ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are included in more detail in other sections of the prescribing information: Hypersensitivity reactions to paroxetine [see Contraindications (4)] Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)] Serotonin Syndrome [see Warnings and Precautions (5.2)] Embryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)] Increased Risk of Bleeding [see Warnings and Precautions (5.5)] Activation of Mania/Hypomania [see Warnings and Precautions (5.6)] Discontinuation Syndrome [see Warnings and Precautions (5.7)] Seizures [see Warnings and Precautions (5.8)] Angle-closure Glaucoma [see Warnings and Precautions (5.9)] Hyponatremia [see Warnings and Precautions (5.10)] Bone Fracture [see Warnings and Precautions (5.12)] Sexual Dysfunction [see Warnings and Precautions (5.13)] Hypersensitivity reactions to paroxetine [see Contraindications (4)] Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)] Serotonin Syndrome [see Warnings and Precautions (5.2)] Embryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)] Increased Risk of Bleeding [see Warnings and Precautions (5.5)] Activation of Mania/Hypomania [see Warnings and Precautions (5.6)] Discontinuation Syndrome [see Warnings and Precautions (5.7)] Seizures [see Warnings and Precautions (5.8)] Angle-closure Glaucoma [see Warnings and Precautions (5.9)] Hyponatremia [see Warnings and Precautions (5.10)] Bone Fracture [see Warnings and Precautions (5.12)] Sexual Dysfunction [see Warnings and Precautions (5.13)] Most common adverse reactions (>=5% and at least twice placebo) are abnormal ejaculation, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, infection, insomnia, libido decreased, male genital disorder, nausea, nervousness, somnolence, sweating, tremor, yawn. (6)To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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 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 PAXIL are from: 6-week clinical trials in MDD patients who received PAXIL 20 mg to 50 mg once daily12-week clinical trials in OCD patients who received PAXIL 20 mg to 60 mg once daily10- to 12-week clinical trials in PD patients who received PAXIL 10 mg to 60 mg once daily12-week clinical trials in SAD patients who received PAXIL 20 mg to 50 mg once daily8-week clinical trials in GAD patients who received PAXIL 10 mg to 50 mg once daily12-week clinical trials in PTSD patients who received PAXIL 20 mg to 50 mg once daily Adverse Reactions Leading to Discontinuation Twenty percent (1,199/6,145) of patients treated with PAXIL in clinical trials in MDD and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with PAXIL in clinical trials in SAD, OCD, PD, GAD, and PTSD, respectively, discontinued treatment due to an adverse reaction. The most common adverse reactions (31%) associated with discontinuation (i.e., those adverse reactions associated with dropout at rate approximately twice or greater for PAXIL compared to placebo) are presented in Table 3:Table 3: Adverse Reactions Reported as Leading to Discontinuation (>=1% of PAXIL-Treated Patients and Greater than Placebo) in MDD, OCD, PD, SAD, GAD, and PTSD TrialsMDDOCDPDSADGADPTSDPAXIL %Placebo %PAXIL %Placebo %PAXIL %Placebo %PAXIL %Placebo %PAXIL %Placebo %PAXIL %Placebo %CNSSomnolence2.30.7---1.90.33.40.32.00.22.80.6Insomnia------1.701.30.33.10------Agitation1.10.5---------Tremor1.10.9---1.701.00.2Anxiety---------1.10------Dizziness------1.501.901.00.2------GastrointestinalConstipation---1.10------Nausea3.21.11.903.21.24.00.32.20.6Diarrhea1.00.3---Dry mouth1.00.3---------Vomiting1.00.3---1.00------Flatulence1.00.3------OtherAsthenia1.60.41.90.42.50.61.80.21.60.2Abnormal Ejaculationa 1.602.104.90.62.50.5------Sweating1.00.3---1.101.10.2------Impotencea ---1.50------Libido Decreased1.00------Where numbers are not provided the incidence of the adverse reactions in patients treated with PAXIL was not >1% or was not greater than or equal to 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 PAXIL (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 presents the adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of PAXIL-treated patients with MDD. Table 4: Adverse Reactions (>=1% of PAXIL-Treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDDBody System/Adverse ReactionPAXIL(n 421)%Placebo(n 421)%Body as WholeHeadache1817Asthenia156CardiovascularPalpitation31Vasodilation31DermatologicSweating112Rash21GastrointestinalNausea269Dry Mouth1812Constipation149Diarrhea128Decreased Appetite62Flatulence42Oropharynx Disordera 20Dyspepsia21MusculoskeletalMyopathy21Myalgia21Myasthenia10Nervous SystemSomnolence239Dizziness136Insomnia136Tremor82Nervousness53Anxiety53Paresthenia42Libido Decreased30Drugged Feeling21Confusion10RespirationYawn40Special SensesBlurred Vision41Taste Perversion20Urogential SystemEjaculatory Disturbanceb,c 130Other Male Genital Disordersb,d 100Urinary Frequency31Urination Disordere 30Female Genital Disordersb,f 20a. Includes mostly lump in throat and tightness in throat.b. Percentage corrected for gender.c. Mostly ejaculatory delay.d. Includes anorgasmia, erectile difficulties, delayed ejaculation/orgasm, and sexual dysfunction, and impotence. e. Includes mostly difficulty with micturition and urinary hesitancy.f. Includes mostly anorgasmia and difficulty reaching climax/orgasm. Adverse Reactions in Patients with OCD, PD, and SAD Table presents adverse reactions that occurred at frequency of 2% or more in clinical trials in patients with OCD, PD, and SAD.Table 5. Adverse Reactions (>=2% of PAXIL-Treated Patients and Greater than Placebo) in 10 to 12-Week Clinical Trials for OCD, PD, and SAD Body System/Preferred TermObsessive Compulsive DisorderPanic DisorderSocial Anxiety DisorderPAXIL (n 542) %Placebo (n 265) %PAXIL (n 469) %Placebo (n 425) %PAXIL (n 425) %Placebo (n 339) %Body as WholeAsthenia22141452214Abdominal Pain------43------Chest Pain32------------Back Pain------32------Chills 2121------Trauma------------31CardiovascularVasodilation41------------Palpitation20------------DermatologicSweating9314692Rash32------------GastrointestinalNausea23102317257Dry Mouth189181193Constipation1668552Diarrhea101012796Decreased Appetite937382Dyspepsia------------2Flatulence------------42Increased Appetite4321------Vomiting------------21MusculoskeletalMyalgia------------43Nervous SystemInsomnia241318102116Somnolence2471911225Dizziness1261410117Tremor1119191Nervousness98------87Libido Decreased7491121Agitation------5431Anxiety------5454Abnormal Dreams41------------Concentration Impaired32------41Depersonalization30------------Myoclonus303221Amnesia21------------Respiratory SystemRhinitis------30------Pharyngitis------------42Yawn------------51Special SensesAbnormal Vision42------41Taste Perversion20------------Urogenital SystemAbnormal Ejaculationa 231211281Dysmenorrhea------------54Female Genital Disordera 309191Impotencea 815051Urinary Frequency3120------Urination Impaired30------------Urinary Tract Infection2121------a. Percentage corrected for gender. Adverse Reactions in Patients with GAD and PTSD Table presents adverse reactions that occurred at frequency of 2% or more in clinical trials in patients with GAD and PTSD.Table 6. Adverse Reactions (>=2% of PAXIL-Treated Patients and Greater than Placebo) in 8- to 12-Week Clinical Trials for GAD and PTSDa Body System/Preferred TermGeneralized Anxiety DisorderPosttraumatic Stress DisorderPAXIL (n 735) %Placebo (n 529) %PAXIL (n 576) %Placebo (n 504) %Body as WholeAsthenia146124Headache1714------Infection6354Abdominal Pain43Trauma65CardiovascularVasodilation3121DermatologicSweating6251GastrointestinalNausea205198Dry Mouth115105Constipation10253Diarrhea97115Decreased Appetite5163Vomiting3232Dyspepsia------53Nervous SystemInsomnia1181211Somnolence155165Dizziness6565Tremor5141Nervousness43------Libido Decreased9252Abnormal Dreams3Respiratory SystemRespiratory Disorder75------Sinusitis43------Yawn4---2<1Special SensesAbnormal Vision2131Urogenital SystemAbnormal Ejaculationa 252132Female Genital Disordera 4151Impotencea 4391a. Percentage corrected for gender. Dose Dependent Adverse Reactions MDD comparison of adverse reaction rates in fixed-dose study comparing PAXIL10 mg, 20 mg, 30 mg, and 40 mg once daily with placebo in the treatment of MDD revealed dose dependent adverse reactions, as shown in Table 7:Table 7. Adverse Reactions (>=5% of PAXIL-Treated Patients and >= Twice the Rate of Placebo) (in Dose-Comparison Trial in the Treatment of MDDBody System/Preferred TermPlacebo PAXILn 51 %10 mg = 102 %20 mg = 104 %30 mg = 101 %40 mg = 104 %Body as WholeAsthenia0.02.910.613.912.7DermatologySweating2.01.06.78.911.8GastrointestinalConstipation5.94.97.79.912.7Decreased Appetite2.02.05.84.04.9Diarrhea7.89.819.27.914.7Dry Mouth2.010.818.315.820.6Nausea13.714.726.934.736.3Nervous SystemAnxiety0.02.05.85.95.9Dizziness3.96.96.78.912.7Nervousness0.05.95.84.02.9Paresthesia0.02.91.05.05.9Somnolence 7.812.718.320.821.6Tremor0.00.07.77.914.7Special SensesBlurred Vision2.02.92.92.07.8Urogenital SystemAbnormal Ejaculation0.05.86.510.613.0Impotence0.01.94.36.41.9Male Genital Disorders0.03.88.76.43.7OCDIn fixed-dose study comparing placebo and PAXIL 20 mg, 40 mg, and 60 mg in the treatment of OCD, there was no clear relationship between adverse reactions and the dose of PAXIL to which patients were assigned. PD In fixed-dose study comparing placebo and PAXIL 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. SADIn fixed-dose study comparing placebo and PAXIL 20 mg, 40 mg and 60 mg in the treatment of SAD, for most of the adverse reactions, there was no clear relationship between adverse reactions and the dose of PAXIL to which patients were assigned.GADIn fixed-dose study comparing placebo and PAXIL 20 mg and 40 mg in the treatment of GAD, the following adverse reactions were shown to be dose-dependent: asthenia, constipation, and abnormal ejaculation. PTSD In fixed-dose study comparing placebo and PAXIL 20 mg and 40 mg in the treatment of PTSD, the following adverse reactions were shown to be dose-dependent: impotence and abnormal ejaculation.Male and Female Sexual Dysfunction Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of psychiatric disorder, they may also be 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 PAXIL in Clinical Trials of MDD, OCD, PD, SAD, GAD, and PTSDPAXILPlacebon (males)1446 %1042 %Decreased Libido6 to 150 to 5Ejaculatory Disturbance13 to 280 to 2Impotence2 to 90 to 3n (females)1822 %1340 %Decreased Libido0 to 90 to 2Orgasmic Disturbance2 to 90 to 1PAXIL treatment has been associated with several cases of priapism. In those cases with known outcome, patients recovered without sequelae. Hallucinations In pooled clinical trials of PAXIL, hallucinations were observed in 0.2% of PAXIL-treated patients compared to 0.1% of patients receiving placebo. Less Common Adverse Reactions The following adverse reactions occurred during the clinical studies of PAXIL 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 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 WholeInfrequent: Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular SystemFrequent: 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 SystemInfrequent: 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 SensesFrequent: 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.. 6-week clinical trials in MDD patients who received PAXIL 20 mg to 50 mg once daily. 12-week clinical trials in OCD patients who received PAXIL 20 mg to 60 mg once daily. 10- to 12-week clinical trials in PD patients who received PAXIL 10 mg to 60 mg once daily. 12-week clinical trials in SAD patients who received PAXIL 20 mg to 50 mg once daily. 8-week clinical trials in GAD patients who received PAXIL 10 mg to 50 mg once daily. 12-week clinical trials in PTSD patients who received PAXIL 20 mg to 50 mg once daily 6.2 Postmarketing Experience The following reactions have been identified during post approval use of PAXIL. Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish 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-Barre syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, 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, 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-Schonlein purpura), and premature births in pregnant women. There has been case report of severe hypotension when PAXIL was added to chronic metoprolol treatment.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action The mechanism of action of PAXIL in the treatment of MDD, SAD, OCD\, PD, GAD, and PTSD is unknown, but is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). 12.2 Pharmacodynamics. Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is potent and highly selective inhibitor of neuronal serotonin reuptake (SSRI) and has only very weak effects on norepinephrine and dopamine neuronal reuptake. 12.3 Pharmacokinetics Nonlinearity in pharmacokinetics is observed with increasing doses of PAXIL. In meta-analysis of paroxetine from studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit significantly lower Cmax or AUC than females. Absorption Paroxetine hydrochloride is completely absorbed after oral dosing of solution of the hydrochloride salt. In study in which normal male subjects (n 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and 1/2 were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is consequence of the fact that of the enzymes that metabolizes paroxetine is readily saturable. Paroxetine is equally bioavailable from the oral suspension and tablet.Effect of Food The effects of food on the bioavailability of paroxetine were studied in subjects administered single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Distribution Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Elimination Metabolism The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about to times greater than doubled.Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions [see Drug Interactions (7)]. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).Excretion Approximately 64% of 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.Drug Interaction StudiesThere are clinically significant, known drug interactions between paroxetine and other drugs [see Drug Interactions (7)].Figure 1. Impact of Paroxetine on the Pharmacokinetics of Co-Administered Drugs (log scale)Figure 2. Impact of Co-Administered Drugs on the Pharmacokinetics of ParoxetineTheophylline: Reports of elevated theophylline levels associated with PAXIL treatment have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.Drugs Metabolized by Cytochrome CYP3A4 An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Paroxetines extent of inhibition of CYP3A4 activity is not expected to be of clinical significance.Specific PopulationsThe impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3. The recommended starting dosage and maximum dosage of PAXIL is reduced in elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment [see Dosage and Administration (2.4)]. Figure 3. Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Major Depressive Disorder. The efficacy of PAXIL as treatment for major depressive disorder (MDD) has been established in placebo-controlled studies of patients with MDD (aged 18 to 73). In these studies, PAXIL was shown to be statistically significantly more effective than placebo in treating MDD by at least of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood text, and the Clinical Global Impression (CGI)-Severity of Illness. PAXIL was statistically significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood text, sleep disturbance factor, and anxiety factor.Long-term efficacy of PAXIL for treatment of MDD in outpatients was demonstrated in randomized withdrawal study. Patients who responded to PAXIL (HDRS total score <8) during an initial 8-week open-label treatment phase were then randomized to continue PAXIL or placebo, for up to year. Patients treated with PAXIL demonstrated 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 Obsessive Compulsive Disorder The effectiveness of PAXIL in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies and 2). Patients had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. In study 1, dose-range finding study, patients received fixed daily doses of PAXIL 20 mg, 40 mg, or 60 mg. Study demonstrated that daily doses of PAXIL 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving doses of PAXIL 40 mg and 60 mg experienced mean reduction of approximately and points, respectively, on the YBOCS total score which was statistically significantly greater than the approximate 4-point reduction at 20 mg and 3-point reduction in the placebo-treated patients. Study was flexible-dose study comparing PAXIL 20 mg to 60 mg daily with clomipramine 25 mg to 250 mg daily or placebo). In this study, patients receiving PAXIL experienced mean reduction of approximately points on the YBOCS total score, which was statistically significantly greater than the mean reduction of approximately points in placebo-treated patients.The following table provides the outcome classification by treatment group on Global Improvement texts of the Clinical Global Impression (CGI) scale for Study 1.Table 10: Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study in Patients with OCDOutcome ClassificationPlacebo(n 74)%PAXIL 20 mg (n 75)%PAXIL 40 mg(n 66)%PAXIL 60 mg(n 66)%Worse14773No Change44352219Minimally Improved24332934Much Improved11182224Very Much Improved772020Subgroup analyses did not indicate that there were any differences in treatment outcomes as function of age or gender.The long-term efficacy of PAXIL for the treatment of OCD was established in long-term extension to Study 1. Patients who responded to PAXIL during the 3-month double-blind phase and 6-month extension on open-label PAXIL 20 mg to 60 mg daily were randomized to either PAXIL or placebo in 6-month double-blind relapse prevention phase. Patients randomized to PAXIL were statistically significantly less likely to relapse than placebo-treated patients.. 14.3 Panic Disorder. The effectiveness of PAXIL in the treatment of panic disorder (PD) was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1, 2, and 3). Patients had PD (DSM-IIIR), with or without agoraphobia. In these studies, PAXIL was shown to be statistically significantly more effective than placebo in treating PD by at least out of measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score.Study was 10-week dose-range finding study; patients received fixed doses of PAXIL 10 mg, 20 mg, or 40 mg daily or placebo. statistically significant difference from placebo was observed only for the PAXIL 40 mg daily group. At endpoint, 76% of patients receiving PAXIL 40 mg daily were free of panic attacks, compared to 44% of placebo-treated patients.Study was 12-week flexible-dose study comparing PAXIL 10 mg to 60 mg daily and placebo. At endpoint, 51% of PAXIL-treated patients were free of panic attacks compared to 32% of placebo-treated patients.Study was 12-week flexible-dose study comparing PAXIL 10 mg to 60 mg daily to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the PAXIL-treated patients showed reduction to or panic attacks compared to 14% of placebo-treated patients.In Studies and 3, the mean PAXIL dose for completers at endpoint was approximately 40 mg daily.Long-term efficacy of PAXIL in PD was demonstrated in an extension to Study 1. Patients who responded to PAXIL during the 10-week double-blind phase and during 3-month double-blind extension phase were randomized to either PAXIL 10 mg, 20 mg, or 40 mg daily or placebo in 3-month double-blind relapse prevention phase. Patients randomized to PAXIL were statistically significantly less likely to relapse than placebo-treated patients.Subgroup analyses did not indicate that there were any differences in treatment outcomes as function of age or gender.. 14.4 Social Anxiety Disorder. The effectiveness of PAXIL in the treatment of social anxiety disorder (SAD) was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with SAD (DSM-IV). In these studies, the effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by Clinical Global Impression (CGI) Improvement score of (very much improved) or (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS).Studies and were flexible-dose studies comparing PAXIL 20 mg to 50 mg daily and placebo. PAXIL demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of PAXIL-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the PAXIL- and placebo-treated patients, respectively.Study was 12-week study comparing fixed doses of PAXIL 20 mg, 40 mg, or 60 mg daily with placebo. PAXIL 20 mg was statistically significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the PAXIL 40 mg and 60 mg daily dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg daily.Subgroup analyses generally did not indicate differences in treatment outcomes as function of age, race, or gender.. 14.5 Generalized Anxiety Disorder The effectiveness of PAXIL in the treatment of generalized anxiety disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies and 2) of adult outpatients with GAD (DSM-IV). Study was an 8-week study comparing fixed doses of PAXIL 20 mg or 40 mg daily with placebo. Doses of PAXIL 20 mg or 40 mg were both demonstrated to be statistically significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest greater benefit for the PAXIL 40 mg daily dose compared to the 20 mg daily dose. Study was flexible-dose study comparing PAXIL 20 mg to 50 mg daily and placebo. PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. third study, flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo, did not demonstrate statistically significant superiority of PAXIL over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.In long-term trial, 566 patients meeting DSM-IV criteria for GAD, who had responded during single-blind, 8-week acute treatment phase with PAXIL 20 mg to 50 mg daily, were randomized to continuation of PAXIL at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having decrease of >=2 points compared to baseline on the CGI-Severity of Illness scale, to score of <=3. Relapse during the double-blind phase was defined as an increase of >=2 points compared to baseline on the CGI-Severity of Illness scale to score of >=4, or withdrawal due to lack of efficacy. Patients continuing to receive PAXIL experienced statistically significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo. 14.6 Posttraumatic Stress Disorder. The effectiveness of PAXIL in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-controlled studies (Studies and 2) of adult outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the studies combined was 13 years (ranging from 0.1 year to 57 years). The percentage of patients with secondary MDD or non-PTSD anxiety disorders in the combined studies was 41% (356 out of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (1) the Clinician-Administered PTSD Scale Part (CAPS-2) score and (2) the Clinical Global Impression-Global Improvement Scale (CGI-I). The CAPS-2 is multi-text instrument that measures aspects of PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal. The primary outcomes for each trial were (1) change from baseline to endpoint on the CAPS-2 total score (17 texts), and (2) proportion of responders on the CGI-I, where responders were defined as patients having score of (very much improved) or (much improved).Study was 12-week study comparing fixed doses of PAXIL 20 mg or 40 mg daily to placebo. Doses of PAXIL 20 mg and 40 mg were demonstrated to be statistically significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. There was not sufficient evidence in this study to suggest greater benefit for the 40 mg daily dose compared to the 20 mg daily dose.Study was 12-week flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo. PAXIL was demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.A third study, flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo, demonstrated PAXIL to be statistically significantly superior to placebo on change from baseline for CAPS-2 total score, but not on proportion of responders on the CGI-I.The majority of patients in these trials were women (68% women: 377 out of 551 subjects in Study and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not indicate differences in treatment outcomes as function of gender. There were an insufficient number of patients who were 65 years and older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table presents clinically significant drug interactions with PAXIL.Table : Clinically Significant Drug Interactions with PAXILMonoamine Oxidase Inhibitors (MAOIs)Clinical ImpactThe concomitant use of SSRIs, including PAXIL, and MAOIs increases the risk of serotonin syndrome.InterventionPAXIL is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)]. Examplesselegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene bluePimozide and ThioridazineClinical ImpactIncreased plasma concentrations of pimozide and thioridazine, drugs with narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias.InterventionPAXIL is contraindicated in patients taking pimozide or thioridazine [see Contraindications (4)].Other Serotonergic DrugsClinical ImpactThe concomitant use of serotonergic drugs with PAXIL increases the risk of serotonin syndrome.InterventionMonitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of PAXIL and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].Examplesother SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. Johns WortDrugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)Clinical ImpactThe concurrent use of an antiplatelet agent or anticoagulant with PAXIL may potentiate the risk of bleeding.InterventionInform patients of the increased risk of bleeding associated with the concomitant use of PAXIL and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions (5.5)].Examplesaspirin, clopidogrel, heparin, warfarinDrugs Highly Bound to Plasma ProteinClinical ImpactPAXIL is highly bound to plasma protein. The concomitant use of PAXIL with another drug that is highly bound to plasma protein may increase free concentrations of PAXIL or other tightly-bound drugs in plasma.InterventionMonitor for adverse reactions and reduce dosage of PAXIL or other protein-bound drugs as warranted.ExampleswarfarinDrugs Metabolized by CYP2D6Clinical ImpactPAXIL is CYP2D6 inhibitor [see Clinical Pharmacology (12.3)]. The concomitant use of PAXIL with CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.InterventionDecrease the dosage of CYP2D6 substrate if needed with concomitant PAXIL use. Conversely, an increase in dosage of CYP2D6 substrate may be needed if PAXIL is discontinued.Examplespropafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone.TamoxifenClinical ImpactConcomitant use of tamoxifen with PAXIL may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifenInterventionConsider use of an alternative antidepressant with little or no CYP2D6 inhibition [see Warnings and Precautions (5.11)].Fosamprenavir/RitonavirClinical ImpactCo-administration of fosamprenavir/ritonavir with PAXIL significantly decreased plasma levels of PAXIL.InterventionAny dose adjustment should be guided by clinical effect (tolerability and efficacy).. Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of PAXIL or other protein-bound drugs (e.g., warfarin) as warranted. (7)Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. (7)Concomitant use with tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. (5.11, 7). Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of PAXIL or other protein-bound drugs (e.g., warfarin) as warranted. (7). Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. (7). Concomitant use with tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. (5.11, 7).

SPL MEDGUIDE SECTION.

Medication Guide. PAXIL(R) (PAX-il) (paroxetine hydrochloride) Tablets oral suspensionWhat is the most important information should know about PAXILPAXIL can cause serious side effects, including:Increased risk of suicidal thoughts or actions. PAXIL and other antidepressant medicines may increase suicidalthoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. PAXIL is not for use in children.Depression or other mental illnesses are the most important causes of suicidal thoughts and actions.How can watch for and try to prevent suicidal thoughts and actionsPay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if youdevelop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when thedoes is changed.Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or ifyou develop suicidal thoughts or actions.Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits asneeded, especially if you have concerns about symptoms.Call your healthcare provider or get emergency medical help right away if you have any of the followingsymptoms, especially if they are new, worse, or worry you:attempts to commit suicideacting aggressive or violentnew or worse depressionfeeling agitated, restless, angry, or irritablean increase in activity and talking more than what is normal for youacting on dangerous impulsesthoughts about suicide or dyingnew or worse anxiety or panic attackstrouble sleepingother unusual changes in behavior or mood What is PAXILPAXIL is prescription medicine used in adults to treat: certain type of depression called Major Depressive Disorder (MDD)Obsessive Compulsive Disorder (OCD)Panic Disorder (PD)Social Anxiety Disorder (SAD)Generalized Anxiety Disorder (GAD)Posttraumatic Stress Disorder (PTSD)Do not take PAXIL if you:take monoamine oxidase inhibitor (MAOI) have stopped taking an MAOI in the last 14 days are being treated with the antibiotic linezolid or the intravenous methylene blue are taking pimozideare taking thioridazineare allergic to paroxetine or any of the ingredients in PAXIL. See the end of this Medication Guide for complete list of ingredients in PAXIL. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI or one of these medicines, including the antibiotic linezolid or intravenous methylene blue. Do not start taking an MAOI for at least 14 days after you stop treatment with PAXIL.Before taking PAXIL, tell your healthcare provider about all your medical conditions, including if you:have heart problemshave or had bleeding problemshave, or have family history of, bipolar disorder, mania or hypomaniahave or had seizures or convulsionshave glaucoma (high pressure in the eye)have low sodium levels in your bloodhave bone problems have kidney or liver problemsare pregnant or plan to become pregnant. PAXIL may harm your unborn baby. Talk to your healthcare provider about the risks to your unborn baby if you take PAXIL during pregnancy. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with PAXIL. are breastfeeding or plan to breastfeed. PAXIL passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with PAXIL. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Especially tell your healthcare provider if you take:medicines used to treat migraine headaches called triptanstricyclic antidepressantsfentanyllithiumtramadoltryptophan buspironeamphetaminesSt. Johns Wortmedicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarindiureticstamoxifenmedicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serontonin reuptake (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)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 PAXIL with your other medicines. Do not start or stop any other medicines during treatment with PAXIL without talking to your healthcare provider first. Stopping PAXIL suddenly may cause you to have serious side effects. See, What are the possible side effects of PAXILKnow the medicines you take. Keep list of them to show to your healthcare provider and pharmacist when you get new medicine.How should take PAXILTake PAXIL exactly as prescribed. Your healthcare provider may need to change the dose of PAXIL until it is the right dose for you.Take PAXIL time each day in the morning. PAXIL may be taken with or without food. If you are taking PAXIL oral suspension, shake suspension well before taking. If you take too much PAXIL, call your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away.What are possible side effects of PAXILPAXIL can cause serious side effects, including: See, What is the most important information should know about PAXIL Serotonin syndrome. potentially life-threatening problem called serotonin syndrome can happen when you take PAXIL with certain other medicines. See, Who should not take PAXIL 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: agitationseeing or hearing things that are not real (hallucinations)confusionfast heart beatchanges in blood pressuredizzinesssweatingflushinghigh body temperature (hyperthermia)shaking (tremors), stiff muscles, or muscle twitchingloss of coordinationseizuresnausea, vomiting, diarrhea Eye problems (angle-closure glaucoma). PAXIL may cause 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. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Medicine interactions. Taking PAXIL with certain other medicines including thioridazine and pimozide may increase the risk of developing serious heart problem called QT prolongation.Seizures (convulsions).Manic episodes. Manic episodes may happen in people with bipolar disorder who take PAXIL. Symptoms may include:greatly increased energyracing thoughtsunusually grand ideastalking more or faster than usualsevere problems sleepingreckless behaviorexcessive happiness or irritabilityDiscontinuation syndrome. Suddenly stopping PAXIL may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: nauseasweatingchanges in your moodirritability and agitationdizzinesselectric shock feeling (paresthesia)tremoranxietyconfusionheadachetirednessproblems sleepinghypomaniaringing in your ears (tinnitus)seizuresLow 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 PAXIL. Elderly people and people who take certain medicines may be at greater risk for developing low sodium levels in your blood. Signs and symptoms may include:headachedifficulty concentratingmemory changesconfusionweakness and unsteadiness on your feet which can lead to fallsIn more severe or more sudden cases, signs and symptoms include:seeing or hearing things that are not real (hallucinations)faintingseizurescomastopping breathing (respiratory arrest)Abnormal bleeding. Taking PAXIL with aspirin, NSAIDs, or blood thinners may increase this risk. Tell your healthcare provider about any unusual bleeding or bruising. Bone fracturesSexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including PAXIL, may cause sexual problems. Symptoms in males may include:Delayed ejaculation or inability to have an ejaculationDecreased sex driveProblems getting or keeping an erectionSymptoms in females may include:Decreased sex driveDelayed orgasm or inability to have an orgasmTalk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with PAXIL. There may be treatments your healthcare provider can suggest.The most common side effects of PAXIL include:male and female sexual function problems constipationdiarrheadry mouthproblems sleepingnervousnesssweatingyawningweakness (asthenia)decreased appetitedizzinessinfectionnauseasleepinessshaking (tremor) These are not all the possible side effects of PAXIL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store PAXILStore PAXIL tablets between 59oF to 86oF (15oC to 30oC).Store PAXIL oral suspension at or below 77oF (25oC). Keep PAXIL and all medicines out of the reach of children.General information about the safe and effective use of PAXIL.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not take PAXIL for condition for which it was not prescribed. Do not give PAXIL 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 PAXIL that is written for healthcare professionals.What are the ingredients in PAXILActive ingredient: paroxetine hydrochlorideInactive ingredients:Tablets: dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. aluminum lake, FD&C Yellow No. aluminum lake Oral suspension: citric acid (anhydrous), FD&C yellow No. 6, flavorings, glycerin, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polacrilin potassium, propylene glycol, propylparaben, purified water, saccharin sodium, simethicone emulsion and sodium citrate (dihydrate) Manufactured by: Apotex Inc.Toronto, Ontario, Canada M9L 1T9Manufactured for: Apotex Corp. Weston, Florida USA 33326PAXIL(R) and PAXIL CR(R) are registered trademarks of the GlaxoSmithKline group of companies.All other registered trademarks are the property of their respective owners. For more information about PAXIL call 1-800-706-5575.This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 9/2021. Increased risk of suicidal thoughts or actions. PAXIL and other antidepressant medicines may increase suicidalthoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. PAXIL is not for use in children.. Depression or other mental illnesses are the most important causes of suicidal thoughts and actions.. Depression or other mental illnesses are the most important causes of suicidal thoughts and actions.. Depression or other mental illnesses are the most important causes of suicidal thoughts and actions.. Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if youdevelop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when thedoes is changed.Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or ifyou develop suicidal thoughts or actions.Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits asneeded, especially if you have concerns about symptoms.. Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if youdevelop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when thedoes is changed.. Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or ifyou develop suicidal thoughts or actions.. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits asneeded, especially if you have concerns about symptoms.. attempts to commit suicideacting aggressive or violentnew or worse depressionfeeling agitated, restless, angry, or irritablean increase in activity and talking more than what is normal for youacting on dangerous impulsesthoughts about suicide or dyingnew or worse anxiety or panic attackstrouble sleepingother unusual changes in behavior or mood. attempts to commit suicide. acting aggressive or violent. new or worse depression. feeling agitated, restless, angry, or irritable. an increase in activity and talking more than what is normal for you. acting on dangerous impulses. thoughts about suicide or dying. new or worse anxiety or panic attacks. trouble sleeping. other unusual changes in behavior or mood. certain type of depression called Major Depressive Disorder (MDD). Obsessive Compulsive Disorder (OCD). Panic Disorder (PD). Social Anxiety Disorder (SAD). Generalized Anxiety Disorder (GAD). Posttraumatic Stress Disorder (PTSD). take monoamine oxidase inhibitor (MAOI) have stopped taking an MAOI in the last 14 days are being treated with the antibiotic linezolid or the intravenous methylene blue are taking pimozide. are taking thioridazine. are allergic to paroxetine or any of the ingredients in PAXIL. See the end of this Medication Guide for complete list of ingredients in PAXIL. have heart problems. have or had bleeding problems. have, or have 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. PAXIL may harm your unborn baby. Talk to your healthcare provider about the risks to your unborn baby if you take PAXIL during pregnancy. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with PAXIL. are breastfeeding or plan to breastfeed. PAXIL passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with PAXIL. medicines used to treat migraine headaches called triptans. tricyclic antidepressants. fentanyl. lithium. tramadol. tryptophan buspirone. amphetamines. St. Johns Wort. medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin. diuretics. tamoxifen. medicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serontonin reuptake (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Take PAXIL exactly as prescribed. Your healthcare provider may need to change the dose of PAXIL until it is the right dose for you.. Take PAXIL time each day in the morning. PAXIL may be taken with or without food. If you are taking PAXIL oral suspension, shake suspension well before taking.. If you take too much PAXIL, call your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away.. See, What is the most important information should know about PAXIL Serotonin syndrome. potentially life-threatening problem called serotonin syndrome can happen when you take PAXIL with certain other medicines. See, Who should not take PAXIL 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: agitationseeing or hearing things that are not real (hallucinations)confusionfast heart beatchanges in blood pressuredizzinesssweatingflushinghigh body temperature (hyperthermia)shaking (tremors), stiff muscles, or muscle twitchingloss of coordinationseizuresnausea, vomiting, diarrhea agitation. seeing or hearing things that are not real (hallucinations). confusion. fast heart beat. changes in blood pressure. dizziness. sweating. flushing. high body temperature (hyperthermia). shaking (tremors), stiff muscles, or muscle twitching. loss of coordination. seizures. nausea, vomiting, diarrhea. Eye problems (angle-closure glaucoma). PAXIL may cause 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. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Medicine interactions. Taking PAXIL with certain other medicines including thioridazine and pimozide may increase the risk of developing serious heart problem called QT prolongation.. Seizures (convulsions).. Manic episodes. Manic episodes may happen in people with bipolar disorder who take PAXIL. Symptoms may include:greatly increased energyracing thoughtsunusually grand ideastalking more or faster than usualsevere problems sleepingreckless behaviorexcessive happiness or irritability. greatly increased energy. racing thoughts. unusually grand ideas. talking more or faster than usual. severe problems sleeping. reckless behavior. excessive happiness or irritability. Discontinuation syndrome. Suddenly stopping PAXIL may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: nauseasweatingchanges in your moodirritability and agitationdizzinesselectric shock feeling (paresthesia)tremoranxietyconfusionheadachetirednessproblems sleepinghypomaniaringing in your ears (tinnitus)seizures. nausea. sweating. changes in your mood. irritability and agitation. dizziness. electric shock feeling (paresthesia). tremor. anxiety. confusion. headache. tiredness. problems sleeping. hypomania. ringing in your ears (tinnitus). seizures. 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 PAXIL. Elderly people and people who take certain medicines may be at greater risk for developing low sodium levels in your blood. Signs and symptoms may include:headachedifficulty concentratingmemory changesconfusionweakness and unsteadiness on your feet which can lead to falls. headache. difficulty concentrating. memory changes. confusion. weakness and unsteadiness on your feet which can lead to falls. seeing or hearing things that are not real (hallucinations)faintingseizurescomastopping breathing (respiratory arrest). seeing or hearing things that are not real (hallucinations). fainting. seizures. coma. stopping breathing (respiratory arrest). Abnormal bleeding. Taking PAXIL with aspirin, NSAIDs, or blood thinners may increase this risk. Tell your healthcare provider about any unusual bleeding or bruising. Bone fractures. Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including PAXIL, may cause sexual problems. Delayed ejaculation or inability to have an ejaculationDecreased sex driveProblems getting or keeping an erection. Delayed ejaculation or inability to have an ejaculation. Decreased sex drive. Problems getting or keeping an erection. Decreased sex driveDelayed orgasm or inability to have an orgasm. Decreased sex drive. Delayed orgasm or inability to have an orgasm. male and female sexual function problems constipation. diarrhea. dry mouth. problems sleeping. nervousness. sweating. yawning. weakness (asthenia). decreased appetite. dizziness. infection. nausea. sleepiness. shaking (tremor). Store PAXIL tablets between 59oF to 86oF (15oC to 30oC).. Store PAXIL oral suspension at or below 77oF (25oC).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Can cause fetal and neonatal harm. Advise women of potential risk to the fetus. (8.1)Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3). Pregnancy: Can cause fetal and neonatal harm. Advise women of potential risk to the fetus. (8.1). Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3). 8.1 Pregnancy Pregnancy Category [see Warnings and Precautions (5.4)] Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. If paroxetine is used during pregnancy, or if the patient becomes pregnant while taking paroxetine, advise the patient of the potential hazard to the fetus.Clinical ConsiderationsUnless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant [see Warnings and Precautions (5.7)]. For study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery. separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n 815 for paroxetine). This study showed trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). Two large case-control studies using separate databases, each with >9,000 birth defect cases and >4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the OR was 2.5 (95% confidence interval, 1.0 to 6.0, exposed infants) and in the other study the OR was 3.3 (95% confidence interval, 1.3 to 8.8, exposed infants). Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. meta-analysis of epidemiological data over 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n 17 studies that included overall malformations and = 14 studies that included cardiovascular malformations; = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations.Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant [see Warnings and Precautions (5.7)]. For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options [see Warnings and Precautions (5.4)].Treatment of Pregnant Women During Their Third Trimester: Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), including PAXIL, 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, tremor, jitteriness, irritability, and constant crying. These features are consistent with either direct toxic effect of SSRIs and SNRIs or, possibly, drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)].Exposure to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in - per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs.When treating pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment. prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning of pregnancy. The women who discontinued antidepressant medication during pregnancy were more likely to experience relapse of major depression than women who continued antidepressant medication.Animal FindingsReproduction studies were performed at doses up to 50 mg/kg/day in rats and mg/kg/day in rabbits administered during organogenesis. These doses are approximately (rat) and less than (rabbit) times the maximum recommended human dose (MRHD 75 mg) on an mg/m2 basis. These studies have revealed no evidence of developmental effects. However, in rats, there was an increase in pup deaths during the first days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at dose of mg/kg/day which is than the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery. A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n 815 for paroxetine). This study showed trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). Two large case-control studies using separate databases, each with >9,000 birth defect cases and >4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the OR was 2.5 (95% confidence interval, 1.0 to 6.0, exposed infants) and in the other study the OR was 3.3 (95% confidence interval, 1.3 to 8.8, exposed infants). 8.3 Nursing Mothers. Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from PAXIL, decision should be made whether to discontinue nursing infants or to discontinue the drug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. The safety and effectiveness of PAXIL in pediatric patients have not been established [see Box Warning]. Effectiveness was not demonstrated in three placebo-controlled trials in 752 PAXIL-treated pediatric patients with MDD. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)]. 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 PAXIL and occurred at 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 PAXIL in the pediatric clinical trials that included taper phase regimen, which occurred in at least 2% of patients and at 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 .. 8.5 Geriatric Use. In premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed decreased clearance in the elderly, and lower starting dose is recommended;, however, no overall differences in safety or effectiveness were observed between elderly and younger patients [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].SSRIs including PAXIL, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.7)].. 8.6 Renal and Hepatic Impairment. Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage of PAXIL should be reduced in patients with severe renal impairment and in patients with severe hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS and PRECAUTIONS. Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If occurs, discontinue PAXIL and initiate supportive measures. (5.2)Embryofetal and Neonatal Toxicity: Can cause fetal and neonatal harm. Increased risk of cardiovascular malformations with exposure during the first trimester. Exposure in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn. (5.4, 8.1)Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. (5.5)Activation of Mania/Hypomania: Screen patients for bipolar disorder. (5.6)Seizures: Use with caution in patients with seizure disorders. (5.8)Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9)Sexual Dysfunction: PAXIL may cause symptoms of sexual dysfunction. (5.13) Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If occurs, discontinue PAXIL and initiate supportive measures. (5.2). Embryofetal and Neonatal Toxicity: Can cause fetal and neonatal harm. Increased risk of cardiovascular malformations with exposure during the first trimester. Exposure in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn. (5.4, 8.1). Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. (5.5). Activation of Mania/Hypomania: Screen patients for bipolar disorder. (5.6). Seizures: Use with caution in patients with seizure disorders. (5.8). Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9). Sexual Dysfunction: PAXIL may cause symptoms of sexual dysfunction. (5.13) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults. In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age RangeDrug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1,000 Patients TreatedIncreases Compared to Placebo<18 years old14 additional cases18-24 years old5 additional casesDecreases Compared to Placebo25-64 years old1 fewer case>=65 years old6 fewer casesPAXIL is not approved for use in pediatric patients.It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing PAXIL, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.. 5.2 Serotonin Syndrome. SSRIs, including PAXIL, can precipitate serotonin syndrome, potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St. Johns Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone. 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), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of PAXIL with MAOIs is contraindicated. In addition, do not initiate PAXIL in patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in patient taking PAXIL discontinue PAXIL before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)]. Monitor all patients taking PAXIL for the emergence of serotonin syndrome. Discontinue treatment with PAXIL and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of PAXIL with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.. 5.3 Drug Interactions Leading to QT Prolongation. The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of PAXIL is contraindicated in combination with thioridazine and pimozide [see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)]. 5.4 Embryofetal and Neonatal Toxicity. PAXIL can cause fetal harm when administered to pregnant woman. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of cardiovascular malformations. Exposure to paroxetine in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn (PPNH) and/or neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. If PAXIL is used during pregnancy, or if the patient becomes pregnant while taking PAXIL, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including PAXIL, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet 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 drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of PAXIL and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.. 5.6 Activation of Mania or Hypomania. In patients with bipolar disorder, treating depressive episode with PAXIL or another antidepressant may precipitate mixed/manic episode. During controlled clinical trials of PAXIL, hypomania or mania occurred in approximately 1% of PAXIL-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with PAXIL, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.. 5.7 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.7)]. During clinical trials of GAD and PTSD, gradual decreases in the daily dose by 10 mg/day at weekly intervals followed by week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness Adverse reactions have been reported upon discontinuation of treatment with PAXIL in pediatric patients. The safety and effectiveness of PAXIL in pediatric patients have not been established [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. 5.8 Seizures. PAXIL tablets and oral suspension have not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. During clinical studies, seizures occurred in 0.1% of patients treated with PAXIL. PAXIL should be prescribed with caution in patients with seizure disorder. Discontinue PAXIL in any patient who develops seizures.. 5.9 Angle-Closure Glaucoma. The pupillary dilation that occurs following use of many antidepressant drugs including PAXIL may trigger an angle closure attack in patient with anatomically narrow angles who does not have patent iridectomy. Cases of angle-closure glaucoma associated with use of PAXIL have been reported. Avoid use of antidepressants, including PAXIL in patients with untreated anatomically narrow angles.. 5.10 Hyponatremia. Hyponatremia may occur as result of treatment with SSRIs, including PAXIL. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue PAXIL and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [see Use in Specific Populations (8.5)]. 5.11 Reduction of 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 with concomitant use of PAXIL as result of paroxetines irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions (7)]. One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.. 5.12 Bone Fracture. Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment.. 5.13 Sexual Dysfunction. Use of SSRIs, including PAXIL, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.It is important for prescribers to inquire about sexual function prior to initiation of PAXIL and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.