitant SSRI and MAOI, in patients started on an SSRI who recently received an MAOI and in patients started on an MAOI who recently received an SSRI. Therefore, concomitant use of MAOIs with paroxetine capsules or use of paroxetine capsules and an MAOI within 14 days of each other is contraindicated [see Dosage and Administration , Contraindications and Warnings and Precautions ] . Serotonergic Drugs If concomitant use of paroxetine capsules with other serotonergic drugs (e.g., other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) is clinically warranted, consider the increased risk of serotonin syndrome and carefully observe the patient, particularly during treatment initiation [see Warnings and Precautions ] . An interaction between paroxetine and tryptophan may occur when they are co-administered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine capsules with tryptophan is not recommended. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are co-administered with NSAIDs, aspirin, and warfarin or other drugs that affect coagulation. There may be a pharmacodynamic interaction between paroxetine and warfarin that causes an increased bleeding diathesis despite unaltered prothrombin time. Carefully monitor patients receiving warfarin therapy when paroxetine capsules is initiated or discontinued [see Warnings and Precautions ] .

8.1 Pregnancy Pregnancy Category X Risk Summary Paroxetine capsules are contraindicated in pregnant women because menopausal VMS does not occur during pregnancy and paroxetine can cause fetal harm. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy may have an increased risk of cardiovascular malformations. Cardiac malformations are a common congenital abnormality. These data would suggest that the risk of a cardiac abnormality following paroxetine exposure in the first trimester may increase the risk from 1% to 2%. Exposure to SSRIs in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). No teratogenicity was seen in reproductive development studies conducted in rats and rabbits. However, an increase in rat pup deaths was seen during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation, at a dose approximately equal to the maximum recommended human dose (MRHD) for VMS (7.5 mg) on an mg/m 2 basis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Human Data First-Trimester Pregnancy Exposure

• Epidemiologic studies which include data from the Swedish National Registry, a retrospective cohort study using United Healthcare data and a meta-analysis of studies (1992-2008) have shown a less than 2-fold increased risk of cardiac malformations, primarily ventricular septal and atrial septal defects, with first-trimester paroxetine exposure. Two case-control studies using separate databases with > 9000 birth defect cases and > 4000 controls showed 7 and 6 paroxetine-exposed infants respectively, with right ventricular outflow tract obstructions, a 2- to 3-fold increased risk. An increase in overall congenital malformations with first-trimester paroxetine use was not observed in all studies. Third-Trimester Pregnancy Exposure
• Neonates exposed to 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, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs or, possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ] .
• Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1000 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 6-fold higher for infants exposed to SSRIs after the 20 th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. 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 65 (rat) and 16 (rabbit) times the maximum recommended human dose (MRHD) for VMS on an mg/m 2 basis. There were no teratogenic 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 or approximately equal to the MRHD for VMS on an mg/m 2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is unknown.

Nursing Mothers Paroxetine is excreted in human milk.

Because of the potential for serious adverse reactions in nursing infants from paroxetine capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established; paroxetine capsules are not indicated in the pediatric population. 8.5 Geriatric Use Clinical studies of paroxetine capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may have elevated paroxetine plasma concentrations compared to younger patients. However, no paroxetine capsules dose adjustment is considered necessary in elderly patients [see Clinical Pharmacology ] . SSRIs have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions ] . 8.6 Renal Impairment No paroxetine capsules dose adjustment is considered necessary in patients with renal impairment [see Clinical Pharmacology ] . 8.7 Hepatic Impairment No paroxetine capsules dose adjustment is considered necessary in patients with liver impairment [see Clinical Pharmacology ] .