PROSAREX

Paroxetine tablets, USP contains paroxetine hydrochloride, an SSRI.

It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-).

• trans -4 R -(4'-fluorophenyl)-3 S -[(3',4' - methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the molecular formula of C 19 H 20 FNO 3 •HCl•1/2H 2 O. The molecular weight is 374.8 (329.4 as free base).

The structural formula of paroxetine hydrochloride is: Paroxetine hydrochloride, USP is an odorless, white to off-white crystalline powder, having a melting point range of 120°C to 138°C. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in dichloromethane and slightly soluble in water.

Paroxetine tablets are for oral administration.

Each film-coated tablet contains 10 mg, 20 mg, 30 mg, or 40 mg of paroxetine equivalent to 11.1 mg, 22.2 mg, 33.3 mg or 44.4 mg of paroxetine hydrochloride, respectively.

In addition, each tablet contains the following inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose 6 cP, lactose anhydrous, magnesium stearate, polyethylene glycol 6000, povidone, sodium starch glycolate, talc, and titanium dioxide.

• Major depressive episode.

• Obsessive Compulsive disorders.

• Panic disorder with or without agoraphobia.

• Disorder Social anxiety/Social phobia.

• Disorder Generalized anxiety.

• Post-Traumatic stress disorder.

The use of paroxetine should be initiated with caution 2 weeks after stopping irreversible or 24 hours after stopping reversible MAOI.

The dose of paroxetine should be increased gradually until optimal therapeutic response is obtained.

Paediatric population The use of

DEROXAT is not recommended in children and adolescents under 18 years of age.

Suicidal-type behaviours (suicidal and suicidal ideation attempts) and hostile-type behaviours (mainly aggressive, oppositional and anger behaviour) have been more frequently observed in clinical studies in children and adolescents treated with antidepressants compared to those treated with placebo.

If, in case of clinical necessity, the decision to treat is nevertheless made to increase the risk of a patient's serious suicide disorder, thus a controlled suicide disorder may be a serious suicide disorder.

The mechanism of action of paroxetine 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 a 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.

In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower C max or AUC than females.

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt.

In a 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 C max, T max, C min, and T ½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21 hours (CV 32%), respectively.

The steady-state C max and

C min values were about and 14 times what would be predicted from single-dose studies.

Steady-state drug exposure based on

AUC 0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects.

The excess accumulation is a consequence of the fact that of the enzymes that metabolizes paroxetine is readily saturable.

Paroxetine is equally bioavailable from the oral suspension and tablet.

The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food.

AUC was only slightly increased (6%) when drug was administered with food but the C max was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.

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.

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine.

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 a saturable metabolic pathway.

In comparison to

C min values after 20 mg daily, values after 40 mg daily were only about to 3 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.

Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).

Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 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.

There are clinically significant, known drug interactions between paroxetine and other drugs.

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 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.

CYP3A4 An in vivo interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics.

In addition, in vitro studies have shown ketoconazole, a 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, triazolam and cyclosporine.

Paroxetine's extent of inhibition of CYP3A4 activity is not expected to be of clinical significance.

The impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3.

The recommended starting dosage and maximum dosage of paroxetine is reduced in elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment.

Figure 3 Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale) Image Image Image.

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The following have been reported with paroxetine tablet overdosage: Seizures, which may be delayed, and altered mental status including coma.

Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation.

Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.

Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk).

Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a paroxetine overdose.

Consider contacting a Poison

Center or a medical toxicologist for additional overdosage management recommendations.

Paroxetine tablets are contraindicated in patients

Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome.

Taking thioridazine because of risk of QT prolongation Taking pimozide because of risk of QT prolongation.

With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients in paroxetine tablets.

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

Concomitant use of pimozide or thioridazine.

Known hypersensitivity to paroxetine or to any of the inactive ingredients in paroxetine tablets.

Recommended starting and maximum daily dosage for MDD, OCD, PD, and PTSD: Indication Starting Daily Dose Maximum Daily Dose MDD 20 mg 50 mg OCD 20 mg 60 mg PD 10 mg 60 mg PTSD 20 mg 50 mg Recommended starting dosage for SAD and GAD is 20 mg daily.

Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dosage is 10 mg daily.

Maximum dosage is 40 mg daily.

When discontinuing paroxetine tablets, reduce dosage gradually. 2.1 Administration Information Administer paroxetine tablets as a single daily dose in the morning, with or without food. 2.2 Recommended Dosage for MDD, OCD, PD, and PTSD The recommended starting dosages and maximum dosages of paroxetine tablets in patients with MDD, OCD, PD, and PTSD are presented in Table 1.

In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability.

Table 1 Recommended Daily Dosage of Paroxetine Tablets in Patients with MDD, OCD, PD, and PTSD Indication Starting Dose Maximum Dose MDD 20 mg 50 mg OCD 20 mg 60 mg PD 10 mg 60 mg PTSD 20 mg 50 mg 2.3 Recommended Dosage for SAD and GAD SAD The starting and recommended dosage in patients with SAD is 20 mg daily.

In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 mg to 60 mg daily.

While the safety of paroxetine tablets has been evaluated in patients with SAD at doses up to 60 mg daily, available information does not suggest any additional benefit for doses above 20 mg daily.

GAD The starting and recommended dosage in patients with GAD is 20 mg daily.

In clinical trials the effectiveness of paroxetine tablets in GAD was demonstrated in patients dosed in a range of 20 mg to 50 mg daily.

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

In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability. 2.4 Screen for Bipolar Disorder Prior to Starting Paroxetine Tablets Prior to initiating treatment with paroxetine tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania. 2.5 Recommended Dosage for Elderly Patients, Patients with Severe Renal Impairment, and Patients with Severe Hepatic Impairment The recommended initial dosage is 10 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment.

Dosage should not exceed 40 mg/day. 2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI) At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI and initiation of paroxetine tablets.

In addition, at least 14 days must elapse after stopping paroxetine before starting an MAOI antidepressant. 2.7 Discontinuation of Treatment With Paroxetine Tablets Adverse reactions may occur upon discontinuation of paroxetine tablets.

Gradually reduce the dosage rather than stopping paroxetine abruptly whenever possible.

USP, 20 mg are white to off-white, round-shaped, biconvex, film-coated tablets debossed with the logo of 'ZC, 16 and bisect' on one side and plain on other side, and are supplied as follows: NDC: 70518-3518-00 NDC: 70518-3518-01 NDC: 70518-3518-02 NDC: 70518-3518-03 NDC: 70518-3518-04 NDC: 70518-3518-06 PACKAGING: 100 in 1 BOTTLE PLASTIC PACKAGING: 30 in 1 BLISTER PACK PACKAGING: 100 in 1 BOX PACKAGING: 1 in 1 POUCH PACKAGING: 30 in 1 BOTTLE PLASTIC PACKAGING: 45 in 1 BOTTLE PLASTIC Store at 20°C to 25° C (68°F to 77° F) .

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Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage.

Paroxetine is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester.

While individual epidemiological studies on the association between paroxetine use and cardiac malformations have reported inconsistent findings, some meta-analyses of epidemiological studies have identified an increased risk of cardiovascular malformations.

There are risks of persistent pulmonary hypertension of the newborn (PPHN) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including paroxetine during pregnancy.

There also are risks associated with untreated depression in pregnancy.

For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options.

No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits.

These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 60 mg) on an mg/m2 basis.

When paroxetine was administered to female rats during the last trimester of gestation and continued through lactation, there was an increase in the number of pup deaths during the first four days of lactation.

This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis.

The background risks of major birth defects and miscarriage for the indicated populations are unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the

US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and/or embryofetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants.

This finding is from a prospective, longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy.

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum.

Use of paroxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

Fetal/Neonatal adverse reactions Neonates exposed to paroxetine and other SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding.

Such complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability and constant crying.

These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug discontinuation syndrome.

It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

Published epidemiological studies on the association between first trimester paroxetine use and cardiovascular malformations have reported inconsistent results; however, meta-analyses of population-based cohort studies published between 1996 – 2017 indicate a less than 2-fold increased risk for overall cardiovascular malformations.

Specific cardiac malformations identified in two meta-analyses include an approximately to 2.5-fold increased risk for right ventricular outflow tract defects.

One meta-analysis also identified an increased risk (less than 2-fold) for bulbus cordis anomalies and anomalies of cardiac septal closure, and an increased risk for atrial septal defect (pooled OR 2.38, 95% CI 1.14-4.97).

Important limitations of the studies included in these meta-analyses include potential confounding by indication, depression severity and potential exposure misclassification.

Exposure to

SSRIs, particularly later in pregnancy, may have an increased risk for PPHN.

PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality.

Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis.

These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD 60 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 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation.

The no-effect dose for rat pup mortality was not determined.

The cause of these deaths is not known.

The safety and effectiveness of paroxetine in pediatric patients have not been established.

Effectiveness was not demonstrated in three placebo-controlled trials in 752 paroxetine-treated pediatric patients with MDD.

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients.

Decreased appetite and weight loss have been observed in association with the use of SSRIs.

In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of pediatric patients treated with paroxetine and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self - harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.

Adverse reactions upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients and at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain.

In premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older.

Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; however, no overall differences in safety or effectiveness were observed between elderly and younger patients.

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