Drug Safety-related Labeling Changes (SrLC)

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BRISDELLE (NDA-204516)

(PAROXETINE MESYLATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/11/2025 (SUPPL-14)

Approved Drug Label (PDF)

Boxed Warning

Effective 2/11/25, Box Warning in supplement 14 has been revised; see underlined text:

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Selective serotonin reuptake inhibitors (SSRIs) increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term trials for the treatment of major depressive disorder and other psychiatric disorders. Because BRISDELLE is an SSRI, closely monitor BRISDELLE-treated patients closely for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. BRISDELLE is not approved for use in any psychiatric condition or in pediatric and young adult patients [see Indications and Usage (1) and Use in Specific Populations (8.4)].

4 Contraindications

Additions and/or revisions underlined:

BRISDELLE 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 Interaction (7)].
• Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interaction (7)].
• Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interaction (7)].
• With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in BRISDELLE [see Adverse Reactions (6.2)]
• Who are or become pregnant because menopausal VMS does not occur during pregnancy and BRISDELLE may cause fetal harm [see Use in Specific Populations (8.1)].

5 Warnings and Precautions

Extensive changes; please refer to label for complete information

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

The data described below reflect exposure to BRISDELLE in the following randomized, placebo- controlled trials for the treatment of moderate to severe VMS associated with menopause [see Clinical Studies (14)]: (1) one 8-week Phase 2 trial, (2) one 12-week Phase 3 trial and (3) one 24-week Phase 3 trial. In these trials, a total of 635 postmenopausal females received BRISDELLE 7.5 mg administered orally once daily and 641 postmenopausal females received placebo. In these trials, 68% were White, 30% were Black or African American (30%), and 2% were other races, with a mean age of 55 years (range 40 to 73 years). Postmenopausal females with a history of suicidal ideation or suicidal behavior were excluded from these trials.

. . .

Common Adverse Reactions:

Overall, based on investigators’ determinations about what events were likely to be drug- related, about 20% of postmenopausal females treated with BRISDELLE reported at least 1 adverse reaction in the three controlled trials. The most common adverse reactions (greater than or equal to 2% and at a higher incidence in BRISDELLE-treated females compared to placebo-treated females) reported in these trials were headache, fatigue/malaise/lethargy, and nausea/vomiting. Of these commonly reported adverse reactions, nausea occurred primarily within the first 4 weeks of BRISDELLE treatment and fatigue occurred primarily within the first week of BRISDELLE treatment, and decreased in frequency with continued therapy.

The adverse reactions that occurred in greater than or equal to 2% of BRISDELLE-treated patients and at a higher incidence in BRISDELLE-treated females compared to placebo-treated females are shown in Table 1 for the pooled Phase 2 and Phase 3 trials.

Table 1: Incidence of Common Adverse Reactions in the Phase 2 and Phase 3 Trials of Postmenopausal Females with Moderate to Severe VMS1

Refer to label to view changes in Table 1

Adverse Reactions After Discontinuing BRISDELLE

Certain symptoms were seen more frequently in postmenopausal females at the time of discontinuation of BRISDELLE compared to discontinuation of placebo and have also been reported upon discontinuation of other paroxetine products, particularly after abrupt discontinuation. Adverse reactions reported after discontinuation of BRISDELLE included increased dreaming/nightmares, muscle cramps/spasms/twitching, headache, nervousness/anxiety, fatigue/tiredness, restless feeling in legs, and trouble sleeping/insomnia. While these adverse reactions were generally self-limiting, there have been reports of serious discontinuation symptoms with other paroxetine products.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post-approval use of this and other paroxetine products. 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.

. . .

Immune System Disorders: Anaphylaxis, Angioedema, Toxic epidermal necrolysis.

. . .

7 Drug Interactions

7.3 Other Potentially Significant Drug Interactions

Additions and/or revisions underlined:

Monoamine Oxidase Inhibitors

Serious adverse reactions such as serotonin syndrome have been reported in patients treated with a SSRI and a concomitant monoamine oxidase inhibitor (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

. . .

An interaction between paroxetine and tryptophan may occur when they are co-administered. Adverse reactions, 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.

. . .

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and effectiveness of BRISDELLE in pediatric patients have not been established; BRISDELLE is not indicated in the pediatric population.

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical trials of BRISDELLE did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients. Patients 65 years of age and older may have elevated paroxetine plasma concentrations compared to younger adult patients. However, the recommended BRISDELLE dosage in patients 65 years of age and older is that same as that as younger patients [see Clinical Pharmacology (12.3)].

SSRIs have been associated with cases of clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.6)].

8.6 Renal Impairment

Additions and/or revisions underlined:

The recommended BRISDELLE dosage in patients with renal impairment is the same as those with normal renal function [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Additions and/or revisions underlined:

The recommended BRISDELLE dosage in patients with hepatic impairment is the same as those with normal hepatic function [see Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

What is the most important information I should know about BRISDELLE?

BRISDELLE may cause serious side effects, including:

• Increased risk of suicidal thoughts or actions. BRISDELLE and related antidepressant medicines may increase suicidal thoughts or actions within the first few months of treatment.
  • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
  • Watch for these changes and call your healthcare provider right away if you notice:
    • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
    • Pay close attention to any changes when BRISDELLE is started.
  • Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

 . . .

What is BRISDELLE?

• BRISDELLE is a prescription medicine used to treat moderate to severe hot flashes associated with menopause.
• BRISDELLE is not for any psychiatric problems such as depression, obsessive compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and post-traumatic stress disorder.

BRISDELLE is not for use in children.

Who should not take BRISDELLE? Do not take BRISDELLE if you:

• take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or the intravenous methylene blue.
  • Do not take an MAOI within 14 days of stopping BRISDELLE unless directed to do so by your healthcare provider.
  • Do not start BRISDELLE if you stopped taking an MAOI in the last 14 days unless directed to do so by your healthcare provider.
  • People who take BRISDELLE close in time to an MAOI may have a serious or life-threatening side effect called serotonin syndrome. Get medical help right away if you have any of these symptoms:

. . .

• nausea, vomiting, or diarrhea

. . .

What should I tell my healthcare provider before taking BRISDELLE?

Before taking BRISDELLE, tell your healthcare provider about all of your medical conditions, including if you:

. . .

• have or have a family history of bipolar disorder, mania or hypomania

. . .

• have bone problems

. . .

What are the possible side effects of BRISDELLE? BRISDELLE may cause serious side effects, including:

• See “What is the most important information I should know about BRISDELLE?”
• Serotonin syndrome. This condition can be life-threatening and can happen when you take BRISDELLE with certain other medicines. Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following symptoms of serotonin syndrome:

. . .

• Visual problems (angle-closure glaucoma). BRISDELLE may cause a visual problem called angle-closure glaucoma. Symptoms may include:

. . .

• Low salt (sodium) levels in the blood. Elderly people and those taking diuretics or are dehydrated are at greater risk of experiencing low salt levels in their blood. Symptoms may include:

. . .

• seeing or hearing things that are not there (hallucinations)
• fainting (syncope)
• seizures
• stopping breathing (respiratory arrest)

. . .

• Manic episodes. Manic episodes may happen in people with bipolar disorder who take BRISDELLE. Symptoms may include:

. . .

PATIENT COUNSLEING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

. . .

Suicidal Thoughts and Behaviors Advise patients, their families, and their caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and to alert the health care provider if such changes occur [see Boxed Warning and Warnings and Precautions (5.1)].

. . .

Potential Impact on Tamoxifen Efficacy Caution patients that efficacy of tamoxifen may be reduced when administered concomitantly and counsel them about the likely benefit of paroxetine for treating VMS vs. the risk of possible decreased tamoxifen effectiveness [see Warnings and Precautions (5.3)].

Increased Risk of Bleeding

Caution patients about the concomitant use of BRISDELLE and NSAIDs, aspirin, warfarin, and other anticoagulants because combined use of drugs that interfere with serotonin reuptake has been associated with an increased risk of bleeding [see Warnings and Precautions (5.4)].

Angle-Closure Glaucoma Advise patients that taking BRISDELLE can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma - existing [See Warnings and Precautions (5.5)].

Hyponatremia

Caution patients about the risk of hyponatremia, particularly elderly patients and those who are taking diuretics or are volume-depleted [see Warnings and Precautions (5.6)].

Bone Fracture

Inform patients that there is the possibility for an increased risk of fracture [see Warnings and Precautions (5.7)].

Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania

Advise patients, their families, and their caregivers to observe for signs of activation of mania/hypomania [see Warnings and Precautions (5.8)].

Sexual Dysfunction

Advise patients that use of BRISDELLE may cause symptoms of sexual dysfunction in female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.10)].

Allergic Reactions

Advise patients to seek medical attention if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions (6.2)].

02/11/2025 (SUPPL-9)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR Conversion:

Risk Summary

BRISDELLE is contraindicated in pregnant females and not indicated for use in pre-menopausal females. Based on epidemiologic and animal studies, paroxetine can cause fetal harm.

Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.4)].

Paroxetine is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant female 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 BRISDELLE, during pregnancy.

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 64 times (rat) and less than 16 times (rabbit) the maximum recommended human dose (MRHD) of BRISDELLE (7.5 mg) on an mg/m2 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 1.3 times the MRHD on an mg/m2 basis (see Data).

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. PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal 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 64 times (rat) and less than 16 times (rabbit) MRHD of BRISDELLE (7.5 mg) on an mg/m2 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 1.3 times the MRHD on an mg/m2 basis. The no effect dose for rat pup mortality was not determined. The cause of these deaths is not known.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Who should not take BRISDELLE?

Do not take BRISDELLE if you:

. . .

• are pregnant or become pregnant. BRISDELLE can harm your unborn baby. Call your healthcare provider if you become pregnant while taking BRISDELLE.

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Pregnancy

Advise patients to notify their physician if they become pregnant during therapy [see Contraindications (4.5) and Use in Specific Populations (8.1)].

. . .

08/18/2023 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

Additions and/or revisions underlined:

BRISDELLE can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., monoamine oxidase inhibitors (MAOIs) [see Contraindications (4), Drug Interactions (7.3)]. Serotonin syndrome can also occur when these drug are used alone.

…

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Nervous System Disorders: Neuroleptic malignant syndrome, Paresthesia, Somnolence, Tremor, Anosmia, Hyposmia.

…

7 Drug Interactions

7.3 Other Potentially Significant Drug Interactions

Additions and/or revisions underlined:

…

 

Serotonergic Drugs

If concomitant use of BRISDELLE 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 (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.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

• Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of BRISDELLE with triptans, tricyclic antidepressants, opioids, linezolid, tramadol, amphetamines, St. John’s Wort, lithium, tryptophan supplements, other serotonergic agents, or antipsychotic drugs [see Warnings and Precautions (5.2) and Drug Interactions (7.3)]. Instruct patients to contact their health care provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.

  …

  MEDICATION GUIDE

  Additions and/or revisions underlined:

  Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BRISDELLE and some medicines may interact with each other, may not work as well, or may cause serious side effects when taken together.

  …

  Especially tell your healthcare provider if you take:

  …

• tramadol, fentanyl, meperidine, methadone, or other opioids

  …

09/20/2021 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Sexual Dysfunction

(Newly added subsection)

Use of SSRIs, including BRISDELLE, may cause symptoms of sexual dysfunction. In female patients, SSRI/SNRI 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 BRISDELLE 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including BRISDELLE, may cause symptoms of sexual problems.

Symptoms in females may include:

• Decrease sexual drive

• Delayed or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with BRISDELLE. There may be treatments your healthcare provider can suggest.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

• Advise patients that use of BRISDELLE may cause symptoms of sexual dysfunction in female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.12)].

04/28/2017 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are discussed elsewhere in labeling:

• Suicidality
• Serotonin syndrome
• Abnormal bleeding
• Angle-Closure Glaucoma
• Hyponatremia
• Bone Fracture
• Mania/Hypomania
• Seizure
• Akathisia

01/04/2017 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

(Additions and/or revisions are underlined)

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, amphetamines, and St. John’s Wort)…

If concomitant use of BRISDELLE with other serotonergic drugs (e.g., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, 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.

7 Drug Interactions

7.3 Other Potentially Significant Drug Interactions

(Additions and/or revisions are underlined)

Serotonergic Drugs

If concomitant use of BRISDELLE with other serotonergic drugs (e.g., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

• Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of BRISDELLE with triptans, tricyclic antidepressants, linezolid, tramadol, amphetamines, St. John’s Wort, lithium, tryptophan supplements, other serotonergic agents, or antipsychotic drugs

MEDICATION GUIDE

(Additions and/or revisions are underlined)

Especially tell your healthcare provider if you take:

• amphetamines

General information about the safe and effective use of BRISDELLE.

For more information about BRISDELLE call 1-844-732-3521…

Distributed by: Sebela Pharmaceuticals Inc., 645 Hembree Parkway, Suite I, Roswell, Georgia 30076. www.sebelapharma.com

Toll Free 1-844-732-3521