WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), have been shown to increase the risk of suicidal thoughts and behavior in pediatric and young adult patients when used to treat major depressive disorder and other psychiatric disorders. Because BRISDELLE is an SSRI, monitor patients closely for worsening and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Potential for increased risk of suicidal thinking and behavior (5.1) Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1)
1 INDICATIONS AND USAGE BRISDELLE is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. Limitation of Use: BRISDELLE is not indicated for the treatment of any psychiatric condition. BRISDELLE contains 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 BRISDELLE have not been established for any psychiatric condition. Patients who require paroxetine for treatment of a psychiatric condition should discontinue BRISDELLE and initiate a paroxetine-containing medication that is indicated for such use. BRISDELLE is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause (VMS) (1) Limitation of Use: BRISDELLE is not indicated for the treatment of any psychiatric condition (1)
3 DOSAGE FORMS AND STRENGTHS BRISDELLE is available as 7.5 mg pink capsules printed with black edible ink with “NOVEN” and “7.5 mg” on the capsule. Each capsule contains 9.69 mg paroxetine mesylate equivalent to 7.5 mg paroxetine base. Capsules: 7.5 mg (3)
4 CONTRAINDICATIONS Concurrent use with monoamine oxidase inhibitors (MAOI) or use within 14 days of MAOI use (2.2, 4.1, 5.2, 7.3) Use with thioridazine (4.2, 7.1) Use with pimozide (4.3, 7.1) Hypersensitivity to any ingredient in BRISDELLE (4.4) Pregnancy (4.5, 8.1) 4.1 Monoamine Oxidase Inhibitors Concomitant use of an MAOI with BRISDELLE or within 14 days of stopping treatment with BRISDELLE is contraindicated because of an increased risk of serotonin syndrome. The use of BRISDELLE within 14 days of stopping an MAOI is also contraindicated [see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Drug Interactions (7.3)]. Starting BRISDELLE in a patient who is being treated with linezolid or intravenous methylene blue, both of which inhibit monoamine oxidase, is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Drug Interactions (7.3)]. 4.2 Thioridazine Concomitant use of BRISDELLE with thioridazine is contraindicated, because thioridazine prolongs the QT interval, and paroxetine can increase thioridazine levels [see Drug Interactions (7.1)]. 4.3 Pimozide Concomitant use of BRISDELLE with pimozide is contraindicated because pimozide prolongs the QT interval, and paroxetine increases pimozide levels [see Drug Interactions (7.1)]. 4.4 Hypersensitivity to any Ingredient in BRISDELLE BRISDELLE is contraindicated in patients with a history of hypersensitivity to paroxetine or any of the other ingredients in BRISDELLE. 4.5 Pregnancy Menopausal VMS does not occur during pregnancy and BRISDELLE may cause fetal harm [see Use in Specific Populations (8.1)].
5 WARNINGS AND PRECAUTIONS Suicidality: Monitor for suicidality or unusual changes in behavior (5.1) Serotonin Syndrome: Serotonin syndrome, which is potentially life-threatening, has been reported with SSRIs. Discontinue BRISDELLE and initiate supportive treatment (5.2, 7.3) Tamoxifen: Efficacy of tamoxifen may be reduced when administered concomitantly with BRISDELLE (5.3, 7.1) Abnormal Bleeding: Caution patients about the risk of bleeding associated with the concomitant use of BRISDELLE and non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation (5.4, 7.1) Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients who have untreated anatomically narrow angles and who are treated with antidepressants. (5.5) Hyponatremia: Can occur in association with syndrome of inappropriate antidiuretic hormone secretion (SIADH) (5.6) Bone Fracture: Epidemiological studies have reported an association between SSRI treatment and fractures (5.7) Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/hypomania (5.8) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.9) Akathisia: Can occur, most likely in the first few weeks of treatment (5.10) Cognitive and Motor Impairment: May cause impairment; patients should not operate machinery or motor vehicles until certain that BRISDELLE does not affect them adversely (5.11) 5.1 Suicidal Thoughts and Behaviors BRISDELLE is not approved for any psychiatric condition. Antidepressants, including those that contain an SSRI, increase the risk of suicidal thinking and behavior (suicidality) in pediatric and young adult patients when used to treat major depressive disorder (MDD) and other psychiatric disorders. There is limited information regarding suicidality in women who use BRISDELLE for treatment of VMS. The BRISDELLE trials excluded women with a presence or history of previous psychiatric disorders. Consider discontinuing BRISDELLE in patients with worsening depression or those who experience emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. All patients being treated with BRISDELLE should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of treatment. Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in patients being treated with antidepressants for MDD as well as for other psychiatric and nonpsychiatric indications. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Families and caregivers of patients being treated with BRISDELLE should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SSRIs, including paroxetine, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat depression and others such as linezolid and intravenous methylene blue). 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), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Monitor patients for the emergence of serotonin syndrome. The concomitant use of BRISDELLE with MAOIs is contraindicated. Do not start BRISDELLE in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking BRISDELLE. BRISDELLE should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.2)]. If concomitant use of BRISDELLE with other serotonergic drugs (e.g., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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 Contraindications (4.1) Drug Interactions (7.3)]. Discontinue BRISDELLE and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. 5.3 Potential Impact on Tamoxifen Efficacy It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 [see Drug Interactions (7.1)]. However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, weigh the likely benefit of BRISDELLE for treating VMS vs. the risk of possible decreased tamoxifen effectiveness, and consider avoiding the concomitant use of BRISDELLE for VMS treatment. 5.4 Abnormal Bleeding SSRIs, including BRISDELLE, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), 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. Bleeding events related to SSRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Caution patients about the risk of bleeding associated with the concomitant use of BRISDELLE and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.1)]. 5.5 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressants and BRISDELLE may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.6 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including BRISDELLE. Elderly patients may be at greater risk. In many cases, the hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported in patients using SSRIs. Also, patients taking diuretics or who are volume-depleted can be at greater risk. Consider discontinuation of BRISDELLE in patients with symptomatic hyponatremia and institute appropriate medical intervention. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.7 Bone Fracture Epidemiological studies on bone fracture risk following exposure to SSRIs have reported an association between SSRI treatment and fractures. It is unknown to what extent fracture risk is directly attributable to SSRI treatment. If a BRISDELLE-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising, consider the possibility of a fragility fracture. 5.8 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania BRISDELLE is only indicated for the treatment of moderate to severe VMS and is not approved for use in treating either depression or bipolar depression. However, prior to initiating treatment with BRISDELLE, all patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It is generally believed (though not established in controlled trials) that use of an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. 5.9 Seizures In premarketing testing of paroxetine, seizures occurred in 0.1% of paroxetine-treated patients. Use BRISDELLE cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Evaluate and consider discontinuing use in any patient who develops seizures. 5.10 Akathisia The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. Discontinue treatment with BRISDELLLE if akathisia occurs. 5.11 Potential for Cognitive and Motor Impairment BRISDELLE has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that the drug treatment does not affect them adversely.
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: Suicidality [see Warnings and Precautions (5.1)] Serotonin syndrome [see Warnings and Precautions (5.2)] Abnormal bleeding [see Warnings and Precautions (5.4)] Angle-Closure Glaucoma [see Warnings and Precautions (5.5)] Hyponatremia [see Warnings and Precautions (5.6)] Bone Fracture [see Warnings and Precautions (5.7)] Mania/Hypomania [see Warnings and Precautions (5.8)] Seizure [see Warnings and Precautions (5.9)] Akathisia [see Warnings and Precautions (5.10)] The most common adverse reactions (≥ 2%) reported in clinical trials were: headache, fatigue, and nausea/vomiting (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Noven Therapeutics, LLC at 1-800-455-8070 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 BRISDELLE 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 (14)]. In these trials, a total of 635 women were exposed to BRISDELLE 7.5 mg administered orally once daily and 641 women received placebo. The majority of BRISDELLE-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 BRISDELLE 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 BRISDELLE reported at least 1 adverse reaction in the three controlled studies. The most common adverse reactions (≥ 2% and more common among BRISDELLE-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 BRISDELLE 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 (%) BRISDELLE (n = 635) Placebo (n = 641) Nervous system disorders Headache 40 (6.3) 31 (4.8) General disorders and administration site conditions Fatigue, malaise, lethargy 31 (4.9) 18 (2.8) Gastrointestinal disorders Nausea, vomiting 27 (4.3) 15 (2.3) Certain symptoms were seen more frequently in women at the time of discontinuation of BRISDELLE 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 BRISDELLE-treated patients reported a serious adverse reaction of suicidal ideation and one BRISDELLE-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. 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.
7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted with BRISDELLE. Paroxetine is a strong CYP2D6 inhibitor. Co-administration of BRISDELLE can alter concentrations of other drugs that are metabolized by CYP2D6. Consider potential drug interactions prior to and during therapy (5.3, 7.1, 7.3). See Full Prescribing Information for a list of clinically significant drug interactions (7.1, 7.2, 7.3) 7.1 Potential for BRISDELLE 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 (12.3)]. Table 2 contains examples of drugs with a metabolism that may be affected by co-administration with BRISDELLE. 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 BRISDELLE is contraindicated. Pimozide Increased plasma concentrations of pimozide. Potential QTc prolongation Concomitant use of pimozide and BRISDELLE is contraindicated. Tamoxifen Reduced plasma concentrations of active tamoxifen metabolite Consider avoiding concomitant use of tamoxifen and BRISDELLE. Tricyclic Antidepressant (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 BRISDELLE. 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 BRISDELLE 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 BRISDELLE 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 BRISDELLE when administered concomitantly [see Clinical Pharmacology (12.3)]. Table 3 Effects of Other Drugs on Paroxetine Concomitant Drug Name Effect of Concomitant Drug on Paroxetine Clinical Recommendations Phenobarbital Decreased paroxetine exposure Phenytoin Decreased paroxetine exposure Fosamprenavir/ Ritonavir Decreased plasma concentration of paroxetine No dose adjustment for BRISDELLE. Monitor clinical effect of BRISDELLE. Cimetidine Increased plasma concentration of paroxetine Use caution if co-administering BRISDELLE 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 BRISDELLE or use of BRISDELLE and an MAOI within 14 days of each other is contraindicated [see Dosage and Administration (2.2), Contraindications (4.1) and Warnings and Precautions (5.2)]. Serotonergic Drugs If concomitant use of BRISDELLE with other serotonergic drugs (e.g., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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 (5.2)]. 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 BRISDELLE with tryptophan is not recommended. If concomitant use of BRISDELLE with a serotonergic drug is warranted, carefully observe the patient, particularly during treatment initiation. There have been postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. BRISDELLE contains paroxetine, which is also the active ingredient in other drugs. The concomitant use of BRISDELLE with other paroxetine products is not recommended [see Indications and Usage (1)]. 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 BRISDELLE is initiated or discontinued [see Warnings and Precautions (5.4)].
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X Risk Summary BRISDELLE is 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/m2 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 (5.2)]. 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 20th 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/m2 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/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is unknown. 8.3 Nursing Mothers Paroxetine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from BRISDELLE, 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; BRISDELLE is not indicated in the pediatric population. 8.5 Geriatric Use Clinical studies of BRISDELLE 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 BRISDELLE dose adjustment is considered necessary in elderly patients [see Clinical Pharmacology (12.3)]. 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 (5.6)]. 8.6 Renal Impairment No BRISDELLE dose adjustment is considered necessary in patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No BRISDELLE dose adjustment is considered necessary in patients with liver impairment [see Clinical Pharmacology (12.3)].