Side Effects of Brisdelle (paroxetine)

Brisdelle (paroxetine) is a selective serotonin reuptake inhibitor (SSRI) used to treat moderate to severe hot flashes associated with menopause. Brisdelle is a non-hormonal treatment for this condition.

Brisdelle contains a low dose of paroxetine especially formulated to treat hot flashes associated with menopause. Higher doses of paroxetine are commonly used as an antidepressant. How low doses of paroxetine help to treat hot flashes associated with menopause is not known. Brisdelle should not be used to treat depression or any other mood disorders.

Common side effects of Brisdelle include

• headache,
• tiredness,
• nausea,
• vomiting,
• restlessness,
• constipation,
• dry mouth,
• diarrhea, and
• tremor.

Serious side effects of Brisdelle include

• increased risk for suicidal thoughts or actions,
• bone fracture,
• seizure,
• low blood sodium levels (hyponatremia),
• visual problems,
• toxic epidermal necrolysis,
• abnormal bleeding,
• manic episodes,
• glaucoma, and
• restlessness.

Drug interactions of Brisdelle include monoamine oxidase inhibitors (MAOIs), due to the risk of serotonin syndrome, a rare, but potentially life-threatening condition caused by abnormally high levels of the chemical serotonin in the body.

• Similarly, due to a high risk of serotonin syndrome, Brisdelle should not be combined with linezolid or intravenous methylene blue.
• Other medications that also increase the risk of serotonin syndrome and should be used cautiously with Brisdelle include triptans, lithium, tramadol, St. John's wort, dextromethorphan, and antidepressants including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs).
• Brisdelle should not be used with thioridazine or pimozide, which are known to prolong the QT interval.
• Because Brisdelle increases the concentration of these drugs in the blood, coadministration increases the risk of death. SSRI's, including Brisdelle may increase the risk of bleeding, especially if taken with the blood thinner warfarin, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs).
• Paroxetine, the medicine in Brisdelle, is a strong inhibitor of the CYP2D6 enzymes.
• Taking Brisdelle with other drugs that are metabolized by this pathway such as nortriptyline, amitriptyline, imipramine, desipramine, fluoxetine, risperidone, and flecainide may increase the risk for side effects.
• Paroxetine is also a CYP2D6 substrate and is itself metabolized via this pathway.
• Administration with drugs that alter the activity of these enzymes such as rifampin, carbamazepine, and phenytoin may affect the concentration of Brisdelle in the body.
• Strong CYP2D6 inducers may decrease the blood levels of paroxetine, resulting in poor treatment outcomes.

Brisdelle should not be used during pregnancy because menopausal vasomotor symptoms do not occur during pregnancy, and Brisdelle can cause harm to a fetus.

Brisdelle is excreted in human milk. Due to the potential risk of causing harm to a nursing infant, Brisdelle should only be using by breastfeeding mothers if clearly needed.

The most common side effects of Brisdelle are:

• Headache
• Tiredness
• Nausea
• Vomiting

Other side effects include:

• Restlessness
• Constipation
• Dry mouth
• Diarrhea
• Tremor

Possible serious side effects include:

• Increased risk for suicidal thoughts or actions
• Bone fracture
• Seizure
• Low salt (sodium) levels in the blood (hyponatremia)
• Visual problems
• Toxic epidermal necrolysis
• Abnormal bleeding
• Manic episodes
• Glaucoma
• Restlessness

Numerous other side effects may also occur infrequently.

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

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.
• 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 Advers e Reactions in the Phas e 2 and Phas e 3 Trials (≥ 2% and at a higher incidence than placebo)

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.

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.

No drug-drug interaction studies have been conducted with Brisdelle.

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. 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

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).

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.

Table 3 Effects of Other Drugs on Paroxetine

Use caution if co-administering Brisdelle with other drugs that inhibit CYP2D6 (e.g., quinidine).

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.

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.

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.

Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, And Warfarin)

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered 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.