Paroxetine Drug Information

Paroxetine tablets are indicated in adults for the treatment of: Major depressive disorder (MDD) Obsessive compulsive disorder (OCD) Panic disorder (PD) Social anxiety disorder (SAD) Generalized anxiety disorder (GAD) Posttraumatic stress disorder (PTSD) Paroxetine tablets are a selective serotonin reuptake inhibitor (SSRI) indicated in adults for the treatment of: Major Depressive Disorder (MDD) Obsessive Compulsive Disorder (OCD) Panic Disorder (PD) Social Anxiety Disorder (SAD) Generalized Anxiety Disorder (GAD) Posttraumatic Stress Disorder (PTSD)

Administration Information

Administer paroxetine tablets as a single daily dose in the morning, with or without food.

Recommended Dosage for MDD, OCD, PD, and PTSD

The recommended starting dosages and maximum dosages of paroxetine tablets in patients with MDD, OCD, PD, and PTSD are presented in Table 1. In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability. Table 1: Recommended Daily Dosage of Paroxetine Tablets in Patients with

Recommended Dosage for SAD and GAD SAD

The starting and recommended dosage in patients with SAD is 20 mg daily. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 mg to 60 mg daily. While the safety of paroxetine tablets has been evaluated in patients with SAD at doses up to 60 mg daily, available information does not suggest any additional benefit for doses above 20 mg daily.

There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg daily.

Screen for Bipolar Disorder Prior to Starting Paroxetine Tablets Prior to initiating treatment with paroxetine tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania.

Recommended Dosage for Elderly Patients, Patients with Severe Renal Impairment, and Patients with Severe Hepatic Impairment The recommended initial dosage is 10 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment. Dosage should not exceed 40 mg/day.

Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI) At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor MAOI and initiation of paroxetine tablets. In addition, at least 14 days must elapse after stopping paroxetine tablets before starting an MAOI antidepressant.

Discontinuation of Treatment With Paroxetine Tablets

Adverse reactions may occur upon discontinuation of paroxetine tablets. Gradually reduce the dosage rather than stopping paroxetine tablets abruptly whenever possible.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data for paroxetine tablets are from: 6-week clinical trials in MDD patients who received paroxetine tablets 20 mg to 50 mg once daily 12-week clinical trials in OCD patients who received paroxetine tablets 20 mg to 60 mg once daily 10- to 12-week clinical trials in PD patients who received paroxetine tablets 10 mg to 60 mg once daily 12-week clinical trials in SAD patients who received paroxetine tablets 20 mg to 50 mg once daily 8-week clinical trials in GAD patients who received paroxetine tablets 10 mg to 50 mg once daily 12-week clinical trials in PTSD patients who received paroxetine tablets 20 mg to 50 mg once daily Adverse Reactions Leading to Discontinuation Twenty percent (1,199/6,145) of patients treated with paroxetine tablets in clinical trials in MDD and of patients treated with paroxetine tablets in clinical trials in SAD, OCD, PD, GAD, and PTSD, respectively, discontinued treatment due to an adverse reaction. The most common adverse reactions (≥1%) associated with discontinuation (i.e., those adverse reactions associated with dropout at a rate approximately twice or greater for paroxetine tablets compared to placebo) are presented in Table 3: Table 3: Adverse Reactions Reported as Leading to Discontinuation ≥1% of 0 — — Where numbers are not provided the incidence of the adverse reactions in patients treated with paroxetine tablets was not >1% or was not greater than or equal to 2 times the incidence of placebo. a.

Incidence corrected for gender. Most Common Adverse Reactions The most commonly observed adverse reactions associated with the use of paroxetine tablets (incidence of 5% or greater and at least twice that for placebo) were: MDD: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. OCD: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.

PD: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. SAD: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. GAD: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.

PTSD: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence. Adverse Reactions in Patients with MDD Table 4 presents the adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of paroxetine tablets -treated patients with 2 0 Includes mostly “lump in throat” and “tightness in throat.” Percentage corrected for gender. Mostly “ejaculatory delay.” Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.” Includes mostly “difficulty with micturition” and “urinary hesitancy.” Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” Adverse Reactions in Patients with OCD, PD, and SAD Table 5 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with — — Percentage corrected for gender.

Adverse Reactions in Patients with GAD and PTSD Table 6 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with a Percentage corrected for gender. Adverse Reactions (≥5% of Paroxetine -Treated Patients and ≥ Twice the Rate of Placebo) in a Dose-Comparison Trial in the Treatment of In a fixed-dose study comparing placebo and paroxetine tablets 20 mg, 40 mg, and 60 mg in the treatment of OCD, there was no clear relationship between adverse reactions and the dose of paroxetine tablets to which patients were assigned. PD In a fixed-dose study comparing placebo and paroxetine tablets 10 mg, 20 mg, and 40 mg in the treatment of PD, the following adverse reactions were shown to be dose-dependent: asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation.

Male and Female Sexual Dysfunction Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence.

The percentage of patients reporting symptoms of sexual dysfunction in males and females with MDD, OCD, PD, SAD, GAD, and PTSD are displayed in Table 8. Table 8. Adverse Reactions Related to Sexual Dysfunction in Patients Treated with Paroxetine tablets treatment has been associated with several cases of priapism.

In those cases with a known outcome, patients recovered without sequelae. Hallucinations In pooled clinical trials of paroxetine tablets, hallucinations were observed in 0.2% of paroxetine tablets-treated patients compared to 0.1% of patients receiving placebo. Less Common Adverse Reactions The following adverse reactions occurred during the clinical studies of paroxetine tablets and are not included elsewhere in the labeling.

Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular System Frequent: Hypertension, tachycardia; infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles.

Digestive System Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, abnormal liver function tests, rectal hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries. Endocrine System Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia.

Metabolic and Nutritional Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased. Musculoskeletal System Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare: Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany. Nervous System Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome.

Respiratory System Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses Frequent: Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect.

Urogenital System Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis.

Postmarketing Experience

The following reactions have been identified during post approval use of paroxetine tablets. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), syndrome of inappropriate ADH secretion, prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, oculogyric crisis which has been associated with concomitant use of pimozide; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women.

There has been a case report of severe hypotension when paroxetine tablets were added to chronic metoprolol treatment.

Table 9 presents clinically significant drug interactions with paroxetine tablets. Intervention Paroxetine tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue. Paroxetine tablets are contraindicated in patients taking pimozide or thioridazine.

Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with paroxetine tablets increases the risk of serotonin syndrome. Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of paroxetine tablets and/or concomitant serotonergic drugs.

For patients taking warfarin, carefully monitor the international normalized ratio. Paroxetine tablets are a CYP2D6 inhibitor. Consider use of an alternative antidepressant with little or no CYP2D6 inhibition.: Monitor for adverse reactions and reduce dosage of paroxetine tablets or other protein-bound drugs (e.g., warfarin) as warranted.

Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. Concomitant use with tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition.

Pregnancy Risk Summary 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. Paroxetine tablets are associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. While individual epidemiological studies on the association between paroxetine use and cardiac 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 paroxetine tablets during pregnancy. There also are risks associated with untreated depression in pregnancy (see Clinical Considerations). For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options.

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. 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 less than the MRHD on an mg/m 2 basis ( See Data ).

The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Clinical Considerations Disease-associated maternal and/or embryofetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum.

Maternal Adverse Reactions Use of paroxetine tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage. Fetal/Neonatal adverse reactions Neonates exposed to paroxetine tablets and other SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

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 an 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 defect (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 1,000 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 studies have revealed no evidence of developmental 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.

The no effect dose for rat pup mortality was not determined. The cause of these deaths is not known.

Pediatric Use The safety and effectiveness of paroxetine tablets in pediatric patients have not been established. Effectiveness was not demonstrated in three placebo-controlled trials in 752 paroxetine tablets-treated pediatric patients with MDD. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients.

Decreased appetite and weight loss have been observed in association with the use of SSRIs. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of pediatric patients treated with paroxetine tablets and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Adverse reactions upon discontinuation of treatment with paroxetine tablets in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients and at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain.

Paroxetine tablets are 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. Taking thioridazine because of risk of QT prolongation Taking pimozide because of risk of QT prolongation. With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients in paroxetine tablets.

Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOI. Concomitant use of pimozide or thioridazine.

The following have been reported with paroxetine tablet overdosage: Seizures, which may be delayed, and altered mental status including coma. Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.

Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a paroxetine overdose. Consider contacting a poison center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.