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Plisil uses


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 Plisil 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 .

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.


Warnings and Precautions, Serotonin Synrome and amphetamines ( 5.2) 03/2017

1 INDICATIONS AND USAGE

Plisil is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause.

Limitation of Use:

Plisil is not indicated for the treatment of any psychiatric condition. Plisil contains a lower dose of Plisil 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 Plisil in Plisil have not been established for any psychiatric condition. Patients who require Plisil for treatment of a psychiatric condition should discontinue Plisil and initiate a paroxetine-containing medication that is indicated for such use.

Plisil 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: Plisil is not indicated for the treatment of any psychiatric condition ( 1)

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2 DOSAGE AND ADMINISTRATION

The recommended dosage of Plisil is 7.5 mg once daily, at bedtime

2.1 Dosage Information

The recommended dosage of Plisil for the treatment of moderate to severe VMS is 7.5 mg once daily, at bedtime, with or without food.

2.2 Use of Plisil Before or After a Monoamine Oxidase Inhibitor

Wait at least 14 days after discontinuation of an MAOI before initiating therapy with Plisil. Conversely, allow at least 14 days after stopping Plisil before starting an MAOI .

3 DOSAGE FORMS AND STRENGTHS

Plisil 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 Plisil mesylate equivalent to 7.5 mg Plisil base.

Capsules: 7.5 mg ( 3)

4 CONTRAINDICATIONS

4.1 Monoamine Oxidase Inhibitors

Concomitant use of an MAOI with Plisil or within 14 days of stopping treatment with Plisil is contraindicated because of an increased risk of serotonin syndrome. The use of Plisil within 14 days of stopping an MAOI is also contraindicated .

Starting Plisil 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 .

4.2 Thioridazine

Concomitant use of Plisil with thioridazine is contraindicated, because thioridazine prolongs the QT interval, and Plisil can increase thioridazine levels .

4.3 Pimozide

Concomitant use of Plisil with pimozide is contraindicated because pimozide prolongs the QT interval, and Plisil increases pimozide levels .

4.4 Hypersensitivity to any Ingredient in Plisil

Plisil is contraindicated in patients with a history of hypersensitivity to Plisil or any of the other ingredients in Plisil.

4.5 Pregnancy

Menopausal VMS does not occur during pregnancy and Plisil may cause fetal harm .

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5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors

Plisil 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 Plisil for treatment of VMS. The Plisil trials excluded women with a presence or history of previous psychiatric disorders.

Consider discontinuing Plisil 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 Plisil 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 Plisil 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 Plisil, alone but particularly with concomitant use of serotonergic drugs, 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 Plisil with MAOIs is contraindicated. Do not start Plisil 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 Plisil. Plisil should be discontinued before initiating treatment with the MAOI .

If concomitant use of Plisil 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 .

Discontinue Plisil 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 Plisil 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 Plisil as a result of paroxetine’s irreversible inhibition of CYP2D6 . 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 Plisil for treating VMS vs. the risk of possible decreased tamoxifen effectiveness, and consider avoiding the concomitant use of Plisil for VMS treatment.

5.4 Abnormal Bleeding

SSRIs, including Plisil, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, 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 Plisil and NSAIDs, aspirin, or other drugs that affect coagulation .

5.5 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressants and Plisil 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 Plisil. 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. 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 Plisil 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

Plisil 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 Plisil, 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 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 Plisil, seizures occurred in 0.1% of paroxetine-treated patients. Use Plisil 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 Plisil 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

Plisil 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.

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6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in labeling:


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 Plisil 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 Plisil 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 Plisil 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 Plisil 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 Plisil group and at a higher incidence than placebo are shown in Table 1 for the pooled Phase 2 and Phase 3 trials.

Frequency n (%)
Plisil (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 Plisil compared to women discontinuing placebo, and have also been reported upon discontinuation of other formulations of Plisil, 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 Plisil.

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 Plisil and during post-approval use of other formulations of Plisil. 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.

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7 DRUG INTERACTIONS

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

Plisil is a strong CYP2D6 inhibitor. Co-administration of Plisil 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, 7.2, 7.3)

7.1 Potential for Plisil to Affect Other Drugs

Plisil is a strong CYP2D6 inhibitor. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that Plisil 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 Plisil.

Concomitant

Drug Name

Effect of Plisil on

Other Drugs

Clinical Recommendations
Thioridazine

Increased plasma concentrations of thioridazine

Potential QTc prolongation

Concomitant use of thioridazine and Plisil is

contraindicated.

Pimozide

Increased plasma concentrations

of pimozide. Potential QTc

prolongation

Concomitant use of pimozide and Plisil is

contraindicated.

Tamoxifen

Reduced plasma concentrations

of active tamoxifen metabolite

Consider avoiding concomitant use of tamoxifen

and Plisil.


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

Plisil. 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

.

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 Plisil 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 Plisil

The metabolism and pharmacokinetics of Plisil 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 Plisil when administered concomitantly .

Concomitant

Drug Name

Effect of Concomitant Drug

on Plisil

Clinical Recommendations

Phenobarbital

Decreased Plisil exposure


Phenytoin

Decreased Plisil exposure


Fosamprenavir/

Ritonavir

Decreased plasma concentration

of Plisil

No dose adjustment for Plisil.

Monitor clinical effect of Plisil.

Cimetidine Increased plasma concentration

of Plisil


Use caution if co-administering Plisil 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 Plisil or use of Plisil and an MAOI within 14 days of each other is contraindicated .

Serotonergic Drugs

If concomitant use of Plisil 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 Plisil 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 Plisil. Consequently, concomitant use of Plisil with tryptophan is not recommended.

If concomitant use of Plisil 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.

Plisil contains Plisil, which is also the active ingredient in other drugs. The concomitant use of Plisil with other Plisil 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 co-administered with NSAIDs, aspirin, and warfarin or other drugs that affect coagulation. There may be a pharmacodynamic interaction between Plisil and warfarin that causes an increased bleeding diathesis despite unaltered prothrombin time. Carefully monitor patients receiving warfarin therapy when Plisil is initiated or discontinued .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X

Risk Summary

Plisil is contraindicated in pregnant women because menopausal VMS does not occur during pregnancy and Plisil can cause fetal harm. Epidemiological studies have shown that infants exposed to Plisil 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 Plisil 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. 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


Third-Trimester Pregnancy Exposure


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.

8.3 Nursing Mothers

Plisil is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Plisil, 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; Plisil is not indicated in the pediatric population.

8.5 Geriatric Use

Clinical studies of Plisil 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 Plisil plasma concentrations compared to younger patients. However, no Plisil dose adjustment is considered necessary in elderly patients .

SSRIs have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event .

8.6 Renal Impairment

No Plisil dose adjustment is considered necessary in patients with renal impairment .

8.7 Hepatic Impairment

No Plisil dose adjustment is considered necessary in patients with liver impairment .

10 OVERDOSAGE

10.1 Human Experience with Overdosage

There is limited clinical experience with Plisil overdosage in humans, as there were no overdoses reported in the clinical studies.

Spontaneous cases of deliberate or accidental overdosage during Plisil treatment have been reported; some of these cases were fatal and some of the fatalities appeared to involve Plisil alone. Of nonfatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2000 mg of Plisil in a patient who recovered.

Commonly reported adverse reactions associated with Plisil overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving Plisil (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsades de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.

10.2 Management of Overdosage

Treatment should consist of those general measures employed in the management of overdosage with any SSRI. Consult with a certified poison control center for up-to-date guidance and advice on treatment of overdosage.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. In managing overdosage, consider the possibility of multiple drug involvement.

11 DESCRIPTION

Plisil (paroxetine) is an orally administered selective serotonin reuptake inhibitor (SSRI) for the treatment of moderate to severe VMS associated with menopause. It is identified chemically as (-)- trans -4R- (4’-fluorophenyl) - 3S - [(3’, 4’-methylenedioxyphenoxy) methyl] piperidine mesylate and has the empirical formula of C 19H 20FNO 3-CH 3SO 3H. The molecular weight is 425.5 (329.4 as free base). The structural formula is:

The mesylate salt of Plisil is an odorless, off-white powder, having a melting point range of 147° to 150°C and a solubility of more than 1 g/mL in water.

Each pink capsule contains 9.69 mg Plisil mesylate equivalent to 7.5 mg Plisil base.

Inactive ingredients consist of: dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, gelatin, titanium dioxide, FD&C Yellow #6, FD&C Red #3, FD&C Red #40, shellac, and black iron oxide.

Plisil structural formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nonclinical studies have shown that Plisil is an SSRI. Plisil is not an estrogen, and its mechanism of action for the treatment of VMS is unknown.

12.2 Pharmacodynamics

Studies at clinically relevant doses in humans have demonstrated that Plisil blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that Plisil is a selective inhibitor of neuronal serotonin reuptake and has weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that Plisil has little affinity for muscarinic alpha 1-, alpha 2-, beta-adrenergic-, dopamine -, 5-HT 1-, 5-HT 2-, and histamine (H 1)-receptors.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism and Excretion


Specific Populations


Drug Interaction Studies

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies were conducted in rodents given Plisil in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). The doses used in these carcinogenicity studies were approximately 16 (mouse) and 26 (rat) times the MHRD for VMS. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.

Mutagenesis

Plisil produced no genotoxic effect in a battery of 5 in vitro and 2 in vivo assays that included the following: bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.

Impairment of Fertility

A reduced pregnancy rate was found in reproduction studies in rats at a Plisil dose of 15 mg/kg/day, which is 19 times the MRHD for VMS on an mg/m 2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (65 times and 32 times the MHRD for VMS on an mg/m 2 basis, respectively).

14 CLINICAL STUDIES

The efficacy of Plisil as a treatment for moderate to severe VMS associated with menopause was established in two Phase 3 studies (at a dose of 7.5 mg once daily at bedtime) in 1174 postmenopausal women with a minimum of 7-8 moderate to severe vasomotor symptoms per day at baseline (≥ 50 per week) for 30 days prior to receiving study drug.

Study 1 was a 12-week, randomized, double-blind, placebo-controlled clinical trial with a total of 606 postmenopausal women (average age 55 years, 65% Caucasian and 33% African American, 18% surgically menopausal and 82% naturally menopausal).

Study 2 was a 24-week, randomized, double-blind, placebo-controlled clinical trial with a total of 568 postmenopausal women (average age 54 years, 76% Caucasian and 22% African American, 20% surgically menopausal and 81% naturally menopausal).

The co-primary efficacy endpoints for both studies were the reduction from baseline in VMS frequency and severity at Weeks 4 and 12. Data from Study 1 showed a statistically significant reduction from baseline in the frequency of moderate to severe vasomotor symptoms at Week 4 and Week 12 and a statistically significant reduction in the severity of moderate to severe VMS at Week 4 for Plisil compared to placebo ( Table 4). Data from Study 2 showed a statistically significant reduction from baseline in the frequency and severity of moderate to severe vasomotor symptoms at Week 4 and Week 12 for Plisil compared to placebo ( Table 5).

MITT population: all consented and randomized subjects with valid baseline daily hot flash diary data who had taken at least 1 dose of study medication and had at least 1 day of on-treatment daily hot flash diary data.

* Treatment Difference: the difference between the median changes from baseline.

# P-value is obtained from rank-ANCOVA model.

Frequency

Severity

Plisil

Placebo

Plisil

Placebo

Baseline
n 301 305 301 305
Median 10.4 10.4 2.5 2.5
Change from baseline at Week 4
n 289 293 281 289
Median -4.3 -3.1 -0.05 0.00
Treatment Difference* -1.2 -0.05
P-value # <0.01 <0.01
Change from baseline at Week 12
n 264 274 236 253
Median -5.9 -5.0 -0.06 -0.02
Treatment Difference* -0.9 -0.04
P-value #

<0.01 0.17
MITT population: all consented and randomized subjects with valid baseline daily hot flash diary data who had taken at least 1 dose of study medication and had at least 1 day of on-treatment daily hot flash diary data.

* Treatment Difference: the difference between the median changes from baseline.

# P-value is obtained from rank-ANCOVA model.

Frequency

Severity

Plisil

Placebo

Plisil

Placebo

Baseline
n 284 284 284 284
Median 9.9 9.6 2.5 2.5
Change from baseline at Week 4
n 276 274 268 271
Median -3.8 -2.5 -0.04 -0.01
Treatment Difference* -1.3 -0.03
P-value # <0.01 0.04
Change from baseline at Week 12
n 257 244 245 236
Median -5.6 -3.9 -0.05 0.00
Treatment Difference* -1.7 -0.05
P-value #

<0.01 <0.01

Persistence of benefit at 24 weeks in Study 2 was evaluated with a responder analysis where responders were defined as those patients who achieved ≥ 50% reduction from baseline in the frequency of moderate to severe VMS at Week 24. The proportion of patients achieving a ≥ 50% reduction in the frequency of moderate to severe VMS from baseline to Week 24 was 48% in the Plisil group and 36% in the placebo group at Week 24.

16 HOW SUPPLIED/STORAGE AND HANDLING

Plisil is available as 7.5 mg pink capsules printed with black edible ink with “NOVEN” and “7.5 mg” on each capsule.

NDC 68968-9075-3, blister packs of 30

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F). Protect from light and humidity.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling ( Medication Guide).

Instruct patients to read the Medication Guide before starting therapy with Plisil and to reread it each time the prescription is renewed.


Distributed by: Sebela Pharmaceuticals Inc., 645 Hembree Parkway, Suite I, Roswell, GA 30076

www.sebelapharma.com

Toll Free 1-844-732-3521

Plisil is a registered trademark of Sebela International Limited.

© 2017 Sebela Pharmaceuticals Inc. All rights reserved.

MEDICATION GUIDE

Plisil ® (bris-del)

(Paroxetine)

Capsules

Read the Medication Guide that comes with Plisil before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. Plisil contains a lower dose of Plisil, a medicine also used to treat a number of psychiatric disorders. The lower dose of Plisil in Plisil has not been studied in any psychiatric conditions and Plisil is not approved for any psychiatric uses.

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

Plisil may cause serious side effects.

Call your healthcare provider right away if you have any of the following symptoms, or go to the nearest emergency room:

1. Suicidal thoughts or actions:


2. Serotonin Syndrome. This condition can be life-threatening and may include:


3. Reduced effectiveness of tamoxifen. Tamoxifen (a medicine used to treat breast cancer) may not work as well if it is taken while you take Plisil. If you are taking tamoxifen, tell your healthcare provider before starting Plisil.

4. Abnormal bleeding. Plisil may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin or non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, naproxen, or aspirin.

5. Visual problems.

- Eye pain

- Changes in vision - Swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

6. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this condition. Symptoms may include:


7. Bone Fractures. Women who take Plisil may have a higher risk of bone fractures. Contact your healthcare provider if you have pain in a bone.

8. Manic episodes:


9. Seizures or convulsions.

10. Restlessness. Women who take Plisil may feel an inner restlessness, agitation (nervousness), or be unable to sit still or stand still especially when they start taking Plisil. Call your healthcare provider if this happens to you.

11. Driving. Plisil may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other potentially dangerous activities until you know how Plisil affects you.

What is Plisil?

Plisil is a prescription medicine used to reduce moderate to severe hot flashes associated with menopause. Plisil is a selective serotonin reuptake inhibitor (SSRI). It is not a hormone. The way Plisil treats hot flashes associated with menopause is not known. Plisil does not prevent or treat osteoporosis or dryness, itching or burning in and around the vagina.

Plisil is not for psychiatric problems such as depression, obsessive compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and post-traumatic stress disorder.

Plisil is not for use in children.

Talk to your healthcare provider if you do not think that your hot flashes are getting better while taking Plisil.

Who should not take Plisil?

Do not take Plisil if you:


What should I tell my healthcare provider before taking Plisil?

Before starting Plisil, tell your healthcare provider if you:


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

If you take Plisil, you should not take any other medicines that contain Plisil,

including Paxil, Paxil CR and Pexeva.


Especially tell your healthcare provider if you take:


Ask your healthcare provider if you are not sure if you are taking any of these medications.

Your healthcare provider or pharmacist can tell you if it is safe to take Plisil with your other medicines. Do not start or stop any medicine while taking Plisil without talking to your healthcare provider first.

How should I take Plisil?


What should I avoid while taking Plisil?


What are the possible side effects of Plisil?

Plisil may cause serious side effects, including:


The most common side effects of Plisil include:


Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of Plisil. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Plisil?


General information about the safe and effective use of Plisil.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Plisil for a condition for which it was not prescribed. Do not give Plisil to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about Plisil. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about Plisil that is written for healthcare professionals.

For more information about Plisil call 1-800-455-8070 or go to www. BRISDELLE.com.

What are the ingredients in Plisil?

Active ingredient: Plisil

Inactive ingredients: dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, gelatin, titanium dioxide, FD&C Yellow #6, FD&C Red #3, FD&C Red #40, shellac and black iron oxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by: Sebela Pharmaceuticals Inc. 645 Hembree Parkway, Suite I

Roswell, GA 30076

www.sebelapharma.com

Plisil ® is a registered trademark of Sebela International Ltd.

© 2017 Sebela Pharmaceuticals Inc. All rights reserved.

Revised 03/2017

PRINCIPAL DISPLAY PANEL - NDC: 68968-9075-3 - 30-Capsule Blister Card

30-capsule blister card

PRINCIPAL DISPLAY PANEL - NDC: 68968-9075-3 - Blister Pack

blister pack

Plisil pharmaceutical active ingredients containing related brand and generic drugs:


Plisil available forms, composition, doses:


Plisil destination | category:


Plisil Anatomical Therapeutic Chemical codes:


Plisil pharmaceutical companies:


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References

  1. Dailymed."PEXEVA (PAROXETINE MESYLATE) TABLET, FILM COATED [NOVEN THERAPEUTICS, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."PAROXETINE MESYLATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "paroxetine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Plisil?

Depending on the reaction of the Plisil after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Plisil not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Plisil addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Plisil, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Plisil consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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