Prescription Drug Information: Paroxetine (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis

Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to approximately 1.6 (mouse) and 2.5 (rat) times the MRHD on an mg/m2 basis. 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 dose 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

Paroxetine produced no genotoxic effects 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 dose of paroxetine of 15 mg/kg/day, which is approximately twice the MRHD on an mg/m2 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 (approximately 6 and 3 times the MRHD on an mg/m2 basis).

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

The efficacy of paroxetine extended-release tablets as a treatment for major depressive disorder (MDD) was established in two 12-week, multicenter, randomized, double-blind, placebo-controlled, flexible dose studies with paroxetine extended-release tablets (Study 1 and Study 2) in adult patients who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for MDD. Study 1 and 2 included patients 18 to 65 years old who received paroxetine extended-release tablets doses of 25 to 62.5 mg/day (N= 212) or placebo (N= 211) once daily compared to immediate-release paroxetine 20 to 50 mg (N=217). A third 12-week, multicenter, randomized, double-blind, placebo-controlled, flexible dose study with paroxetine extended-release tablets (Study 3) included elderly patients, ranging in age from 60 to 88 years old and used paroxetine extended-release tablets doses of 12.5 to 50 mg/day (N=104) or placebo (N=109) once daily compared to immediate- release paroxetine 10 to 40 mg (N=106). In all three studies, paroxetine extended-release tablets were statistically superior to placebo in improving depressive symptoms as measured by the following: the mean change from baseline in the Hamilton Depression Rating Scale (HDRS) total score at Week 12, the mean change from baseline in the Hamilton Depressed Mood item score at Week 12, and the mean change from baseline in the Clinical Global Impression (CGI)–Severity of Illness score. Long-term efficacy of paroxetine for treatment of MDD in outpatients was established with one randomized withdrawal study with immediate-release paroxetine. Patients who responded to immediate-release paroxetine (HDRS total score <8) during an initial 8-week open-label treatment phase were then randomized to continue immediate-release paroxetine or placebo, for up to 1 year. Patients treated with immediate-release paroxetine demonstrated a statistically significant lower relapse rate during the withdrawal phase (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.

14.2 Panic Disorder

The effectiveness of paroxetine extended-release tablets in the treatment of panic disorder (PD) was evaluated in three 10-week, multicenter, flexible-dose studies (Studies 4, 5, and 6) comparing paroxetine extended-release tablets (12.5 to 75 mg daily) to placebo in adult outpatients 19 to 72 years of age who met panic disorder (with or without agoraphobia) criteria according to DSM-IV. These trials were assessed on the basis of their outcomes on 3 variables: (1) the proportions of patients free of full panic attacks at Week 10; (2) change from baseline to Week 10 in the median number of full panic attacks; and (3) change from baseline to Week 10 in the median Clinical Global Impression Severity score. For Studies 4 and 5, paroxetine extended-release tablets was superior to placebo on 2 of these 3 variables. Study 6 failed to consistently demonstrate a statistically significant difference between paroxetine extended-release tablets and placebo on any of these variables.
For all 3 studies, the mean dose of paroxetine extended-release tablets for completers at Week 10 was approximately 50 mg/day. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.Long-term maintenance effects of paroxetine in patients with PD were demonstrated in a randomized-withdrawal study using immediate-release paroxetine. Patients who were responders during a 10-week, double-blind trial (followed by a 3-month double-blind maintenance phase) of immediate-release paroxetine were re-randomized to continue immediate-release paroxetine or placebo in a 3-month, double-blind withdrawal phase. Patients randomized to immediate-release paroxetine were statistically significantly less likely to relapse than placebo-treated patients.

14.3 Social Anxiety Disorder

The efficacy of paroxetine extended-release tablets as a treatment for social anxiety disorder (SAD) was established, in part, on the basis of extrapolation from the established effectiveness of immediate- release paroxetine in the treatment of SAD. In addition, the effectiveness of paroxetine extended-release tablets in the treatment of SAD was demonstrated in one 12-week, multicenter, double-blind, flexible-dose, placebo-controlled study of adult outpatients with a primary diagnosis of SAD by DSM-IV criteria (Study 7). In Study 7, the effectiveness of paroxetine extended-release tablets (12.5 to 37.5 mg daily) compared to placebo was evaluated on the basis of (1) change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score at Week 12 and (2) the proportion of responders who scored 1 or 2 (very much improved or much improved) on the CGI Global Improvement score at Week 12.

In Study 7, paroxetine extended-release tablets demonstrated statistically significant superiority over placebo on both the change on LSAS total score at Week 12 and the CGI Improvement responder criterion at Week 12. For patients who completed the trial, 64% of patients treated with paroxetine extended-release tablets compared to 35% of patients treated with placebo were CGI Improvement responders at Week 12.Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of gender. Subgroup analyses of studies utilizing the immediate-release formulation of paroxetine generally did not indicate differences in treatment outcomes as a function of age, race, or gender.

14.4 Premenstrual Dysphoric Disorder

The effectiveness of paroxetine extended-release tablets for the treatment of Premenstrual Dysphoric Disorder (PMDD) utilizing a continuous dosing regimen has been established in 2 placebo-controlled trials in female patients ages 18 to 46 (Studies 8 and 9 [N=672]). Patients in these trials met DSM-IV criteria for PMDD. Of 1,030 patients including Study 10, who were treated with daily doses of paroxetine extended-release tablets 12.5 or 25 mg/day, or placebo continuously throughout the menstrual cycle for a period of 3 menstrual cycles, the mean duration of the PMDD symptoms was approximately 11 ± 7 years. Patients on systemic hormonal contraceptives were excluded from these trials. Therefore, the efficacy of paroxetine extended-release tablets in combination with systemic (including oral) hormonal contraceptives for the continuous daily treatment of PMDD is unknown.
The VAS score is a patient-rated instrument that mirrors the diagnostic criteria of PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms associated with PMDD. In Studies 8 and 9, 12.5 mg/day and 25 mg/day of paroxetine extended-release tablets were statistically significantly more effective than placebo as measured by change from baseline to Month 3 on the luteal phase VAS score.
In an additional study employing luteal phase dosing (Study 11), patients (N = 366) were treated for the 2 weeks prior to the onset of menses with 12.5 or 25 mg/day of paroxetine extended-release tablets or placebo for a period of 3 months. In this trial, 12.5 mg/day and 25 mg/day of paroxetine extended-release tablets, as luteal phase dosing, was statistically significantly more effective than placebo as measured by change from baseline to luteal phase VAS score at Month 3.There is insufficient information to determine the effect of race or age on outcome in Studies 8, 9, 10, and 11.

16 HOW SUPPLIED/STORAGE AND HANDLING

Paroxetine extended-release tablets are supplied as follows:

Paroxetine extended-release tablets 12.5 mg are yellow, biconvex, enteric film-coated, extended- release, round tablets, debossed with “X1” on one side and plain on the other side. The tablets should be free from all physical defects.

NDC 71209-094-01 Bottle of 30’s
NDC 71209-094-10 Bottle of 500’s
Paroxetine extended-release tablets 25 mg are pink, biconvex, enteric film-coated, extended- release, round tablets debossed with “X2” on one side and plain on the other side. The tablets should be free from all physical defects.
NDC 71209-095-01 Bottle of 30’s
NDC 71209-095-10 Bottle of 500’s
Paroxetine extended-release tablets 37.5 mg are blue, biconvex, enteric film-coated, extended- release, round tablets debossed with “X3” on one side and plain on the other side. The tablets should be free from all physical defects.
NDC 71209-096-01 Bottle of 30’s
NDC 71209-096-10 Bottle of 500’s
Store at or below 20°C to 25°C (68°F to 77°F) excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

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

Suicidal Thoughts and Behaviors
Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

Important Administration Instructions
Instruct patients to swallow paroxetine extended-release tablets whole and to not chew or crush the tablets [see Dosage and Administration (2.1)].

Serotonin Syndrome
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of paroxetine extended-release tablets with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7.1)].

Concomitant Medications
Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for drug-drug interactions [see Warning and Precautions (5.3), Drug Interactions (7)].

Increased Risk of Bleeding
Inform patients about the concomitant use of paroxetine extended-release tablets with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the counter medications that increase the risk of bleeding [see Warnings and Precautions (5.5)].

Activation of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.6)].

Discontinuation Syndrome
Advise patients not to abruptly discontinue paroxetine extended-release tablets and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur when paroxetine extended-release tablets are discontinued [See Warnings and Precautions (5.7)].

Allergic Reactions
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions (6.1, 6.2)].

Embryo-Fetal Toxicity
Advise women of the potential risk to the fetus [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy because of the risk to the fetus.

Nursing
Advise women to notify their healthcare provider if they are breastfeeding an infant [see Use in Specific Populations (8.3)].

Manufactured by:
Cadila Pharmaceuticals Limited
1389, Trasad Road, Dholka-382225,
District — Ahmedabad,
Gujarat State, INDIA.

All registered trademarks in this document are the property of their respective owners.
Revised: September 2021

Medication Guide
Paroxetine Extended-Release Tablets
(pa rox’ e teen)

What is the most important information I should know about paroxetine extended-release tablets?
Paroxetine extended-release tablets can cause serious side effects, including:

• Increased risk of suicidal thoughts or actions. Antidepressant medicines may increase suicidal thoughts and actions in some children and young adults within the first few months of treatment or when the dose is changed. Paroxetine extended-release tablets are not for use in people younger than 18 years of age.
How can I watch for and try to prevent suicidal thoughts and actions?
o Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions.
o Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.
o Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions.
o Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.Call your healthcare provider or get emergency medical help right away if you have any of the following symptoms, especially if they are new, worse, or worry you:

o attempts to commit suicide o acting on dangerous impulses
o acting aggressive or violent o thoughts about suicide or dying
o new or worse depression o new or worse anxiety or panic attacks
o feeling agitated, restless, angry, or irritable o trouble sleeping
o an increase in activity and talking more than what is normal for you o other unusual changes in behavior or mood

What is paroxetine extended-release tablets?
Paroxetine extended-release tablets are a prescription medicine used in adults to treat:
• A certain type of depression called Major Depressive Disorder (MDD)
• Panic Disorder
• Social Anxiety Disorder (SAD)
• Premenstrual Dysphoric Disorder (PMDD)
Do not take paroxetine extended-release tablets if you:
• take a monoamine oxidase inhibitor (MAOI)
• have stopped taking an MAOI in the last 14 days
• are being treated with the antibiotic linezolid or intravenous methylene blue
• are taking thioridazine
• are taking pimozide
• are allergic to paroxetine or any of the ingredients in paroxetine extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in paroxetine extended-release tablets.
Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI or one of these medicines, including intravenous methylene blue.

Do not start taking an MAOI for at least 14 days after you stop treatment with paroxetine extended-release tablets.

Before taking paroxetine extended-release tablets, tell your healthcare provider about all your medical conditions, including if you:
• have heart problems
• have or had bleeding problems
• have, or have a family history of bipolar disorder, mania or hypomania have or had seizures or convulsions
• have glaucoma (high pressure in the eye)
• have low sodium levels in your blood
• have bone problems
• have kidney or liver problems
• are pregnant or plan to become pregnant. Paroxetine may harm your unborn baby. Talk to your healthcare provider about the risks to your unborn baby if you take paroxetine extended-release tablets during pregnancy. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with paroxetine extended-release tablets.
• are breastfeeding or plan to breastfeed. Paroxetine passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with paroxetine extended-release tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Paroxetine extended-release tablets and some other medicines may affect each other causing possible serious side effects. Paroxetine extended-release tablets may affect the way other medicines work and other medicines may affect the way paroxetine extended-release tablets works.
Especially tell your healthcare provider if you take:
• medicines used to treat migraine headaches called triptans
• tricyclic antidepressants
• fentanyl
• lithium
• tramadol
• tryptophan
• buspirone
• amphetamines
• St. John’s Wort
• medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or warfarin
• diuretics
• tamoxifen
Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take paroxetine extended-release tablets with your other medicines.
Do not start or stop any other medicines during treatment with paroxetine extended-release tablets without talking to your healthcare provider first. Stopping paroxetine extended-release tablets suddenly may cause you to have serious side effects. See, “What are the possible side effects of paroxetine extended-release tablets?”
Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.
How should I take paroxetine extended-release tablets?
• Take paroxetine extended-release tablets exactly as your healthcare provider tell you to. Your healthcare provider may need to change the dose of paroxetine extended-release tablets until it is the right dose for you.
• Take paroxetine extended-release tablets 1 time each day in the morning.
• Paroxetine extended-release tablets may be taken with or without food.
• Swallow paroxetine extended-release tablets whole. Do not chew or crush paroxetine extended-release tablets.
• If you take too much paroxetine extended-release tablets, call your poison control center at 1-800-222-1222 or got to the nearest hospital emergency room right away.
What are possible side effects of paroxetine extended-release tablets?
Paroxetine extended-release tablets can cause serious side effects, including:
• See, “What is the most important information I should know about paroxetine extended release tablets?” • Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take paroxetine extended-release tablets with certain other medicines. See, “Who should not take paroxetine extended-release tablets?” Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome:

o agitation o sweating
o seeing or hearing things that are not real (hallucinations) o flushing
o confusion o high body temperature (hyperthermia)
o coma o shaking (tremors), stiff muscles, or muscle twitching
o fast heart beat o loss of coordination
o changes in blood pressure o seizures
o dizziness o nausea, vomiting, diarrhea

Medicine interactions. Taking paroxetine extended-release tablets with certain other medicines including thioridazine and pimozide may increase the risk of developing a serious heart problem
called QT prolongation.
Abnormal bleeding. Taking paroxetine extended-release tablets with aspirin, NSAIDs, or blood thinners may add to this risk. Tell your healthcare provider about any unusual bleeding or bruising. • Manic episodes. Manic episodes may happen in people with bipolar disorder who take paroxetine extended-release tablets. Symptoms may include:

o greatly increased energy o severe problems sleeping
o racing thoughts o reckless behavior
o unusually grand ideas o excessive happiness or irritability
o talking more or faster than usual

Discontinuation syndrome. Suddenly stopping paroxetine extended-release tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:

o Nausea o electric shock feeling (paresthesia) o tiredness
o sweating o tremor o problems sleeping
o changes in your mood o anxiety o ringing in your ears (tinnitus)
o irritability and agitation o confusion o seizures
o dizziness o headache

• Seizures (convulsions).
Eye problems (angle-closure glaucoma). Paroxetine extended-release tablets may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.
Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with paroxetine extended-release tablets. Elderly people and people who take certain medicines may be at a greater risk for developing low sodium levels in your blood. Signs and symptoms may include:
o headache
o difficulty concentrating
o memory changes
o confusion
o weakness and unsteadiness on your feet which can lead to falls
In more severe or more sudden cases, signs and symptoms include:
o seeing or hearing things that are not real (hallucinations)
o fainting
o seizures
o coma
o stopping breathing (respiratory arrest)
• Bone fractures. The most common side effects paroxetine extended-release tablets include:

• male and female sexual function problems • dry mouth
• blurred vision • problems sleeping
• weakness (asthenia) • nausea
• constipation • sleepiness
• decreased appetite • sweating
• diarrhea • tremor

These are not all the possible side effects of paroxetine extended-release tablets. 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 paroxetine extended-release tablets?
Store paroxetine extended-release tablets at room temperature between 68°F to 77°F (20°C to 25°C).
Keep paroxetine extended-release tablets and all medicines out of the reach of children.
General information about the safe and effective use of paroxetine extended-release tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take paroxetine extended-release tablets for a condition for which it was not prescribed. Do not give paroxetine extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them. You may ask your healthcare provider or pharmacist for information about paroxetine extended-release tablets that is written for healthcare professionals.
What are the ingredients in paroxetine extended-release tablets?
Active ingredient: Paroxetine hydrochloride hemihydrate, USP
Inactive ingredients: ferric oxide yellow, glyceryl behenate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid – ethyl acrylate copolymer (1:1) type A, polyethylene glycols, polysorbate 80, polyvinylpyrrolidone, silicon dioxide, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, film-coating material contains — FD&C Yellow #6/sunset yellow FCF aluminum lake, FD&C blue #2/Indigo carmine AL 3% to 5% and D&C Yellow #10 aluminum lake for 12.5 mg; D&C Red #30/Helendon pink aluminum lake for 25 mg and FD&C blue #2/Indigo carmine AL 3% to 5% and FD&C blue #2 Indigo carmine aluminum lake for 37.5 mg.

All registered trademarks in this document are the property of their respective owners.

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

Manufactured by:
Cadila Pharmaceuticals Limited
1389, Trasad Road, Dholka-382225,
District — Ahmedabad,
Gujarat State, INDIA.

Revised: September 2021

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