PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Nonlinearity in pharmacokinetics is observed with increasing doses of paroxetine tablets.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 paroxetine tablets.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 Studies. There 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 Paroxetine 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 Paroxetine. Theophylline. Reports of elevated theophylline levels associated with paroxetine tablets 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 Populations. The impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3.The recommended starting dosage and maximum dosage of paroxetine tablets are 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) Figure 3. Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale).

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Category D. [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 Considerations. 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)]. ForoA 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.oA 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).oTwo 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)].. oA 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.. oA 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).. oTwo 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).. Treatment of Pregnant Women During Their Third Trimester. Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), including paroxetine tablets, 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 Findings. Reproduction 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.

SPL MEDGUIDE SECTION.

Medication Guide Paroxetine Tablets, USP(pa rox teen)What is the most important information should know about paroxetine tablets Paroxetine tablets can cause serious side effects, including:oIncreased risk of suicidal thoughts or actions. Paroxetine tablets and other antidepressant medicines may increase suicidal thoughts 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.Paroxetine tablets are not for use in children.oDepression 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 actionsoPay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.oCall your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions.oKeep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.Call your healthcare provider or get emergency medical help right away if you have any of the following symptoms, especially if they are new, worse, or worry you:oattempts to commit suicideoacting aggressive or violentonew or worse depressionofeeling agitated, restless, angry, or irritableoan increase in activity and talking more than what is normal for youoacting on dangerous impulsesothoughts about suicide or dyingonew or worse anxiety or panic attacksotrouble sleepingoother unusual changes in behavior or moodWhat are paroxetine tablets Paroxetine tablets are prescription medicine used in adults to treat:oA certain type of depression called Major Depressive Disorder (MDD)oObsessive Compulsive Disorder (OCD)oPanic Disorder (PD)oSocial Anxiety Disorder (SAD)oGeneralized Anxiety Disorder (GAD)oPosttraumatic Stress Disorder (PTSD)Do not take paroxetine tablets if you:otake monoamine oxidase inhibitor (MAOI)ohave stopped taking an MAOI in the last 14 daysoare being treated with the antibiotic linezolid or the intravenous methylene blueoare taking pimozideoare taking thioridazineoare allergic to paroxetine or any of the ingredients in paroxetine tablets. See the end of this Medication Guide for complete list of ingredients in paroxetine tablets.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 paroxetine tablets.Before taking paroxetine tablets, tell your healthcare provider about all your medical conditions, including if you:ohave heart problemsohave or had bleeding problemsohave, or have family history of, bipolar disorder, mania or hypomaniaohave or had seizures or convulsionsohave glaucoma (high pressure in the eye)ohave low sodium levels in your bloodohave bone problemsohave kidney or liver problemsoare pregnant or plan to become pregnant. Paroxetine tablets may harm your unborn baby. Talk to your healthcare provider about the risks to your unborn baby if you take paroxetine tablets during pregnancy. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with paroxetine tablets.oare breastfeeding or plan to breastfeed. Paroxetine passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with paroxetine tablets.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Paroxetine tablets and some other medicines may affect each other causing possible serious side effects. Paroxetine tablets may affect the way other medicines work and other medicines may affect the way paroxetine tablets work. Especially tell your healthcare provider if you take:omedicines used to treat migraine headaches called triptansotricyclic antidepressantsofentanylolithiumotramadolotryptophanobuspironeoamphetaminesoSt. Johns Wortomedicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarinodiureticsotamoxifenomedicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serotonin 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 paroxetine tablets with your other medicines. Do not start or stop any other medicines during treatment with paroxetine tablets without talking to your healthcare provider first. Stopping paroxetine tablets suddenly may cause you to have serious side effects. See, What are the possible side effects of paroxetine tablets Know the medicines you take. Keep list of them to show to your healthcare provider and pharmacist when you get new medicine.How should take paroxetine tabletsoTake paroxetine tablets exactly as prescribed. Your healthcare provider may need to change the dose of paroxetine tablets until it is the right dose for you.oTake paroxetine tablets time each day in the morning.oParoxetine tablets may be taken with or without food.oIf you take too many paroxetine tablets, 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 paroxetine tablets Paroxetine tablets can cause serious side effects, including:oSee, What is the most important information should know about paroxetine tabletsoSerotonin syndrome. potentially life-threatening problem called serotonin syndrome can happen when you take paroxetine tablets with certain other medicines. See, Who should not take paroxetine tablets Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome:oagitationoseeing or hearing things that are not real (hallucinations)oconfusionocomaofast heart beatochanges in blood pressureodizzinessosweatingoflushingohigh body temperature (hyperthermia)oshaking (tremors), stiff muscles, or muscle twitchingoloss of coordinationoseizuresonausea, vomiting, diarrheaoEye problems (angle-closure glaucoma). Paroxetine tablets 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.oMedicine interactions. Taking paroxetine tablets with certain other medicines including thioridazine and pimozide may increase the risk of developing serious heart problem called QT prolongation.oSeizures (convulsions).oManic episodes. Manic episodes may happen in people with bipolar disorder who take paroxetine tablets. Symptoms may include:ogreatly increased energyoracing thoughtsounusually grand ideasotalking more or faster than usualosevere problems sleepingoreckless behavioroexcessive happiness or irritabilityoDiscontinuation syndrome. Suddenly stopping paroxetine tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:onauseaosweatingochanges in your moodoirritability and agitationodizzinessoelectric shock feeling (paresthesia)otremoroanxietyoconfusionoheadacheotirednessoproblems sleepingohypomaniaoringing in your ears (tinnitus)oseizuresoLow sodium levels in your blood (hyponatremia). Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with paroxetine tablets. 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:oheadacheodifficulty concentratingomemory changesoconfusionoweakness and unsteadiness on your feet which can lead to falls In more severe or more sudden cases, signs and symptoms include: oseeing or hearing things that are not real (hallucinations)ofaintingoseizuresocomaostopping breathing (respiratory arrest)oAbnormal bleeding. Taking paroxetine tablets with aspirin, NSAIDs, or blood thinners may increase this risk. Tell your healthcare provider about any unusual bleeding or bruising.oBone fractures.oSexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including paroxetine tablets, may cause sexual problems. Symptoms in males may include:oDelayed ejaculation or inability to have an ejaculationoDecreased sex driveoProblems getting or keeping an erection Symptoms in females may include:oDecreased sex driveoDelayed orgasm or inability to have an orgasm Talk 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 paroxetine tablets. There may be treatments your healthcare provider can suggest.The most common side effects of paroxetine tablets include:omale and female sexual function problemsoconstipationodiarrheaodry mouthoproblems sleepingonervousnessosweatingoyawningoweakness (asthenia)odecreased appetiteodizzinessoinfectiononauseaosleepinessoshaking (tremor)These are not all the possible side effects of paroxetine tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store paroxetine tabletsoStore paroxetine tablets between 20 to 25C (68 to 77F).Keep paroxetine tablets and all medicines out of the reach of children.General information about the safe and effective use of paroxetine tablets. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not take paroxetine tablets for condition for which they were not prescribed. Do not give paroxetine tablets to other people, even if they have the same symptoms that you have. They may harm them. You may ask your healthcare provider or pharmacist for information about paroxetine tablets that is written for healthcare professionals.What are the ingredients in paroxetine tablets Active ingredient: paroxetine hydrochloride Inactive ingredients: Tablets: dibasic calcium phosphate dihydrate, FD&C Blue No. Aluminum Lake, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, sodium starch glycolate (potato), titanium dioxide and triacetin.Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.Manufactured by: ALPHAPHARM PTY LTD, 15 Garnet Street, Carole Park QLD 4300 Australia The brands listed are trademarks of their respective owners. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: ALPHAPHARM PTY LTD 15 Garnet StreetCarole Park QLD 4300AustraliaRevised: 10/2021ALP:PXTT:R12mh/ ALP:MG:PXTT:R5mh(2848/5). oIncreased risk of suicidal thoughts or actions. Paroxetine tablets and other antidepressant medicines may increase suicidal thoughts 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.Paroxetine tablets are not for use in children.oDepression or other mental illnesses are the most important causes of suicidal thoughts and actions.. oDepression 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 actions. oPay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.. oCall your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions.. oKeep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.. oattempts to commit suicide. oacting aggressive or violent. onew or worse depression. ofeeling agitated, restless, angry, or irritable. oan increase in activity and talking more than what is normal for you. oacting on dangerous impulses. othoughts about suicide or dying. onew or worse anxiety or panic attacks. otrouble sleeping. oother unusual changes in behavior or mood. oA certain type of depression called Major Depressive Disorder (MDD). oObsessive Compulsive Disorder (OCD). oPanic Disorder (PD). oSocial Anxiety Disorder (SAD). oGeneralized Anxiety Disorder (GAD). oPosttraumatic Stress Disorder (PTSD). otake monoamine oxidase inhibitor (MAOI). ohave stopped taking an MAOI in the last 14 days. oare being treated with the antibiotic linezolid or the intravenous methylene blue. oare taking pimozide. oare taking thioridazine. oare allergic to paroxetine or any of the ingredients in paroxetine tablets. See the end of this Medication Guide for complete list of ingredients in paroxetine tablets.. ohave heart problems. ohave or had bleeding problems. ohave, or have family history of, bipolar disorder, mania or hypomania. ohave or had seizures or convulsions. ohave glaucoma (high pressure in the eye). ohave low sodium levels in your blood. ohave bone problems. ohave kidney or liver problems. oare pregnant or plan to become pregnant. Paroxetine tablets may harm your unborn baby. Talk to your healthcare provider about the risks to your unborn baby if you take paroxetine tablets during pregnancy. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with paroxetine tablets.. oare breastfeeding or plan to breastfeed. Paroxetine passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with paroxetine tablets.. omedicines used to treat migraine headaches called triptans. otricyclic antidepressants. ofentanyl. olithium. otramadol. otryptophan. obuspirone. oamphetamines. oSt. Johns Wort. omedicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin. odiuretics. otamoxifen. omedicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serotonin reuptake (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). oTake paroxetine tablets exactly as prescribed. Your healthcare provider may need to change the dose of paroxetine tablets until it is the right dose for you.. oTake paroxetine tablets time each day in the morning.. oParoxetine tablets may be taken with or without food.. oIf you take too many paroxetine tablets, call your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away.. oSee, What is the most important information should know about paroxetine tablets. oSerotonin syndrome. potentially life-threatening problem called serotonin syndrome can happen when you take paroxetine tablets with certain other medicines. See, Who should not take paroxetine tablets Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome:. oagitation. oseeing or hearing things that are not real (hallucinations). oconfusion. ocoma. ofast heart beat. ochanges in blood pressure. odizziness. osweating. oflushing. ohigh body temperature (hyperthermia). oshaking (tremors), stiff muscles, or muscle twitching. oloss of coordination. oseizures. onausea, vomiting, diarrhea. oEye problems (angle-closure glaucoma). Paroxetine tablets 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.. oMedicine interactions. Taking paroxetine tablets with certain other medicines including thioridazine and pimozide may increase the risk of developing serious heart problem called QT prolongation.. oSeizures (convulsions).. oManic episodes. Manic episodes may happen in people with bipolar disorder who take paroxetine tablets. Symptoms may include:. ogreatly increased energy. oracing thoughts. ounusually grand ideas. otalking more or faster than usual. osevere problems sleeping. oreckless behavior. oexcessive happiness or irritability. oDiscontinuation syndrome. Suddenly stopping paroxetine tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:. onausea. osweating. ochanges in your mood. oirritability and agitation. odizziness. oelectric shock feeling (paresthesia). otremor. oanxiety. oconfusion. oheadache. otiredness. oproblems sleeping. ohypomania. oringing in your ears (tinnitus). oseizures. oLow sodium levels in your blood (hyponatremia). Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with paroxetine tablets. 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:oheadacheodifficulty concentratingomemory changesoconfusionoweakness and unsteadiness on your feet which can lead to falls In more severe or more sudden cases, signs and symptoms include:. oheadache. odifficulty concentrating. omemory changes. oconfusion. oweakness and unsteadiness on your feet which can lead to falls In more severe or more sudden cases, signs and symptoms include:. oseeing or hearing things that are not real (hallucinations)ofaintingoseizuresocomaostopping breathing (respiratory arrest). oseeing or hearing things that are not real (hallucinations). ofainting. oseizures. ocoma. ostopping breathing (respiratory arrest). oAbnormal bleeding. Taking paroxetine tablets with aspirin, NSAIDs, or blood thinners may increase this risk. Tell your healthcare provider about any unusual bleeding or bruising.. oBone fractures.. oSexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including paroxetine tablets, may cause sexual problems.. Symptoms in males may include:oDelayed ejaculation or inability to have an ejaculationoDecreased sex driveoProblems getting or keeping an erection. oDelayed ejaculation or inability to have an ejaculation. oDecreased sex drive. oProblems getting or keeping an erection. Symptoms in females may include:oDecreased sex driveoDelayed orgasm or inability to have an orgasm. oDecreased sex drive. oDelayed orgasm or inability to have an orgasm. Talk 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 paroxetine tablets. There may be treatments your healthcare provider can suggest.. omale and female sexual function problems. oconstipation. odiarrhea. odry mouth. oproblems sleeping. onervousness. osweating. oyawning. oweakness (asthenia). odecreased appetite. odizziness. oinfection. onausea. osleepiness. oshaking (tremor). oStore paroxetine tablets between 20 to 25C (68 to 77F).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: Can cause fetal and neonatal harm. Advise women of potential risk to the fetus. (8.1)oNursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3). oPregnancy: Can cause fetal and neonatal harm. Advise women of potential risk to the fetus. (8.1). oNursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3). 8.1 Pregnancy Pregnancy Category D. [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 Considerations. 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)]. ForoA 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.oA 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).oTwo 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)].. oA 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.. oA 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).. oTwo 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).. Treatment of Pregnant Women During Their Third Trimester. Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), including paroxetine tablets, 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 Findings. Reproduction 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. 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 paroxetine tablets, 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 paroxetine tablets in pediatric patients have not been established [see Box Warning]. 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 [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 paroxetine tablets 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 paroxetine tablets 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 paroxetine tablets, 17% of patients treated with paroxetine tablets (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 paroxetine tablets, 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) ].. 8.6Renal and Hepatic Impairment Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage of paroxetine tablets 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 oSerotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If occurs, discontinue paroxetine tablets and initiate supportive measures. (5.2)oEmbryofetal 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)oIncreased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. (5.5)oActivation of Mania/Hypomania: Screen patients for bipolar disorder. (5.6)oSeizures: Use with caution in patients with seizure disorders. (5.8)oAngle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9)oSexual Dysfunction: Paroxetine tablets may cause symptoms of sexual dysfunction (5.13). oSerotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If occurs, discontinue paroxetine tablets and initiate supportive measures. (5.2). oEmbryofetal 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). oIncreased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. (5.5). oActivation of Mania/Hypomania: Screen patients for bipolar disorder. (5.6). oSeizures: Use with caution in patients with seizure disorders. (5.8). oAngle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9). oSexual Dysfunction: Paroxetine tablets may cause symptoms of sexual dysfunction (5.13). 5.1Suicidal 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 PatientsAge 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 casesParoxetine tablets are 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 paroxetine tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.. 5.2Serotonin Syndrome SSRIs, including paroxetine tablets, 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 paroxetine tablets with MAOIs is contraindicated. In addition, do not initiate paroxetine tablets 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 paroxetine tablets discontinue paroxetine tablets before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)].Monitor all patients taking paroxetine tablets for the emergence of serotonin syndrome. Discontinue treatment with paroxetine tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of paroxetine tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.. 5.3Drug 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 paroxetine tablets is contraindicated in combination with thioridazine and pimozide [see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)].. 5.4Embryofetal and Neonatal Toxicity Paroxetine tablets 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 paroxetine tablets are used during pregnancy, or if the patient becomes pregnant while taking paroxetine tablets, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].. 5.5Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including paroxetine tablets, 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 paroxetine tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.. 5.6Activation of Mania or Hypomania In patients with bipolar disorder, treating depressive episode with paroxetine tablets or another antidepressant may precipitate mixed/manic episode. During controlled clinical trials of paroxetine tablets, hypomania or mania occurred in approximately 1% of paroxetine tablets-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with paroxetine tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.. 5.7Discontinuation 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 paroxetine tablets and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. Adverse reactions have been reported upon discontinuation of treatment with paroxetine tablets in pediatric patients. The safety and effectiveness of paroxetine tablets in pediatric patients have not been established [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)].. 5.8Seizures Paroxetine 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 paroxetine tablets. Paroxetine tablets should be prescribed with caution in patients with seizure disorder. Discontinue paroxetine tablets in any patient who develops seizures.. 5.9Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including paroxetine tablets 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 paroxetine tablets have been reported. Avoid use of antidepressants, including paroxetine tablets in patients with untreated anatomically narrow angles.. 5.10Hyponatremia Hyponatremia may occur as result of treatment with SSRIs, including paroxetine tablets. 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 paroxetine tablets 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)].. 5.11Reduction 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 paroxetine tablets 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.. 5.12Bone 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. 5.13Sexual Dysfunction Use of SSRIs, including paroxetine tablets, 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 paroxetine tablets 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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are included in more detail in other sections of the prescribing information:oHypersensitivity reactions to paroxetine [see Contraindications (4)]oSuicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)]oSerotonin Syndrome [see Warnings and Precautions (5.2)]oEmbryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)]oIncreased Risk of Bleeding [see Warnings and Precautions (5.5)]oActivation of Mania/Hypomania [see Warnings and Precautions (5.6)]oDiscontinuation Syndrome [see Warnings and Precautions (5.7)]oSeizures [see Warnings and Precautions (5.8)]oAngle-closure Glaucoma [see Warnings and Precautions (5.9)]oHyponatremia [see Warnings and Precautions (5.10)]oBone Fracture [see Warnings and Precautions (5.12)]oSexual Dysfunction [see Warnings and Precautions (5.13)]. oHypersensitivity reactions to paroxetine [see Contraindications (4)]. oSuicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)]. oSerotonin Syndrome [see Warnings and Precautions (5.2)]. oEmbryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)]. oIncreased Risk of Bleeding [see Warnings and Precautions (5.5)]. oActivation of Mania/Hypomania [see Warnings and Precautions (5.6)]. oDiscontinuation Syndrome [see Warnings and Precautions (5.7)]. oSeizures [see Warnings and Precautions (5.8)]. oAngle-closure Glaucoma [see Warnings and Precautions (5.9)]. oHyponatremia [see Warnings and Precautions (5.10)]. oBone Fracture [see Warnings and Precautions (5.12)]. oSexual 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical 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 paroxetine tablets are from:o6-week clinical trials in MDD patients who received paroxetine tablets 20 mg to 50 mg once dailyo12-week clinical trials in OCD patients who received paroxetine tablets 20 mg to 60 mg once dailyo10- to 12-week clinical trials in PD patients who received paroxetine tablets 10 mg to 60 mg once dailyo12-week clinical trials in SAD patients who received paroxetine tablets 20 mg to 50 mg once dailyo8-week clinical trials in GAD patients who received paroxetine tablets 10 mg to 50 mg once dailyo12-week clinical trials in PTSD patients who received paroxetine tablets 20 mg to 50 mg once daily. o6-week clinical trials in MDD patients who received paroxetine tablets 20 mg to 50 mg once daily. o12-week clinical trials in OCD patients who received paroxetine tablets 20 mg to 60 mg once daily. o10- to 12-week clinical trials in PD patients who received paroxetine tablets 10 mg to 60 mg once daily. o12-week clinical trials in SAD patients who received paroxetine tablets 20 mg to 50 mg once daily. o8-week clinical trials in GAD patients who received paroxetine tablets 10 mg to 50 mg once daily. o12-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 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 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 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 Paroxetine Tablets Treated Patients and Greater than Placebo) in MDD, OCD, PD, SAD, GAD, and PTSD TrialsWhere 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 times the incidence of placebo.MDDOCDPDSADGADPTSDParoxetineTablets%Placebo%ParoxetineTablets%Placebo%ParoxetineTablets%Placebo%ParoxetineTablets%Placebo%ParoxetineTablets%Placebo%ParoxetineTablets%Placebo%CNSSomnolence2.30.7-1.90.33.40.32.00.22.80.6Insomnia--1.701.30.33.10--Agitation1.10.5---Tremor1.10.3-1.701.00.2Anxiety---1.10--Dizziness--1.501.901.00.2--GastrointestinalConstipation-1.10--Nausea3.21.11.903.21.24.00.32.00.22.20.6Diarrhea1.00.3-Dry mouth1.00.3---Vomiting1.00.3-1.00--Flatulence1.00.3--OtherAsthenia1.60.41.90.42.50.61.80.21.60.2AbnormalEjaculationIncidence corrected for gender. 1.602.104.90.62.50.5--Sweating1.00.3-1.101.10.2--Impotence -1.50--LibidoDecreased1.00-- 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 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 MDD.Table 4: Adverse Reactions (>= 1% of Paroxetine Tablets-Treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDDBody System/Adverse ReactionParoxetine Tablets(n 421)%Placebo(n 421)%Body as WholeHeadache1817Asthenia156CardiovascularPalpitation31Vasodilation31DermatologicSweating112Rash21GastrointestinalNausea269Dry Mouth1812Constipation149Diarrhea128Decreased Appetite62Flatulence42Oropharynx DisorderIncludes mostly lump in throat and tightness in throat. 20Dyspepsia21MusculoskeletalMyopathy21Myalgia21Myasthenia10Nervous SystemSomnolence239Dizziness136Insomnia136Tremor82Nervousness53Anxiety53Paresthesia42Libido Decreased30Drugged Feeling21Confusion10RespirationYawn40Special SensesBlurred Vision41Taste Perversion20Urogenital SystemEjaculatory DisturbancePercentage corrected for gender. Mostly ejaculatory delay. 130Other Male Genital Disorders Includes anorgasmia, erectile difficulties, delayed ejaculation/orgasm, and sexual dysfunction, and impotence. 100Urinary Frequency31Urination DisorderIncludes mostly difficulty with micturition and urinary hesitancy. 30Female Genital Disorders Includes mostly anorgasmia and difficulty reaching climax/orgasm. 20 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 Paroxetine Tablets-Treated Patients and Greater than Placebo) in 10 to 12-Week Clinical Trials for OCD, PD, and SADBody System/Preferred TermObsessive Compulsive DisorderPanic DisorderSocial Anxiety DisorderParoxetineTablets(n 542)%Placebo(n 265)%Paroxetine Tablets(n 469)%Placebo(n 324)%Paroxetine Tablets(n 425)%Placebo(n 339)%Body as WholeAsthenia22141452214Abdominal Pain--43--Chest Pain32----Back Pain--32--Chills2121--Trauma----31CardiovascularVasodilation41----Palpitation20----DermatologicSweating9314692Rash32----GastrointestinalNausea23102317257Dry Mouth189181193Constipation1668552Diarrhea101012796Decreased Appetite937382Dyspepsia----42Flatulence----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 EjaculationPercentage corrected for gender. 231211281Dysmenorrhea----54Female Genital Disorder 309191Impotence 815051Urinary Frequency3120--Urination Impaired30----Urinary Tract Infection2121-- 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 Paroxetine Tablets-Treated Patients and Greater than Placebo) in to 12 Week Clinical Trials for GAD and PTSDa Body System/Preferred TermGeneralized Anxiety DisorderPosttraumatic Stress DisorderParoxetineTablets(n 735)%Placebo(n 529)%ParoxetineTablets(n 676)%Placebo(n 504)%Body as WholeAsthenia146124Headache714--Infection6354Abdominal Pain43Trauma65CardiovascularVasodilation3121DermatologicSweating6251GastrointestinalNausea205198Dry Mouth115105Constipation10253Diarrhea97115Decreased Appetite5163Vomiting3232Dyspepsia--53Nervous SystemInsomnia1181211Somnolence155165Dizziness6565Tremor5514Nervousness43--Libido Decreased9252Abnormal Dreams3Respiratory SystemRespiratory Disorder75--Sinusitis43--Yawn4-2<1Special SensesAbnormal Vision2131Urogenital SystemAbnormal EjaculationPercentage corrected for gender. 252132Female Genital Disorder 4151Impotence 4391 Dose Dependent Adverse Reactions. MDD A comparison of adverse reaction rates in fixed-dose study comparing paroxetine tablets 10 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 Paroxetine Tablets-Treated Patients and >= Twice the Rate of Placebo) (in Dose-Comparison Trial in the Treatment of MDDPlaceboParoxetine TabletsBody System/Preferred Termn 51%10 mgn 102%20 mgn 104%30 mgn 101%40 mgn 102%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 SystemAnxiety0.02.05.85.95.9Dizziness3.96.96.78.912.7Nervousness0.05.95.84.02.9Paresthesia0.02.91.05.05.9Somnolence7.812.718.320.821.6Tremor0.00.07.77.914.7Special SensesBlurred Vision2.02.92.92.07.8Urogenital SystemAbnormal Ejaculation0.05.86.510.613.0Impotence0.01.94.36.41.9Male Genital Disorders0.03.88.76.43.7. OCD In 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 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.. SAD In fixed-dose study comparing placebo and paroxetine tablets 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 paroxetine tablets to which patients were assigned.. GAD In fixed-dose study comparing placebo and paroxetine tablets 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 paroxetine tablets 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 Paroxetine Tablets in Clinical Trials of MDD, OCD, PD, SAD, GAD, and PTSDParoxetine TabletsPlacebon (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 1Paroxetine tablets 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 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 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 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.. 6.2Postmarketing Experience The following reactions have been identified during post approval use of paroxetine tablets. 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 paroxetine tablets were added to chronic metoprolol treatment.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of paroxetine tablets 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 paroxetine tablets.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 paroxetine tablets.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 Studies. There 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 Paroxetine 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 Paroxetine. Theophylline. Reports of elevated theophylline levels associated with paroxetine tablets 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 Populations. The impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3.The recommended starting dosage and maximum dosage of paroxetine tablets are 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) Figure 3. Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1Major Depressive Disorder The efficacy of paroxetine tablets 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, paroxetine tablets were 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. Paroxetine tablets were 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 paroxetine tablets for treatment of MDD in outpatients was demonstrated in randomized withdrawal study. Patients who responded to paroxetine tablets (HDRS total score <8) during an initial 8-week open-label treatment phase were then randomized to continue paroxetine tablets or placebo, for up to year. Patients treated with paroxetine tablets 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.. 14.2Obsessive Compulsive Disorder The effectiveness of paroxetine tablets 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 paroxetine tablets 20 mg, 40 mg, or 60 mg. Study demonstrated that daily doses of paroxetine tablets 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving doses of paroxetine tablets 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 paroxetine tablets 20 mg to 60 mg daily with clomipramine 25 mg to 250 mg daily or placebo). In this study, patients receiving paroxetine tablets 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)%ParoxetineTablets 20 mg(n 75)%ParoxetineTablets 40 mg(n 66)%ParoxetineTablets 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 paroxetine tablets for the treatment of OCD was established in long-term extension to Study 1. Patients who responded to paroxetine tablets during the 3-month double-blind phase and 6-month extension on open-label paroxetine tablets 20 mg to 60 mg daily were randomized to either paroxetine tablets or placebo in 6-month double-blind relapse prevention phase. Patients randomized to paroxetine tablets were statistically significantly less likely to relapse than placebo-treated patients.. 14.3Panic Disorder The effectiveness of paroxetine tablets 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, paroxetine tablets were 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 paroxetine tablets 10 mg, 20 mg, or 40 mg daily or placebo. statistically significant difference from placebo was observed only for the paroxetine tablets 40 mg daily group. At endpoint, 76% of patients receiving paroxetine tablets 40 mg daily were free of panic attacks, compared to 44% of placebo-treated patients.Study was 12-week flexible-dose study comparing paroxetine tablets 10 mg to 60 mg daily and placebo. At endpoint, 51% of paroxetine tablets-treated patients were free of panic attacks compared to 32% of placebo-treated patients.Study was 12-week flexible-dose study comparing paroxetine tablets 10 mg to 60 mg daily to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine tablets-treated patients showed reduction to or panic attacks compared to 14% of placebo-treated patients.In Studies and 3, the mean paroxetine tablets dose for completers at endpoint was approximately 40 mg daily.Long-term efficacy of paroxetine tablets in PD was demonstrated in an extension to Study 1. Patients who responded to paroxetine tablets during the 10-week double-blind phase and during 3-month double-blind extension phase were randomized to either paroxetine tablets 10 mg, 20 mg, or 40 mg daily or placebo in 3-month double-blind relapse prevention phase. Patients randomized to paroxetine tablets 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.. 14.4Social Anxiety Disorder The effectiveness of paroxetine tablets 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 paroxetine tablets 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 paroxetine tablets 20 mg to 50 mg daily and placebo. Paroxetine tablets 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 paroxetine tablets-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 paroxetine tablets- and placebo-treated patients, respectively.Study was 12-week study comparing fixed doses of paroxetine tablets 20 mg, 40 mg, or 60 mg daily with placebo. Paroxetine tablets 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 paroxetine tablets 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.. 14.5Generalized Anxiety Disorder The effectiveness of paroxetine tablets 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 paroxetine tablets 20 mg or 40 mg daily with placebo. Doses of paroxetine tablets 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 paroxetine tablets 40 mg daily dose compared to the 20 mg daily dose.Study was flexible-dose study comparing paroxetine tablets 20 mg to 50 mg daily and placebo. Paroxetine tablets demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score.A third study, flexible-dose study comparing paroxetine tablets 20 mg to 50 mg daily to placebo, did not demonstrate statistically significant superiority of paroxetine tablets 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 paroxetine tablets 20 mg to 50 mg daily, were randomized to continuation of paroxetine tablets 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 >= 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 >= 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 paroxetine tablets experienced statistically significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.. 14.6Posttraumatic Stress Disorder The effectiveness of paroxetine tablets 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 paroxetine tablets 20 mg or 40 mg daily to placebo. Doses of paroxetine tablets 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 paroxetine tablets 20 mg to 50 mg daily to placebo. Paroxetine tablets were 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 paroxetine tablets 20 mg to 50 mg daily to placebo, demonstrated paroxetine tablets 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 paroxetine tablets.Table 9: Clinically Significant Drug Interactions with Paroxetine TabletsMonoamine Oxidase Inhibitors (MAOIs)Clinical ImpactThe concomitant use of SSRIs, including paroxetine tablets, and MAOIs increases the risk of serotonin syndrome.InterventionParoxetine tablets are 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.InterventionParoxetine tablets are contraindicated in patients taking pimozide or thioridazine [see Contraindications (4)]. Other Serotonergic DrugsClinical ImpactThe concomitant use of serotonergic drugs with paroxetine tablets 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 paroxetine tablets 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 paroxetine tablets may potentiate the risk of bleeding.InterventionInform patients of the increased risk of bleeding associated with the concomitant use of paroxetine tablets 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 ImpactParoxetine tablets are highly bound to plasma protein. The concomitant use of paroxetine tablets with another drug that is highly bound to plasma protein may increase free concentrations of paroxetine tablets or other tightly-bound drugs in plasma. InterventionMonitor for adverse reactions and reduce dosage of paroxetine tablets or other protein-bound drugs as warranted.ExampleswarfarinDrugs Metabolized by CYP2D6Clinical ImpactParoxetine tablets are CYP2D6 inhibitor [see Clinical Pharmacology (12.3)]. The concomitant use of paroxetine tablets with CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.InterventionDecrease the dosage of CYP2D6 substrate if needed with concomitant paroxetine tablets use. Conversely, an increase in dosage of CYP2D6 substrate may be needed if paroxetine tablets are discontinued.Examplespropafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone.TamoxifenClinical ImpactConcomitant use of tamoxifen with paroxetine tablets 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 paroxetine tablets significantly decreased plasma levels of paroxetine tablets.InterventionAny dose adjustment should be guided by clinical effect (tolerability and efficacy).. oDrugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of paroxetine tablets or other protein-bound drugs (e.g., warfarin) as warranted. (7)oDrugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. (7)oConcomitant Use with Tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. (5.11, 7). oDrugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of paroxetine tablets or other protein-bound drugs (e.g., warfarin) as warranted. (7). oDrugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. (7). oConcomitant Use with Tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. (5.11, 7).