Paxil CR

Combined use of PAXIL CR and thioridazine is contraindicated due to a potential for elevated thioridazine plasma levels. Thioridazine treatment alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death (see Contraindications).

Chronic daily dosing with phenobarbital (100 mg qid for 14 days) decreased the systemic availability of a single 30 mg dose of paroxetine in some subjects. The AUC and T_½ of PAXIL IR were reduced by an average of 25% and 38% respectively compared to PAXIL IR administered alone. The effect of PAXIL CR or IR on phenobarbital pharmacokinetics was not studied. No initial PAXIL CR or IR dosage adjustment is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

The concomitant use of PAXIL CR or IR and alcohol has not been studied and is not recommended. Patients should be advised to avoid alcohol while taking PAXIL CR.

The metabolism and pharmacokinetics of PAXIL CR may be affected by the induction or inhibition of drug metabolizing enzymes.

Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when PAXIL CR is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, tramadol, or St. John's wort (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome). Concomitant use of PAXIL CR and MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated (see Contraindications).

In a study of depressed patients stabilized on lithium, no pharmacokinetic interaction between paroxetine and lithium was observed. However, due to the potential for serotonin syndrome, caution is advised when PAXIL CR is coadministered with lithium.

As with other SSRIs, PAXIL CR should be used with caution in patients already receiving antipsychotics/neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases have been reported with this combination (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine and other antidepressants can lead to reduced plasma concentrations of an active metabolite and hence potential for reduced efficacy of tamoxifen (see Warnings and Precautions, Potential for Reduced Efficacy of Tamoxifen with Concomitant SSRI use, Including PAXIL CR).

In a limited number of patients with epilepsy on long-term treatment with anticonvulsants (carbamazepine 600-900 mg/day, n=6; phenytoin 250-400 mg/day, n=6; sodium valproate 300-2500 mg/day, n=8) the coadministration of PAXIL IR (30 mg/day for 10 days) had no significant effect on the plasma concentrations of these anticonvulsants. In healthy volunteers, coadministration of paroxetine with phenytoin has been associated with decreased plasma levels of paroxetine and an increased incidence of adverse experiences. However, no initial dosage adjustment of PAXIL CR is considered necessary when the drug is to be coadministered with known drug metabolizing enzyme inducers (e.g. carbamazepine, phenytoin, sodium valproate) and any subsequent dosage adjustment should be guided by clinical effect. Coadministration of PAXIL CR with anticonvulsants may be associated with an increased incidence of adverse experiences.

PAXIL IR has been reported to increase significantly the systemic bioavailability of procyclidine. Steady state plasma levels of procyclidine (5 mg daily) were elevated by about 40% when 30 mg paroxetine was coadministered to steady-state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.

A multiple dose study of the interaction between PAXIL IR and diazepam showed no alteration in the pharmacokinetics of PAXIL IR that would warrant changes in the dose of PAXIL CR for patients receiving both drugs. The effects of PAXIL IR or CR on the pharmacokinetics of diazepam were not evaluated.

Tryptophan can be metabolized to serotonin. As with other serotonin reuptake inhibitors, the use of PAXIL CR together with tryptophan may result in adverse reactions consisting primarily of headache, nausea, sweating and dizziness as well as serotonin syndrome. Consequently, concomitant use of PAXIL CR with tryptophan is not recommended (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Combined use of PAXIL CR and monoamine oxidase inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Contraindications and Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

An in vivo interaction study involving the coadministration under steady state conditions of PAXIL and terfenadine, a substrate for CYP3A4, revealed no effect of PAXIL 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, astemizole, cisapride, triazolam and cyclosporin. Based on the assumption that the relationship between paroxetine's in vitro Ki and its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity would not be expected to be of clinical significance.

Like some other selective serotonin re-uptake inhibitors, paroxetine inhibits the specific hepatic cytochrome P450 isozyme CYP2D6 which is responsible for the metabolism of debrisoquine and sparteine. Poor metabolizers of debrisoquine/sparteine represent approximately 5-10% of Caucasians. The median C_min (ss) for PAXIL (20 mg daily) at steady state in poor metabolizers (n=8) was almost triple that reported for extensive metabolizers (n=9). Although the full clinical significance of this effect has not been established, inhibition of CYP2D6 can lead to elevated plasma levels of coadministered drugs which are metabolized by this isozyme. Consideration should be given to decreasing the dose of the CYP2D6 metabolized drug or paroxetine and/or monitoring of drug plasma levels, especially when PAXIL is coadministered with drugs with a narrow therapeutic index.

PAXIL CR coadministration has been associated with elevated levels of the anticholinergic procyclidine, certain neuroleptics/antipsychotics (e.g., perphenazine, risperidone), tricyclic antidepressants (e.g., desipramine), atomoxetine, type 1C antiarrhythmics (e.g., propafenone), and theophylline.

Coadministration of phenobarbitol or phenytoin with PAXIL CR has been associated with decreased levels of PAXIL CR or IR. When coadministered with cimetidine, PAXIL CR levels were elevated.

The concomitant use of PAXIL CR and alcohol has not been studied.

In an open label study of healthy volunteers, coadministration of a single dose of 2 mg pimozide, under steady state conditions of PAXIL (titrated to 60 mg daily) was associated with mean increases in pimozide AUC of 151% and C_max of 62%, compared to pimozide administered alone. This is likely explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, and produce severe cardiac arrhythmias including torsades de pointes, concomitant use of pimozide and PAXIL CR is contraindicated (see Contraindications).

Multiple dose treatment with PAXIL IR 30 mg/day has little or no effect on the steady-state pharmacokinetics of digoxin (0.25 mg qd) or propanolol (80 mg bid).

Paroxetine is highly bound to plasma protein, therefore administration of PAXIL CR to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.

At steady state, the bioavailability of 25 mg PAXIL CR is not affected by food.

In two studies, daily dosing of PAXIL (20 mg qd) under steady state conditions increased the following mean pharmacokinetic parameters for a single (100 mg) dose of desipramine in extensive metabolizers: C_max (2 fold), AUC (6 fold), and T_½ (3-5 fold). Concomitant steady-state PAXIL treatment did not result in any further impairment of desipramine elimination in poor metabolizers. Insufficient information is available to provide recommendations on the necessary dosage adjustments for tricyclic antidepressants or PAXIL CR, if these drugs are to be used in combination. Plasma tricyclic antidepressant concentrations may need to be monitored in such instances.

Concomitant use of PAXIL CR with other drugs metabolized by CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either PAXIL CR or the other drug. Drugs metabolized by CYP2D6 include certain tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), selective serotonin reuptake inhibitors (e.g. fluoxetine), phenothiazine neuroleptics (e.g. perphenazine), risperidone, atomoxetine, Type IC antiarrhythmics (e.g. propafenone and flecainide), and metoprolol. Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, PAXIL CR and thioridazine should not be coadministered (see Contraindications).

Coadministration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine (by ~60% in one study). Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Interactions with laboratory tests have not been established.

St. John's wort: In common with other SSRIs, pharmakodynamic interactions between paroxetine and the herbal remedy St. John's wort may occur and may result in an increase in undesirable effects.

Reports of elevated theophylline levels associated with PAXIL treatment have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.

Experience in a limited number of healthy subjects has shown that PAXIL IR does not increase the sedation and drowsiness associated with haloperidol, amylbarbitone or oxazepam, when given in combination. Since the effects of concomitant administration of PAXIL CR or IR with neuroleptics have not been studied, the use of PAXIL CR with these drugs should be approached with caution.

Coadministration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine (by ~60% in one study). Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Steady state levels of PAXIL (30 mg daily) were elevated by about 50% when cimetidine (300 mg tid), a known drug metabolizing enzyme inhibitor, was coadministered to steady-state. Consideration should be given to using doses of PAXIL CR towards the lower end of the range when coadministered with known drug metabolizing enzyme inhibitors.

There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and the 5HT₁ agonist, sumatriptan. If concomitant treatment with triptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised. The possibility of such interactions should also be considered if other 5HT₁ agonists are to be used in combination with SSRIs (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Symptoms associated with the discontinuation of PAXIL IR and PAXIL CR have been reported in clinical trials and post marketing. Patients should be monitored for these and other symptoms when discontinuing treatment, regardless of the indication for which PAXIL CR is being prescribed. (See Warnings and Precautions, Discontinuation of Treatment with PAXIL CR and Adverse Reactions, Adverse Events following Discontinuation of Treatment (or Dose Reduction).)

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. (See Adverse Reactions.)

PAXIL CR is not indicated for use in children under 18 years of age (see Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

Lower initial doses of PAXIL CR are recommended for elderly and debilitated patients, and patients with renal or hepatic impairment (see Dosage and Administration, Special Patient Populations).

PAXIL CR should be administered as a single daily dose, usually in the morning, with or without food. Patients should be cautioned that the PAXIL CR tablet should not be chewed or crushed, and should be swallowed whole.

PAXIL CR should be used with caution in patients with renal or hepatic impairment. The recommended initial dose is 12.5 mg/day in patients with clinically significant renal or hepatic impairment. A maximum dose of 50 mg/day should not be exceeded (see Warnings and Precautions and Action and Clinical Pharmacology).

Administration of PAXIL CR to the elderly is associated with increased plasma levels and prolongation of the elimination half-life relative to younger adults. (See Action and Clinical Pharmacology.) The recommended initial dose of PAXIL CR is 12.5 mg/day for elderly patients and debilitated patients. The dose may be increased if indicated up to a maximum of 50 mg/day.

Usual Initial Dosage: Patients should be started on 12.5 mg/day. Dose changes should occur in 12.5 mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 12.5 to 75 mg/day in the clinical trials demonstrating the effectiveness of PAXIL CR. The maximum dosage should not exceed 75 mg/day.

Maintenance Therapy: Panic disorder is a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Usual Initial Dosage: In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be effective with continuous dosing, or intermittent luteal phase dosing.

The recommended dose is 12.5 mg/day limited to the luteal phase of the menstrual cycle, starting 14 days prior to the expected onset of menses, and terminating on the first day of menses. Some patients not responding to a 12.5 mg dose may benefit from a dose increase to 25 mg/day. Dose changes should occur at intervals of at least 1 week. Continuous dosing of PAXIL CR, administered daily throughout the menstrual cycle may be considered if efficacy with luteal phase dosing is sub-optimal. Dose changes should occur at intervals of at least 1 week.

Maintenance/Continuation Therapy: The effectiveness of PAXIL CR in long-term use, that is, for more than 3 menstrual cycles has not been evaluated in controlled trials. Therefore, the physician who elects to use PAXIL CR for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

PAXIL CR is not indicated for use in children under 18 years of age (see Indications and Clinical Use and Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

Usual Initial Dosage: The recommended initial dose is 25 mg/day. Patients were dosed in a range of 25 mg to 62.5 mg/day in the clinical trials demonstrating the effectiveness of PAXIL CR in the treatment of depression. As with all drugs effective in the treatment of depression, the full effect may be delayed. Some patients not responding to a 25 mg dose may benefit from dose increases, in 12.5 mg/day increments, up to a maximum of 62.5 mg/day. Dose changes should occur at intervals of at least 1 week.

Maintenance Therapy: There is no body of evidence available to answer the question of how long a patient should continue to be treated with PAXIL CR for the symptoms of panic and depression. It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Whether the dose of an antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Systematic evaluation of the efficacy of PAXIL IR has shown that efficacy is maintained for at least 6 months with doses that averaged about 30 mg, which corresponds to a 37.5 mg dose of PAXIL CR, based on relative bioavailability considerations.

Epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. If a patient becomes pregnant while taking PAXIL CR, she should be informed of the current estimate of risk to the fetus (see Warnings and Precautions, Special Populations) and consideration should be given to switching to other treatment options. Treatment with PAXIL CR should only be continued for an individual patient, if the potential benefits outweigh the potential risks. For women who intend to become pregnant, or are in their first trimester of pregnancy, initiation of paroxetine should be considered only after other treatment options have been evaluated (see Warnings and Precautions, Special Populations for more details).

Post-marketing reports indicate that some neonates exposed to PAXIL CR, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see Warnings and Precautions, Special Populations). When treating pregnant women with PAXIL CR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering PAXIL CR in the third trimester.

Usual Initial Dosage: The recommended initial dose is 12.5 mg/day. In the clinical trial demonstrating the effectiveness of PAXIL CR in the treatment of social anxiety disorder, patients were dosed in a range of 12.5 mg to 37.5 mg/day. Some patients not responding to a 12.5 mg dose may benefit from dose increases, in 12.5 mg/day increments, up to a maximum of 37.5 mg/day. Dose changes should occur at intervals of at least 1 week.

Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with PAXIL CR should remain on it. Although the efficacy of PAXIL CR beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Depression: The most commonly observed adverse events associated with the use of PAXIL CR in a pool of two trials (incidence of 5.0% or greater and incidence for PAXIL CR at least twice that for placebo, derived from Table 2) were: abnormal ejaculation, abnormal vision, constipation, decreased libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma, tremor, and yawning. Using the same criteria, the adverse events associated with the use of PAXIL CR in a study of elderly patients with depression were: abnormal ejaculation, constipation, decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor.

Panic Disorder: In the pool of panic disorder studies, the adverse events meeting these criteria were: abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating, and female genital disorders (generally anorgasmia or difficulty achieving orgasm).

Social Anxiety Disorder: The most commonly observed adverse events associated with the use of PAXIL CR (incidence of 5.0% or greater and incidence for PAXIL CR at least twice that for placebo, derived from Table 5) in the social phobia (social anxiety disorder) study were nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence, insomnia, and libido decreased.

Premenstrual Dysphoric Disorder: The most commonly observed adverse events associated with the use of PAXIL CR, either during continuous dosing or luteal phase dosing (incidence of 5.0% or greater and incidence for PAXIL CR at least twice that for placebo, derived from Table 6) were: nausea, asthenia, libido decreased, somnolence, insomnia, female genital disorders, sweating, dizziness, diarrhea and constipation.

In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day of PAXIL CR limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the 3 off-drug phases were combined, the following adverse events were reported at an incidence of 2% or greater for PAXIL CR and were at least twice the rate of that reported for placebo: infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%), sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%).

Adverse events not listed above which have been reported since market introduction in patients taking immediate-release paroxetine hydrochloride include acute pancreatitis, hepatic events such as elevation of hepatic enzymes, and hepatitis, sometimes associated with jaundice, and/or liver failure (in very rare circumstances, with fatal outcomes), Guillain-Barré syndrome, toxic epidermal necrolysis, priapism, thrombocytopenia, aggravated hypertension, syndrome of inappropriate ADH secretion, symptoms suggestive of hyperprolactinemia and galactorrhea, blurred vision, extrapyramidal symptoms which have included akathisia, (characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress), bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide, tremor and trismus, neuroleptic malignant syndrome-like events; serotonin syndrome (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome), persistent pulmonary hypertension (PPHN; see also Warnings and Precautions, Pregnant Women and Newborns, Risk of PPHN and Exposure to SSRIs (including paroxetine)). There has been a case report of an elevated phenytoin level after 4 weeks of PAXIL IR and phenytoin coadministration. There has been a case report of severe hypotension when PAXIL IR was added to chronic metoprolol treatment. The causal relationship between PAXIL IR and the emergence of these events has not been established.

There have been spontaneous reports of adverse events upon the discontinuation of PAXIL CR and other selective serotonin reuptake inhibitors (particularly when abrupt) (see Warnings and Precautions, General, Discontinuation of Treatment with PAXIL CR and Adverse Reactions, Adverse Events following Discontinuation of Treatment (or Dose Reduction)).

Infrequent were bruxism, dysphagia, eructation, gastritis, gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function tests abnormal, melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis, glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction, peptic ulcer, stomach ulcer, throat tightness; also observed were aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue edema.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Clinically and statistically relevant increases in cholesterol levels have been noted in studies using paroxetine (see Warnings and Precautions, Endocrine and Metabolism).

Of the patients in placebo-controlled clinical trials for whom baseline and on-treatment measurements were taken, total serum levels of cholesterol showed a mean increase of ~1.5 mg/dL in n=653 paroxetine-treated patients, compared to a mean decrease of ~5.0 mg/dL in placebo-treated patients (n=379). Increases from baseline of 45 mg/dL or greater were recorded in 6.6% of paroxetine-treated patients compared to 2.6% of placebo-treated patients.

The information included under the “Adverse Events Leading to Discontinuation of Treatment” subsection of Adverse Reactions is based on data from seven short-term placebo-controlled clinical trials. Three of these studies were conducted in patients with depression, three studies were done in patients with panic disorder, and one study was conducted in patients with social anxiety disorder. Two of the studies in depression, which enrolled patients in the age range 18 to 65 years, are pooled. Information from a third study of depression, which focussed on elderly patients (ages 60 to 88), is presented separately as is the information from the panic disorder studies and the information from the social anxiety disorder study. Information on additional adverse events associated with PAXIL CR and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection (see Other Events Observed During the Clinical Development of Paroxetine).

Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis, photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss.

Frequent were increases in cholesterol levels. Infrequent were generalized edema, hyperglycemia, hyperkalemia, hypokalemia, peripheral edema, AST increased, ALT increased, thirst; rare were billirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased, gout, hypercalcemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.

Frequent were rash; infrequent were acne, alopecia, dry skin, eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash, seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash.

Infrequent were arthritis, bursitis, tendonitis; rare were myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis, tenosynovitis, tetany.

Infrequent were, chills, face edema, fever, flu syndrome, malaise; rare were abscess, anaphylactoid reaction, anticholinergic syndrome, hypothermia; also observed were adrenergic syndrome, neck rigidity, sepsis.

There have been spontaneous reports of adverse events upon the discontinuation of PAXIL and PAXIL CR (particularly when abrupt), including but not limited to the following: dizziness, sensory disturbances (including paresthesias, electric shock sensations and tinnitus), agitation/restlessness, anxiety, nausea, tremor, confusion, diarrhea, vomiting, sweating, headache, and sleep disturbances (abnormal dreams). Generally these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors.

Patients should be monitored for these or any other symptoms when discontinuing treatment. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Warnings and Precautions and Dosage and Administration).

Adverse events while discontinuing therapy with PAXIL CR were not systematically evaluated in most clinical trials; however, in one placebo-controlled clinical trial in social anxiety disorder involving 370 patients (186 on PAXIL CR and 184 on placebo), utilizing daily doses of PAXIL CR up to 37.5 mg/day, spontaneously reported adverse events while discontinuing therapy with PAXIL CR were evaluated. Patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose by 12.5 mg/day to a dose of 25 mg/day for 1 week before treatment was stopped. For patients receiving 25 mg/day or 12.5 mg/day, treatment was stopped without an incremental decrease in dose. With this regimen, the following adverse events were reported at an incidence of 2% or greater for PAXIL CR and were at least twice that reported for placebo: dizziness (13.9% versus 2.2%), insomnia (4.4% versus 2.2%), paresthesia (4.4% versus 0%) vertigo (3.3% versus 0%), and additional symptoms described by the investigator as associated with tapering or discontinuing PAXIL CR including electric shock sensations (5.6% versus 0.6%), including electric shock sensations. These events were reported as serious in 1.7% (3/180) of patients who discontinued therapy with PAXIL CR.

The following adverse events have been reported at an incidence of 2% or greater for PAXIL IR and were at least twice that reported for placebo: abnormal dreams (2.3% vs 0.5%), paresthesias (2.0% vs 0.4%), and dizziness (7.1% vs 1.5%). The majority of these events were mild to moderate, self-limiting and did not require medical intervention. These adverse events were noted in GAD and PTSD clinical trials employing a taper phase regimen for discontinuation of treatment. This regimen involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped.

In placebo-controlled clinical trials conducted with pediatric patients aged 7 to 18 years with depression, OCD and Social Anxiety Disorder (involving 633 patients treated with paroxetine and 542 patients treated with placebo), the following adverse events were reported in at least 2% of pediatric patients treated with PAXIL IR 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, (predominantly aggression, oppositional behaviour and anger) decreased appetite, tremor, sweating, hyperkinesia, and agitation.

In the pediatric clinical trials in depression, OCD and Social Anxiety Disorder that included a taper phase regimen (307 patients aged 7 to 18 years treated with paroxetine and 291 patients treated with placebo), events reported upon discontinuation of treatment, which occurred in at least 2% of patients who received PAXIL IR and which occurred 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 (see Warnings and Precautions, Discontinuation of Treatment with PAXIL CR).

Infrequent were angina pectoris, bradycardia, bundle branch block, hematoma, hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia, syncope ; rare were bundle branch block; also observed were arrhythmia nodal, atrial fibrillation, cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles.

The following adverse events were reported during the clinical development of PAXIL CR tablets and/or the clinical development of the immediate-release formulation of paroxetine.

Adverse events for which frequencies are provided below occurred in clinical trials with the controlled release formulation of paroxetine. During its premarketing assessment in depression, panic disorder, social anxiety disorder, and PMDD, multiple doses of PAXIL CR were administered to 1627 patients in phase 3 double-blind, controlled, outpatient studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of the 1627 patients exposed to PAXIL CR controlled release who experienced an event of the type cited on at least one occasion while receiving PAXIL CR. All reported events are included except those already listed in Table 2, Table 3, Table 4, Table 5 or Table 6 and those events where a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was deleted or, when possible, replaced with a more informative term. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Adverse events for which frequencies are not provided occurred during the premarketing assessment of immediate-release paroxetine in phase 2 and 3 studies of depression, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to immediate-release paroxetine varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. Only those events not previously listed for controlled release paroxetine are included. The extent to which these events may be associated with PAXIL CR is unknown.

Events are listed alphabetically within the respective body system. Events of major clinical importance are also described in Warnings and Precautions.

Infrequent were, ovarian cyst, testes pain; rare were diabetes mellitus, hyperthyroidism; also observed were, goiter, hypothyroidism, thyroiditis.

Frequent were depression; infrequent were amnesia, convulsion, depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis, vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis, withdrawal syndrome; also observed were abnormal gait, akathisis, akinesia, aphasia, choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction, manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic depression, reflexes decreased, reflexes increased, stupor, trismus.

There are no adequate, controlled studies examining sexual dysfunction with paroxetine treatment.

Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Frequent were dysmennorhea{*Based on the number of men and women as appropriate.}; infrequent were albuminuria, amenorrhea*, breast pain*, cystitis, dysuria, prostatitis*, urinary retention; rare were breast enlargement, breast neoplasm*, female lactation, hematuria, kidney calculus, metorrhagia, nephritis, nocturia, pregnancy and puerperal disorders*, salpingitis, urinary incontinence, uterine fibroids enlarged*; also observed were breast atrophy, ejaculatory disturbance, endometrial disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria, urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage.

Three percent (5/186) of patients treated with PAXIL CR in the social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the above criteria included the following:

Frequent were pharyngitis; infrequent were asthma, dyspnea, epistaxis, laryngitis, pneumonia; rare were stridor; also observed were dysphonia, emphysema, hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum increased.

Eleven percent (50/444) of PAXIL CR patients in panic disorder studies discontinued treatment due to an adverse event. Events meeting the above criteria included the following:

A comparison of adverse event rates in a fixed-dose study comparing immediate-release paroxetine with placebo in the treatment of depression revealed a clear dose dependency for some of the more common adverse events associated with the use of immediate-release paroxetine.

Ten percent (21/212) of PAXIL CR patients discontinued treatment due to an adverse event in a pool of two studies of patients with depression. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for PAXIL CR compared to placebo) included the following:

In a placebo-controlled study of elderly patients with depression, 13% (13/104) of PAXIL CR patients discontinued due to an adverse event. Events meeting the above criteria included the following:

Infrequent were anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare were thrombocytopenia; also observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis, lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia.

Evidence from clinical studies indicates that there are differences in the pharmacokinetic profile of paroxetine in the geriatric population relative to younger adults, which may be associated with differences in safety or effectiveness. A brief discussion can be found in the appropriate sections (see Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age); Action and Clinical Pharmacology and Dosage and Administration).

The effectiveness of PAXIL CR in long-term use (i.e. more than 12 weeks for depression, panic disorder and social phobia and more than 3 menstrual cycles for premenstrual dysmorphic disorder) has not yet been established in controlled trials for depression, panic disorder, social phobia or premenstrual dysmorphic disorder. The physician who elects to use PAXIL CR for extended periods in these indications should periodically re-evaluate the long-term usefulness of the drug for individual patients (see Dosage and Administration).

PAXIL CR is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

PAXIL CR is indicated for the symptomatic treatment of panic disorder, with or without agoraphobia.

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

PAXIL CR is indicated for the symptomatic treatment of premenstrual dysphoric disorder (PMDD). The efficacy of PAXIL CR in the treatment of PMDD was established in 3 placebo-controlled trials.

The essential features of PMDD, according to DSM-IV, include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur regularly, in most menstrual cycles, during the luteal phase and remit within a few days following the onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. Typically, the symptoms are comparable in severity (but not duration) to those of a major depressive episode. The presence of the cyclical pattern of symptoms must be confirmed by at least two consecutive months of prospective daily symptom ratings. It is estimated that at least 75% of women report minor or isolated premenstrual changes; however, only 3 to 5% of women experience symptoms that may meet the criteria for PMDD. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.

PAXIL CR (paroxetine hydrochloride) is indicated for symptomatic relief of Major Depressive Disorder.

PAXIL CR has not been systematically evaluated beyond 12 weeks in controlled clinical trials; however, the effectiveness of immediate release paroxetine hydrochloride in maintaining a response in depression for at least 6 months has been demonstrated in a placebo controlled trial. The physician who elects to use PAXIL CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

PAXIL CR is indicated for the symptomatic relief of generalized social phobia (social anxiety disorder), a disorder characterized by marked and persistent fear, anxious anticipation, or avoidance of multiple social situations (e.g. interacting with strangers, attending social gatherings, dealing with authority figures) and/or performance situations (e.g. eating, writing, working while being observed, or public speaking). A diagnosis of social phobia/social anxiety disorder should not be made unless the fear, anxious anticipation, or avoidance of social and/or performance situations interferes significantly with the person's normal routine, occupational functioning, or social life, or causes marked distress.

The most commonly reported adverse events subsequent to paroxetine-only overdose include: somnolence, nausea, tremor, dizziness, vomiting, diarrhea, agitation, aggression, anxiety, confused state, headache, fatigue, insomnia, tachychardia, hyperhydrosis, mydriasis, convulsion, paraethesia, serotonin syndrome, fever, blood pressure changes, involuntary muscle contraction and loss of consciousness. It should be noted that in some cases, patients may have consumed alcohol in addition to taking an overdose of paroxetine. Some of these symptoms may also be seen with clinical use.

Events such as coma and ECG changes have also been reported.

The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

No specific antidote is known. Treatment should consist of those general measures employed in the management of overdose with any antidepressant. Establish and maintain an airway; ensure adequate oxygenation and ventilation.

Activated charcoal effectively prevents gastrointestinal absorption of paroxetine, and should be considered as the primary means to reduce paroxetine exposure. It is most effective when administered within one hour of ingestion; usual dose is 25 to 100 grams in adults as an aqueous slurry. During the first 24 hours after ingestion of the overdose, 20 to 30 grams of activated charcoal may be administered every 4 to 6 hours. Due to the large volume of distribution of PAXIL CR, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.

Supportive care with frequent monitoring of vital signs and careful observation is indicated. An ECG should be taken and monitoring of cardiac function instituted if there is any evidence of abnormality.

In managing overdosage, consider the possibility of multiple drug involvement.

A specific caution involves patients taking or recently having taken PAXIL CR who might ingest by accident or intent excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation.

Each yellow, round and biconvex, enteric, film-coated, controlled-release tablet, with the product name engraved on one side and strength engraved on the other side, contains: paroxetine HCl equivalent to paroxetine 12.5 mg. Nonmedicinal ingredients: colloidal silicon dioxide, D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, glyceryl behenate, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type C, polyethylene glycol, polysorbate 80, polyvinylpyrrolidone, sodium lauryl sulphate, talc, titanium dioxide, triethyl citrate and yellow ferric oxide. Bottles of 30.

Each pink, round and biconvex, enteric, film-coated, controlled-release tablet, with the product name engraved on one side and strength engraved on the other side, contains: paroxetine HCl equivalent to paroxetine 25 mg. Nonmedicinal ingredients: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake, glyceryl behenate, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type C, polyethylene glycol, polysorbate 80, polyvinylpyrrolidone, red ferric oxide, sodium lauryl sulphate, talc, titanium dioxide and triethyl citrate. Bottles of 30.

Post-marketing reports indicate that some neonates exposed to PAXIL CR, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants 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 a direct toxic effect of SSRIs and other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome). When treating a pregnant woman with PAXIL CR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage and Administration, Special Patient Populations, Treatment of Pregnant Women during the third trimester).

There have been post-marketing reports of premature birth in pregnant women exposed to paroxetine or other SSRIs. The casual relationship between PAXIL CR and the emergence of these events has not been established.

Of the patients in placebo-controlled clinical trials for whom baseline and on-treatment measurements were taken, increases from baseline of 45 mg/dL or greater were recorded in 6.6% of paroxetine-treated patients compared to 2.6% of placebo-treated patients (see Adverse Reactions, Laboratory Changes—Cholesterol and Warnings and Precautions, Endocrine and Metabolism).

These data should be taken into consideration when treating patients with underlying cardiac risk factors.

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment of PAXIL CR, particularly when given in combination with other serotonergic and/or neuroleptic/antipsychotic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with PAXIL CR should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome PAXIL CR should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (triptans, lithium, tramadol, St. John's wort, most tricyclic antidepressants) or neuroleptics/antipsychotics (see Contraindications and Drug Interactions).

There have been several reports of abnormal bleeding (mostly ecchymosis) associated with paroxetine IR treatment, including a report of impaired platelet aggregation. While a causal relationship to paroxetine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences.

Skin and mucous membrane bleedings (including upper gastrointestinal bleeding) have been reported following treatment with paroxetine IR. Paroxetine CR should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding (e.g. anticoagulants, nonsteroidal anti-inflammatories and ASA) and in patients with a known tendency for bleeding or those with predisposing conditions.

As with other antidepressants, PAXIL CR should be used with caution in patients with epilepsy.

The antitumor agent tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 can lead to reduced plasma concentrations of a primary active metabolite (endoxifen). Chronic use of CYP2D6 inhibitors, including certain SSRIs, together with tamoxifen can lead to persistent reduction in levels of endoxifen (see also Drug Interactions, Tamoxifen). The clinical significance of this in terms of efficacy of tamoxifen is unclear.

PAXIL CR or PAXIL IR has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PAXIL CR.

In one epidemiological case-control study on persistent pulmonary hypertension (PPHN) with n=377 infants with PPHN and n=836 matched control infants, PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of pregnancy compared to babies whose mothers did not take an antidepressant. The study was too small to determine relative risks among the specific SSRIs. This information is considered to be preliminary at this time. The absolute risk of PPHN in the general population is reported to be 1-2 per 1000 (see Adverse Reactions, Post-Market Adverse Drug Reactions).

The efficacy and safety of the concurrent use of PAXIL CR and ECT have not been studied.

Clinical experience with PAXIL CR or PAXIL IR in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using PAXIL CR in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

PAXIL CR is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm). See also Indications, Pediatrics (<18 years of age) and Dosage and Administration, Special Patient Populations, Pediatrics).

Controlled clinical studies in depression failed to demonstrate efficacy and do not support the use of paroxetine in the treatment of children under the age of 18 years with depression. Moreover, a higher incidence of adverse events related to behavioral and emotional changes, including self harm, was reported with paroxetine treatment compared to placebo during controlled clinical trials in depression, OCD and social anxiety disorder (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Pediatrics).

Epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is approximately 1/50 (2%), compared with an expected rate for such defects of approximately 1/100 (1%) infants in the general population. In general, septal defects range from those that are symptomatic and may require surgery, to those that are asymptomatic and may resolve spontaneously. Information about the severity of the septal defects reported in the studies is not available.

Pharmacokinetic studies of PAXIL IR in subjects with clinically significant hepatic impairment suggest that prolongation of the elimination half-life and increased plasma levels can be expected in this patient group. PAXIL CR should be used with caution and dosages restricted to the lower end of the range in patients with clinically significant hepatic impairment (see Dosage and Administration, Special Patient Populations and Actions and Clinical Pharmacology, Hepatic Insufficiency).

During clinical testing in a patient population comprised primarily of unipolar depressed patients, approximately 1% of PAXIL IR-treated patients experienced manic reactions. When bipolar patients were considered as a sub-group the incidence of mania was 2%. As with all drugs effective in the treatment of depression, PAXIL CR should be used with caution in patients with a history of mania.

A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.

Administration of PAXIL CR to the elderly is associated with increased plasma levels and prolongation of the elimination half-life relative to younger adult (see Action and Clinical Pharmacology). Elderly patients should be initiated and maintained at the lowest daily dose of paroxetine which is associated with clinical efficacy (see Dosage and Administration).

Evaluation of approximately 800 elderly patients (≥65 years) treated with PAXIL IR (10-40 mg daily) in worldwide premarketing clinical trials revealed no unusual pattern of adverse events relative to the clinical experience in younger patients.

In a controlled study focusing specifically on elderly patients with depression, PAXIL CR ( 12.5-50 mg daily) was demonstrated to be safe and effective in the treatment of elderly patients (>60 years of age) with depression. (See Adverse Reactions, Table 3.) However, it is not possible to rule out potential age-related differences in safety and effectiveness during chronic use, particularly in elderly patients who have concomitant systemic illnesses or who are receiving concomitant drugs.

Patients currently taking PAXIL CR should not be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

Although paroxetine did not cause sedation or interfere with psychomotor performance in placebo-controlled studies in normal subjects, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that PAXIL CR does not affect them adversely.

The following additional precautions are listed alphabetically.

Since PAXIL CR is extensively metabolized by the liver, excretion of unchanged drug in urine is a minor route of elimination. However, single dose pharmacokinetic studies in subjects with clinically significant renal impairment suggest that plasma levels of paroxetine are elevated in such subjects. Paroxetine should therefore be used with caution and the dosage restricted to the lower end of the range in patients with clinically significant renal impairment (see Dosage and Administration, Special Patient Populations and Actions and Clinical Pharmacology, Renal Insufficiency).

When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation [e.g. dizziness, sleep disturbances including abnormal dreams, sensory disturbances (including paresthesias electric shock sensations and tinnitus), agitation, anxiety, headache, tremor, confusion, diarrhea, nausea, vomiting and sweating] or other symptoms which may be of clinical significance [see Adverse Reactions, Adverse Events following Discontinuation of Treatment (or Dose Reduction), Post-Marketing]. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. (See Adverse Reactions and Dosage and Administration.)

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer antidepressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when PAXIL IR was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.

Epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. If a patient becomes pregnant while taking PAXIL CR, consideration should be given to switching to other treatment options. Treatment with PAXIL CR should only be continued for an individual pregnant patient, if the potential benefits outweigh the potential risks. Initiation of paroxetine, for women who intend to become pregnant, or are in their first trimester of pregnancy, should be considered only after other treatment options have been evaluated (see Warnings and Precautions, Special Populations).

Post-marketing reports indicate that some neonates exposed to PAXIL CR, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. When treating a pregnant woman with PAXIL CR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Warnings and Precautions, Special Populations and Dosage and Administration, Special Patient Populations, Treatment of Pregnant Women during the third trimester).

During clinical trials, the overall incidence of seizures was 0.15% in patients treated with PAXIL IR. However, patients with a history of convulsive disorders were excluded from these studies. Caution is recommended when the drug is administered to patients with a history of seizures. The drug should be discontinued in any patient who develops seizures.

As with other SSRIs, PAXIL CR can cause mydriasis and should be used with caution in patients with narrow angle glaucoma.

The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications. Not withstanding, high risk patients should be closely supervised throughout therapy with appropriate consideration to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescriptions for PAXIL CR should be written for the smallest quantity of drug consistent with good patient management.

Because of the well established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders (see Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

For women who intend to become pregnant, or are in their first trimester of pregnancy, initiation of paroxetine should be considered only after other treatment options have been evaluated.

If a patient becomes pregnant while taking PAXIL CR, or intends to become pregnant, she should be informed of the current estimate of increased risk to the fetus with PAXIL CR over other antidepressants. Examinations of additional databases, as well as updated analyses, may result in changes to the current risk estimates. Consideration should be given to switching to other treatment options, including another antidepressant or non-pharmaceutical treatment such as cognitive behavioral therapy. Treatment with PAXIL CR should only be continued for an individual patient, if the potential benefits outweigh the potential risks.

Due to the potential for discontinuation symptoms, if a decision is taken to discontinue PAXIL CR treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (see Warnings and Precautions, Discontinuation of Treatment with PAXIL CR; Adverse Reactions, Adverse Events following Discontinuation of Treatment (or Dose Reduction) and Dosage and Administration, Discontinuation of Treatment with PAXIL CR).

The concentrations of paroxetine detected in the breast milk of lactating women are similar to those in the mother's plasma. Lactating women should not nurse their infants while receiving paroxetine unless in the opinion of the treating physician, breast feeding is necessary, in which case the infant should be closely monitored.

PAXIL CR or PAXIL IR has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. The usual precautions should be observed in patients with cardiac conditions.

The results from a multiple dose pharmacokinetic study with paroxetine IR, in subjects with severe hepatic dysfunction, suggest that the clearance of paroxetine is markedly reduced in this patient group (see Table 9). As the elimination of paroxetine is dependent upon extensive hepatic metabolism, its use in patients with hepatic impairment should be undertaken with caution (see Dosage and Administration, Special Patient Populations).

In elderly subjects, increased steady-state plasma concentrations and prolongation of the elimination half-life were observed relative to younger adult controls (Table 9). Elderly patients should, therefore, be initiated and maintained at the lowest daily dosage of paroxetine which is associated with clinical efficacy (see Dosage and Administration).

At therapeutic concentrations, the plasma protein binding of paroxetine is approximately 95%. After the administration of a single 50 mg oral dose of paroxetine IR to lactating women, the concentrations of paroxetine detected in breast milk were similar to those in plasma.

PAXIL CR tablets contain a degradable polymeric matrix (Geomatrix, a trademark of Jago Pharma, Muttenz, Switzerland) designed to control the dissolution rate of paroxetine over a period of approximately 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric coat delays the start of drug release until PAXIL CR tablets have left the stomach.

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male and female subjects (n=23) received single oral doses of PAXIL CR at four dosage strengths (12.5 mg, 25 mg, 37.5 mg and 50 mg), paroxetine C_max and AUC_0-inf increased disproportionately with dose (as seen also with immediate-release formulations). Mean C_max and AUC_0-inf values at these doses were 2.0, 5.5, 9.0, and 12.5 ng/mL, and 121, 261, 338, and 540 ng·h/mL, respectively. T_max was observed typically between 6 and 10 hours post-dose, reflecting a reduction in absorption rate compared with immediate-release formulations (IR). The mean elimination half-life of paroxetine was 15 to 20 hours throughout this range of single PAXIL CR doses. The bioavailability of 25 mg PAXIL CR is not affected by food.

During repeated administration of PAXIL CR (25 mg once daily), steady state was reached within two weeks (i.e., comparable to immediate-release formulations). In a repeat-dose study in which normal male and female subjects (n=23) received PAXIL CR (25 mg daily), mean steady state C_max, C_min and AUC_0-24 values were 30 ng/mL, 20 ng/mL and 550 ng·h/mL, respectively.

Based on studies using IR formulations, steady-state drug exposure based on AUC_0-24 was several-fold greater than would have been predicted from single-dose data. The excess accumulation is a consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable.

In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of the IR formulation of 20 to 40 mg daily for the elderly and 20 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 2 to 3 times greater than doubled.

In healthy young volunteers receiving a 20 mg daily dose of paroxetine IR for 15 days, the mean maximal plasma concentration was 41 ng/mL at steady state (see Table 9). Peak plasma levels generally occurred within 3 to 7 hours.

Paroxetine is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). This activity of the drug on brain neurons is thought to be responsible for its antidepressant and anxiolytic action in the treatment of depression, panic disorder and social anxiety disorder.

Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (α1, α2, β), dopaminergic, serotonergic (5HT₁, 5HT₂), or histaminergic receptors of rat brain membrane. A weak affinity for the muscarinic acetylcholine receptor was evident. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors.

Approximately 64% of an administered dose of paroxetine is eliminated by the kidneys and 36% in the faeces. Less than 2% of the dose is recovered in the form of the parent compound.

Paroxetine is subject to a biphasic process of metabolic elimination which involves presystemic (first-pass) and systemic pathways. First-pass metabolism is extensive, but may be partially saturable, accounting for the increased bioavailability observed with multiple dosing. The metabolism of paroxetine is accomplished in part by cytochrome P450 (IID₆). 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). The majority of the dose appears to be oxidized to a catechol intermediate which is converted to highly polar glucuronide and sulphate metabolites through methylation and conjugation reactions. The glucuronide and sulphate conjugates of paroxetine are about >10 000 and 3000 times less potent, respectively, than the parent compound as inhibitors of 5-HT reuptake in rat brain synaptosomes.