Antidepressant - Antiobsessional -

Antipanic - Anxiolytic Agent - Social Phobia (Social Anxiety Disorder) - Posttraumatic Stress Disorder Therapy

ratiopharm inc.

17 800 Lapointe Mirabel, Quebec Canada, J7J 1P3

Date of Preparation: June 13, 2003 Date of Revision: February 26, 2008 Submission Control No: 119904

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 13 DRUG INTERACTIONS 23 DOSAGE AND ADMINISTRATION 28 OVERDOSAGE 31 ACTION AND CLINICAL PHARMACOLOGY 31 STORAGE AND STABILITY 35 DOSAGE FORMS, COMPOSITION AND PACKAGING 35

PART II: SCIENTIFIC INFORMATION 36

PHARMACEUTICAL INFORMATION 36 CLINICAL TRIALS 37 DETAILED PHARMACOLOGY 39 TOXICOLOGY 41 REFERENCES 43

PART III: CONSUMER INFORMATION 49

ratio-PAROXETINE

paroxetine hydrochloride tablets

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Hypersensitivity: ratio-PAROXETINE

is contraindicated in patients who are known to be hypersensitive to the drug or any of its components. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

Monoamine Oxidase Inhibitors: ratio-PAROXETINE ratio-PAROXETINE ratio-PAROXETINE

In patients receiving serotonin reuptake inhibitors (SSRIs) in combination with a MAO inhibitor, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have begun treatment on a MAO inhibitor. Some cases presented with features resembling serotonin syndrome or neuroleptic malignant syndrome. (See WARNINGS AND PRECAUTIONS; Serotonin Syndrome/Neuroleptic Malignant Syndrome). Therefore,

should not be used in combination with MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) or within a minimum of 2 weeks of terminating treatment with MAO inhibitors. Treatment with

should then be initiated cautiously and dosage increased gradually until optimal response is reached. MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with

.

Thioridazine: Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose-related. An in vivo study suggests that drugs which inhibit P450 2D6, including certain SSRIs such as paroxetine, fluoxetine and fluvoxamine, will elevate plasma levels of thioridazine. Therefore, ratio-PAROXETINE should not be used in combination with thioridazine or within a minimum of 2 weeks of terminating treatment with thioridazine. At least 2 weeks should be allowed after discontinuing ratio-PAROXETINE therapy before initiating treatment with thioridazine.

Pimozide: ratio-PAROXETINE

The concomitant use of

and pimozide is contraindicated as paroxetine has been shown to increase plasma pimozide levels. Elevation of pimozide blood

concentration may result in QT interval prolongation and severe arrhythmias including Torsade de Pointe. (See Drug Interactions).

WARNINGS AND PRECAUTIONS

General

POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.

Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants 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.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

Adults and Pediatrics: Additional data

There are clinical trial and post-marketing reports with SSRIs and other newer anti-depressants, 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.

Discontinuation Symptoms: Patients currently taking ratio-PAROXETINE 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 anti-depressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

Discontinuation of Treatment with ratio-PAROXETINE

When discontinuing treatment, regardless of the indication for which ratio-PAROXETINE is being prescribed, patients should be monitored for symptoms which may be associated with discontinuation (e.g. dizziness, sleep disturbances including abnormal dreams, sensory disturbances (including paresthesias and 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)-Postmarketing)]. 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).

ratio-PAROXETINE Treatment During Pregnancy Effects on Newborns

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 ratio-PAROXETINE, consideration should be given to switching to other treatment options. Treatment with ratio-PAROXETINE 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 WARNING AND PRECAUTIONS, Special Populations). Post-marketing reports indicate that some neonates exposed to paroxetine, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants 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 paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see WARNINGS AND PRECAUTIONS, Special Populations; DOSAGE AND ADMINISTRATION, Special Patient Populations-Treatment of Pregnant Women During the Third Trimester).

Psychomotor Impairment

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 ratio-PAROXETINE does not affect them adversely.

The following additional precautions are listed alphabetically. Carcinogenesis and Mutagenesis

See TOXICOLOGY for animal data.

Cardiovascular

Paroxetine 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.

Concomitant Illnesses

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

Dependence Liability

Paroxetinehas 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 ratio- PAROXETINE.

Endocrine and Metabolism

Serum Cholesterol Elevation: Several public domain studies have shown increased LDL- cholesterol levels of ~ 10% in volunteers and patients taking paroxetine for 8 to 12 weeks, which generally normalized after paroxetine discontinuation. In addition, 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 (see Monitoring and Laboratory Tests, Serum Cholesterol Elevation). These data should be taken into consideration when treating patients with underlying cardiac risk factors.

Hematologic

Abnormal Bleeding:

There have been several reports of abnormal bleeding (mostly ecchymosis) associated with paroxetine 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. Paroxetine 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.

Hepatic/Biliary/Pancreatic

Hepatic Impairment: ratio-PAROXETINE

Pharmacokinetic studies of paroxetine 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.

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; ACTIONS AND CLINICAL PHARMACOLOGY, Hepatic Insufficiency)

Neurologic

Epilepsy: ratio-PAROXETINE

As with other antidepressants,

should be used with caution in patients with epilepsy.

Seizures:

During clinical trials, the overall incidence of seizures was 0.15% in patients treated with paroxetine. 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.

Serotonin Syndrome/Neuroleptic Malignant Syndrome: On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment of paroxetine, 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 ratio-PAROXETINE 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 ratio-PAROXETINE 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).

Ophthalmologic

Glaucoma:

As with other SSRIs, paroxetine can causes mydriasis and should be used with caution in patients with narrow angle glaucoma.

Psychiatric

Suicide: ratio-PAROXETINE

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

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).

Activation of Mania/Hypomania:

During clinical testing in a patient population comprised primarily of unipolar depressed patients, approximately 1% of paroxetine-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, paroxetine 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.

Electroconvulsive Therapy (ECT):

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

Renal

Hyponatremia:

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

Renal Impairment:

Since paroxetine 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; ACTIONS AND CLINICAL PHARMACOLOGY, Renal Insufficiency)

Special Populations

Pregnant Women and Newborns:

Risk of Cardiovascular Malformations following first trimester exposure to SSRIs:

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.

While on ratio-PAROXETINE: Pregnancy, or intent to become pregnant:

If a patient becomes pregnant while taking paroxetine, or intends to be become pregnant, she should be informed of the current estimate of increased risk to the fetus with paroxetine 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 paroxetine 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 paroxetine treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (see WARNING AND PRECAUTIONS, Discontinuation of Treatment With ratio-PAROXETINE, ADVERSE REACTIONS, Adverse Reactions Following Discontinuation of Treatment, and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment).

Initiation of paroxetine:

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.

Complications following late third trimester exposure to SSRIs:

Post-marketing reports indicate that some neonates exposed to paroxetine, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants 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 anti-depressants, 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 paroxetine 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).

Risk of PPHN and exposure to SSRIs (including paroxetine):

In one epidemiological case-control study on persistent pulmonary hypertension (PPHN) with n = 377 infants with PPHN and n = 836 matched control in 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 PPHN in the general population is reported to be 1 - 2 per 1000 (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Nursing Women: 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.

Pediatrics (< 18 years of age): ratio-PAROXETINE 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; DOSAGE AND ADMINISTRATION, Special Patient Populations-Children).

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 behavioural 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 DRUG REACTIONS, Clinical Trial Adverse Drug Reactions-Pediatrics).

Geriatrics ($ 65 years of age):

Administration of paroxetine 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). 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 paroxetine (10-40 mg daily) in worldwide pre-marketing clinical trials revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. 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.

Monitoring and Laboratory Tests

Serum Cholesterol Elevation: 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.

DRUG INTERACTIONS

Serious Drug Interactions

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS

Thioridazine: See CONTRAINDICATIONS

Pimozide: See CONTRAINDICATIONS

Overview

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 Cmin (ss) for paroxetine (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 co-administered 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 paroxetine is co-administered with drugs with a narrow therapeutic index. Paroxetine co-administration 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. Co-administration of phenobarbitol or phenytoin with paroxetine has been associated with decreased levels of paroxetine. When co-administered with cimetidine, paroxetine levels were elevated. The concomitant use of ratio-PAROXETINE and alcohol has not been studied.

Drug-Drug Interactions

Monoamine Oxidase Inhibitors:

Combined use of paroxetine 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; WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Thioridazine:

Combined use of paroxetine and thioridazide 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 torsade de pointes-type arrhythmias, and sudden death (See CONTRAINDICATIONS).

Pimozide: In an open label study of healthy volunteers, co-administration of a single dose of 2 mg pimozide, under steady state conditions of paroxetine (titrated to 60 mg daily) was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. This is likely explained by the known CYPRD6 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 Torsade de Pointes, concomitant use of pimozide and paroxetine is contraindicated (See CONTRAINDICATIONS). Drugs Metabolized by Cytochrome P450 (CYP2D6): In two studies, daily dosing of paroxetine (20 mg qd) under steady state conditions increased the following mean pharmacokinetic parameters for a single (100 mg) dose of desipramine in extensive metabolizers: Cmax (2 fold), AUC (6 fold), and T2 (3-5 fold). Concomitant steady-state paroxetine 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 paroxetine, if these drugs are to be used in combination. Plasma tricyclic antidepressant concentrations may need to be monitored in such instances. Concomitant use of paroxetine with other drugs metabolized by CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine 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, paroxetine and thioridazine should not be co-administered (See CONTRAINDICATIONS). Fosamprenavir/ritonavir: Co-administration 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). Drugs Metabolized by Cytochrome P450 (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, 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.

Microsomal Enzyme Inhibition/Induction:

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

Drugs Highly Bound to Plasma Protein:

Paroxetine is highly bound to plasma protein, therefore administration of paroxetine 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.

Alcohol: ratio-PAROXETINE

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

.

Anti-cholinergic Drugs:

Paroxetine 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 co-administered to steady state. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.

Antiretroviral:

Co-administration 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).

Phenobarbital: 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 T2 of paroxetine were reduced by an average of 25% and 38% respectively compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. No initial paroxetine dosage adjustment is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

Anticonvulsants:

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 co-administration of paroxetine (30 mg/day for 10 days) had no significant effect on the plasma concentrations of these anticonvulsants. In healthy volunteers, co-administration 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 paroxetine is considered necessary when the drug is to be co-administered with known drug metabolizing enzyme inducers (e.g. carbamazepine, phenytoin, sodium valproate) and any subsequent dosage adjustment should be guided by clinical effect. Co-administration of paroxetine with anticonvulsants may be associated with an increased incidence of adverse experiences.

Antipsychotic Drugs/Neuroleptic Malignant Syndrome:

As with other SSRIs, paroxetine 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, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Serotonergic Drugs: Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when paroxetine 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, Serotonin Syndrome/Neuroleptic Malignant Syndrome). Concomitant use of paroxetine and MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated (see CONTRAINDICATIONS).

Lithium:

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 paroxetine is coadministered with lithium.

Triptans: There have been rare post-marketing 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, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Tryptophan:

Tryptophan can be metabolized to serotonin. As with other serotonin reuptake inhibitors, the use of paroxetine 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 paroxetine with tryptophan is not recommended. (See WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

CNS Drugs:

Experience in a limited number of healthy subjects has shown that paroxetine does not increase the sedation and drowsiness associated with haloperidol, amylbarbitone or oxazepam, when

given in combination. Since the effects of concomitant administration of paroxetine with neuroleptics have not been studied, the use of paroxetine with these drugs should be approached with caution.

Diazepam:

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

Cardiovascular Drugs:

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

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.

Cimetidine:

Steady-state levels of paroxetine (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 paroxetine towards the lower end of the range when coadministered with known drug metabolizing enzyme inhibitors.

Drug-Food Interactions

The absorption and pharmacokinetics of paroxetine are not affected by food or antacids.

Drug-Herb Interactions

St. John's Wort:

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

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

General

ratio-PAROXETINE (paroxetine HCl) 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 ratio-PAROXETINE are recommended for elderly and debilitated patients, and patients with renal or hepatic impairment (See DOSAGE AND ADMINISTRATION, Special Patient Populations).

ratio-PAROXETINE

should be administered once daily in the morning and may be taken with or without food. The tablet should be swallowed rather than chewed.

Dose Adjustments:

Based on pharmacokinetic parameters, steady-state paroxetine plasma levels are achieved over a 7-14 day interval. Hence, dosage adjustments in 10 mg increments should be made at 1-2 week intervals or according to clinician judgment.

Maintenance:

During long term therapy for any indication, the dosage should be maintained at the lowest effective level.

There is no body of evidence available to answer the question of how long a patient should continue to be treated with paroxetine. 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 paroxetine hydrochloride has shown that efficacy is maintained for at least 6 months with doses that averaged about 30 mg (See CLINICAL TRIALS, Depression). Discontinuation of Treatment: Symptoms associated with the discontinuation of paroxetine 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 ratio-PAROXETINE is being prescribed. (See WARNINGS AND PRECAUTIONS, Discontinuation of Treatment with ratio-PAROXETINE and ADVERSE REACTIONS, Adverse Reactions Following Discontinuation of Treatment). 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).

Adults

Depression

Usual Adult Dose: The administration of ratio-PAROXETINE should be initiated at 20 mg daily. For most patients, 20 mg daily will also be the optimum dose. The therapeutic response may be delayed until the third or fourth week of treatment.

Dose Range:

For those patients who do not respond adequately to the 20 mg daily dose, a gradual increase in dosage up to 40 mg daily may be considered. The maximum recommended daily dose is 50 mg.

Obsessive-Compulsive Disorder

Usual Adult Dose: The administration of ratio-PAROXETINE should be initiated at 20 mg/day. The recommended dose of ratio-PAROXETINE in the treatment of OCD is 40 mg daily.

Dose Range:

For those patients who do not respond adequately to the 40 mg daily dose, a gradual increase in dosage may be considered. The maximum recommended daily dose is 60 mg.

Panic Disorder

Usual Adult Dose: The recommended starting dose of ratio-PAROXETINE in the treatment of panic disorder is 10 mg/day. The recommended dose of ratio-PAROXETINE in the treatment of panic disorder is 40 mg daily.

Dose Range:

For those patients who do not respond adequately to the 40 mg daily dose, a gradual increase in dosage may be considered. The maximum recommended daily dose is 60 mg.

Social Phobia (Social Anxiety Disorder)

Usual Adult Dose:

The recommended initial dosage is 20 mg/day. No clear dose-relationship has been demonstrated over a 20 to 60 mg/day dose range.

Dose Range:

Some patients not responding adequately to a 20 mg dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Generalized Anxiety Disorder

Usual Adult Dose:

The recommended initial dosage is 20 mg/day.

Dose Range:

Some patients not responding adequately to a 20 mg dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Posttraumatic Stress Disorder

Usual Adult Dose:

The recommended starting dosage is 20 mg/day.

Dose Range:

Some patients not responding adequately to a 20 mg/day dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Special Patient Populations:

Treatment of Pregnant Women:

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 ratio-PAROXETINE, 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 ratio- PAROXETINE 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 paroxetine, SSRIs, or other newer anti-depressants 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 paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering paroxetine in the third trimester. Geriatrics: (> 65 years): Administration of ratio-PAROXETINE 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 is 10 mg/day for elderly and/or debilitated patients. The dose may be increased if indicated up to a maximum of 40 mg daily.

Pediatrics: .

ratio-PAROXETINE is not indicated for use in children under 18 years of age (see INDICATION and WARNINGS AND PRECAUTIONS, Potential Association With Behavioural and Emotional Changes, Including Self-Harm)

Renal/Hepatic Impairment:

ratio-PAROXETINE

should be used with caution in patients with renal or hepatic impairment. The recommended initial dose is 10 mg/day in patients with clinically

significant renal or hepatic impairment. A maximum dose of 40 mg should not be exceeded. (See WARNINGS AND PRECAUTIONS; ACTION AND CLINICAL PHARMACOLOGY).

OVERDOSAGE

Symptoms of Overdosage

Patients have generally recovered without serious sequelae even when doses of up to 2000 mg have been taken alone. Events such as coma or ECG changes have occasionally been reported and, very rarely a fatal outcome, but generally when paroxetine was taken in conjunction with other psychotropic drugs, with or without alcohol. Experience of paroxetine in overdose has indicated that, in addition to those symptoms mentioned under AADVERSE REACTIONS @, vomiting, dilated pupils, fever, blood pressure changes, headache, involuntary muscle contractions, agitation, anxiety and tachycardia have been reported.

Treatment of Overdosage

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. Where appropriate, the stomach should be emptied by lavage. Following evacuation, 20 to 30 grams of activated charcoal may be administered every 4 to 6 hours during the first 24 hours after ingestion. An ECG should be taken and monitoring of cardiac function instituted if there is any evidence of abnormality. Supportive care with frequent monitoring of vital signs and careful observation is indicated. Due to the large volume of distribution of paroxetine, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. A specific caution involves patients taking or recently having taken paroxetine 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. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

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, obsessive-compulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder), generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). 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 (a1, a2, b), 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.

Pharmacokinetics

No clear dose relationship has been demonstrated for the antidepressant effects of paroxetine at doses above 20 mg/day. The results of fixed-dose studies comparing paroxetine and placebo in the treatment of depression, panic disorder, generalized anxiety disorder and posttraumatic stress disorder revealed a dose dependency for some adverse events.

Absorption:

Paroxetine is well absorbed after oral administration. In healthy volunteers, the absorption of a single 30 mg oral dose of paroxetine was not appreciably affected by the presence or absence of food.

Both the rate of absorption and the terminal elimination half-life appear to be independent of dose. Steady-state plasma concentrations of paroxetine are generally achieved in 7 to 14 days. No correlation has been established between paroxetine plasma concentrations and therapeutic efficacy or the incidence of adverse reactions. In healthy young volunteers receiving a 20 mg daily dose of paroxetine for 15 days, the mean maximal plasma concentration was 41 ng/mL at steady-state (see Table 4). Peak plasma levels generally occurred within 3 to 7 hours.

Distribution:

Owing to the extensive distribution of paroxetine into the tissues, less than 1% of the total drug in the body is believed to reside in the systemic circulation.

At therapeutic concentrations, the plasma protein binding of paroxetine is approximately 95%. After the administration of a single 50 mg oral dose to lactating women, the concentrations of paroxetine detected in breast milk were similar to those in plasma. Metabolism: 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(2D6). 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 3,000 times less potent, respectively, than the parent compound as inhibitors of 5-HT reuptake in rat brain synaptosomes.

Elimination:

Following the single or multiple dose administration of paroxetine at doses of 20 to 50 mg, the mean elimination half-life value for healthy subjects appears to be about 24 hours, although a range of 3 to 65 hours has been reported.

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.

Special Populations and Conditions

Geriatrics:

In elderly subjects, increased steady-state plasma concentrations and prolongation of the elimination half-life were observed relative to younger adult controls (Table 4). 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).

Hepatic Insufficiency:

The results from a multiple dose pharmacokinetic study in subjects with severe hepatic dysfunction suggest that the clearance of paroxetine is markedly reduced in this patient group (see Table 4). 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).

Renal Insufficiency:

In a single dose pharmacokinetic study in patients with mild to severe renal impairment, plasma levels of paroxetine tended to increase with deteriorating renal function (see Table 5). As multiple-dose pharmacokinetic studies have not been performed in patients with renal disease, paroxetine should be used with caution in such patients (See DOSAGE AND ADMINISTRATION, Special Patient Populations).

Table 4 Steady-state pharmacokinetics of paroxetine after doses of 20 mg daily (mean and range)

*Galactose elimination capacity 30-70% of normal.

A wide range of interindividual variation is observed for the pharmacokinetic parameters.

Table 5 Pharmacokinetics of paroxetine after a single 30 mg dose in normal subjects and those with renal impairment

a Creatinine clearance = 13-27 mL/min b Creatinine clearance = 32-46 mL/min c Creatinine clearance > 100 mL/min

Abbreviations:

Cmax = maximum plasma concentration; Tmax = time to reach Cmax AUC4 = Area under the plasma concentration time curve at infinity. T2 = terminal elimination half-life

STORAGE AND STABILITY

Store at 15-30degC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ratio-PAROXETINE 10 mg is available as yellow, scored, film coated modified-oval tablets engraved on one side with 1 and 0 on either side of the score mark respectively, and plain on the other side. Available in bottles of 30's

ratio-PAROXETINE 20 mg is available as pink, scored, film coated modified-oval tablets engraved on one side with 2 and 0 on either side of the score mark respectively, and plain on the other side. Available in bottles of 100's and 500's.

ratio-PAROXETINE 30 mg is available as blue, film coated modified-oval tablets engraved on one side with "30" and plain on the other side. Available in bottles of 30's.

Composition:

Paroxetine hydrochloride, dibasic calcium phosphate dihydrate USP, hydroxypropyl methylcellulose, hypromellose, magnesium stearate NF, polyethylene glycols, polysorbate 80, sodium starch glycolate NF, titanium dioxide, and one or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: paroxetine hydrochloride Chemical Name: (-)-trans-4R-(4'-fluorophenyl)-3S-(3',4'-methylene- dioxyphenoxymethyl)-piperidine hydrochloride hemihydrate. Or (-)-trans-4R-(4'-fluorophenyl)-3S-(3',4'-methylene-dioxyphenoxymethyl)- piperidine hydrochloride anhydrate. Molecular Formula: C19H20NO3F$HCl Molecular Weight: 374.8 (as hemihydrate salt) 365.8 (as anhydrate salt) 329.4 (as free base) Structural Formula: paroxetine hydrochloride Physicochemical properties:

Description:

a white to off-white solid

Melting point: 120-138EC

pKa and pH Values:

It is not possible to measure directly the pKa of paroxetine in water owing to the aliphatic nature of the piperidine ring system and the low solubility of paroxetine base. Measurements in 50% aqueous dimethyl sulphoxide indicate an aqueous pKa of 9.90 compared to a calculated value of 9.84. The pH of a saturated solution of paroxetine hydrochloride is 5.7 and a solution containing 2 mg/mL of paroxetine hydrochloride is 6.3.

Oil-Water Coefficient of Partition:

The apparent partition coefficient of paroxetine hydrochloride in the octanol-water system (Poct/water) is 3.38 (log P=0.53). The partition coefficient of paroxetine base between octanol-water determined using a solution of paroxetine hydrochloride in octanol and an aqueous phase of sodium hydroxide solution (1M) is 222 (log P=2.35). Paroxetine hydrochloride is slightly soluble in water (4.9 mg pure free base/mL).

CLINICAL TRIALS

Depression

The efficacy of paroxetine as a treatment for depression has been established in six placebo- controlled clinical trials of 6 weeks in duration performed in patients with depression (ages 18 to 73). In these studies, paroxetine was shown to be significantly more effective than placebo in treating depression according to the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI) - Severity of Illness. A study of outpatients with recurrent major depressive disorder who had responded to paroxetine (HDRS total score < 8) during an initial 8-week open-treatment phase and were then randomized to continuation on paroxetine or placebo for 1 year demonstrated that a significantly lower proportion of patients treated with paroxetine (15%) compared to placebo (39%) met criteria for partial relapse1. Criteria for full relapse2 were met by a significantly lower percentage of paroxetine treated patients (12%) compared to placebo treated patients (28%). Effectiveness was similar for male and female patients.

1. Partial relapse was characterized by requirement for additional antidepressant medication and fulfilment of DSM IIIR criteria for major depressive episode.

2. Full relapse was characterized by requirement for additional antidepressant treatment, fulfilment of DSM IIIR criteria for major depressive episode, deterioration in depressive symptoms for at least 1 week, increase in CGI-Severity of Illness score by $2 points and CGI-Severity of Illness score by $4 (least moderately ill).

Obsessive-Compulsive Disorder

Three double-blind, placebo-controlled clinical trials of 12 weeks in duration have been performed to investigate the efficacy of paroxetine in obsessive-compulsive disorder: two flexible dose studies (20-60 mg/day) and one fixed dose study (20, 40, & 60 mg/day). Results for the fixed dose study and one of the flexible dose studies showed statistically significant differences from placebo in favour of paroxetine in terms of mean change from baseline to endpoint on the Yale-Brown Obsessive-Compulsive Scale and/or the National Institute of Mental Health Obsessive-Compulsive Scale. In the fixed dose study, the proportion of patients who were considered to be much or very much improved at endpoint according to a Clinical Global Impression of Improvement was 15% (13/88) in the placebo group, 20% (17/85) in the 20 mg/day group, 36% (30/83) in the 40 mg/day group, and 37% (31/83) in the 60 mg/day group. In the two flexible dose studies, placebo response rates according to this criterion were 28% (28/99) and 25% (19/75), while paroxetine response rates were 45% (89/198) and 35% (28/79), respectively.

Panic Disorder

One fixed dose and three flexible dose placebo-controlled clinical trials of 10 to 12 weeks in duration have been performed to investigate the efficacy of paroxetine in panic disorder. The fixed dose study and two of the three flexible dose studies were supportive of differences from placebo in favour of paroxetine for measures of panic attack frequency. At endpoint, in the fixed dose study, the proportion of patients who were free of panic attacks was 44% (29/66) for the placebo group, 56% (33/59) for the 10 mg/day paroxetine group, 57% (35/61) for the 20 mg/day paroxetine group, and 76% (47/62) for the 40 mg/day paroxetine group.

Social Phobia (Social Anxiety Disorder)

One fixed dose and two flexible dose placebo-controlled clinical trials of 12 weeks in duration have been performed to investigate the efficacy of paroxetine in social phobia (social anxiety disorder). These studies showed statistically significant differences from placebo in favour of paroxetine in terms of mean change from baseline to endpoint on the Liebowitz Social Anxiety Scale and the percentage of therapeutic responders according to the Clinical Global Impression of Improvement. In the fixed dose study, the proportion of patients who were considered to be much or very much improved at week 12 of treatment according to the Clinical Global Impression of Improvement was 28.3% (26/92) in the placebo group, 44.9% (40/89) in the 20 mg/day group, 46.6% (41/88) in the 40 mg/day group, and 42.9% (39/91) in the 60 mg/day group. In the two flexible dose (20-50 mg/day) studies, placebo response rates according to this criterion were 23.9% (22/92) and 32.4% (47/145), while paroxetine response rates were 54.9% (50/91) and 65.7% (90/137), respectively.

Generalized Anxiety Disorder

The effectiveness of paroxetine in the treatment of Generalized Anxiety Disorder (GAD) (DSM IV) was demonstrated in two 8-week, multicentre, placebo-controlled studies. One trial was a flexible dose (20-50 mg/day) study while the other was a multiple fixed dose (20 or 40 mg/day) study. In both studies paroxetine demonstrated statistically significant superiority over placebo on the primary outcome measure - the Hamilton Rating Scale for Anxiety (HAM-A) total score, and on a number of secondary outcomes including the HAM-A anxiety and tension items, the Clinical Global Impression (CGI) responder criterion and the Sheehan Disability Scale (SDS). An additional 8-week flexible dose study did not demonstrate a significant difference between paroxetine (20-50 mg/day), and placebo on the primary outcome measure. However, paroxetine (20-50 mg/day) was more effective than placebo on many secondary study outcomes.

Posttraumatic Stress Disorder

The efficacy of paroxetine in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12 week, multicenter placebo controlled studies (Study 1 and Study 2) in adult patients who met the DSM-IV criteria for PTSD. Study outcome was assessed by (i) the Clinician Administered PTSD Scale Part (CAPS-2) score and (ii) the Clinical Global Impression Global Improvement Item (CGI-I). The CAPS-2 is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of: reexperiencing/intrusion, avoidance/numbing and hyperarousal. The two primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2 total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved). Study 1 was a 12 week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to placebo. Paroxetine 20 mg and 40 mg were demonstrated to be significantly superior to placebo for the CAPS-2 total score, and on proportion of responders on the CGI-I.. Study 2 was a 12-week flexible-dose study comparing paroxetine (20 mg to 50 mg daily) to placebo. Paroxetine was demonstrated to be significantly superior to placebo for the CAPS-2 total scorer, and on proportion of responders on the CGI-I. The majority (66-68%) of patients in these trials were women. Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years or older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively.

DETAILED PHARMACOLOGY

Animal Pharmacology

In vitro: Paroxetine showed a high potency for the inhibition of 5-HT reuptake in rat hypothalamic synaptosomes (Ki=1.1nM), but exerted relatively weak effects upon noradrenaline reuptake (Ki=350nM). The predominant metabolites of paroxetine, a sulphate and a glucuronide conjugate, were essentially inactive as 5-HT reuptake inhibitors. Paroxetine has a low affinity for muscarinic cholinergic receptors (Ki of 89 nM for displacement of [3H]quinuclidinyl benzilate). Animal studies have indicated only weak anticholinergic properties. Radioligand binding techniques in rat brain, in vitro, have indicated that paroxetine has little affinity for a1, a2 and b-adrenoceptors, dopamine (D2), 5-HT1-like, 5-HT2 and histamine (H1) receptors at concentrations below 1 mM. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate a lack of CNS depressant and hypotensive properties. In vivo: In mice, paroxetine (ED50=0.4 mg/kg p.o.) was associated with potent and prolonged potentiation of the hypermotility induced by the 5-HT precursor, 5-hydroxytryptophan. Similarly, the anticonvulsant effects of 5-hydroxytryptophan in a mouse electroshock model were potentiated by paroxetine (ED50=0.4 mg/kg p.o. ). In rats paroxetine (ED50=0.8 mg/kg p.o.) inhibited the hypermotility induced by p-chloroamphetamine, an agent which depletes neuronal 5-HT stores. Paroxetine, 1 mg/kg i.p., in conscious rats with chronically implanted cortical electrodes, produced essentially no changes in the power spectrum and frequency analysis of the EEG. Electrophysiological measures have demonstrated that paroxetine has a vigilance-increasing activity in animals. Oral doses of paroxetine 0.32 to 18 mg/kg to rats lengthened the waking period and shortened the slow-wave and paradoxical sleep periods in a dose-dependent fashion. As with other selective 5-HT uptake inhibitors, paroxetine, at a dose of 5 mg/kg i.p., causes symptoms of excessive 5-HT receptor stimulation when administered to rats previously given monoamine oxidase (MAO) inhibitors such as tranylcypromine or phenelzine, or the 5-HT precursor L-tryptophan. Behavioural and EEG studies indicate that paroxetine is weakly activating at doses above those generally required to inhibit 5-HT reuptake. The activating properties are not "amphetamine-like" in nature. In rats trained to discriminate d-amphetamine, 1 mg/kg i.p., from saline, no generalization to amphetamine was observed after administration of paroxetine (0.3, 1, 3 or 10 mg/kg i.p. ). Paroxetine caused seizures in mice at a lethal dose of 300 mg/kg p.o. At a dose of 50 mg/kg p.o., paroxetine lowered the threshold for electroshock-induced seizures in mice. Animal studies indicate that paroxetine is well tolerated by the cardiovascular system. When the cardiovascular effects of paroxetine and amitriptyline were compared in the conscious rabbit and anaesthetized cat, intravenous doses of paroxetine approximately 2 to 4 times higher (on a mg/kg basis) than those of amitriptyline were required to produce significant changes in blood pressure, heart rate and electrocardiographic parameters. Similarly, in the pentobarbital anaesthetized dog, i.v. imipramine, amitriptyline and clomipramine (in doses of 10 mg/kg) caused severe atrioventricular block and ventricular arrhythmia's, while equivalent doses of paroxetine resulted in only slight prolongation of the PQ interval. In addition, low doses (0.3 to 1 mg/kg) of the tricyclic antidepressants caused marked tachycardia, whereas paroxetine in doses up to 10 mg/kg had no effect on heart rate. Studies in the spontaneous hypertensive rat indicate that, in contrast to antidepressants which inhibit the uptake of noradrenaline, paroxetine at 5 mg/kg i.v. has a much reduced propensity to inhibit the antihypertensive effects of guanethidine. 5-HT is transported into blood platelets and central neurons by a similar active uptake transporter mechanism in the cell membrane. Thus, in common with other selective 5-HT reuptake inhibitors, administration of paroxetine results in depletion of 5-HT from platelets. This has been reported after repeated daily administration of paroxetine at doses of 0.1, 1 and 10 mg/kg i.p. in mice and rats, 1-7.5 mg/kg p.o. in monkeys and 10-50 mg orally to healthy human volunteers. Similarly, whole blood 5-HT levels were shown to be depleted in depressed patients after paroxetine administration.

Human Pharmacology:

Paroxetine 30 mg administered in single doses to healthy non-depressed volunteers did not impair psychomotor function which was measured by psychomotor tasks such as Morse tapping and motor manipulation, assessment of subjective perception and general assessment of arousal. Paroxetine at doses of up to 40 mg daily produces no clinically significant changes in blood pressure, heart rate or ECG after administration to healthy subjects.

TOXICOLOGY

General toxicity studies have been conducted in rhesus monkeys and rats, in both of which the metabolic pathway for paroxetine is the same as in man.

Acute Toxicity

In relation to the clinical dose, the acute LD50 of paroxetine is very high in both mice and rats (approximately 350 mg/kg).

Long-Term Toxicity

The no-toxic effect levels in the rhesus monkeys and rats were 4-10 times and 6-15 times the recommended range of clinical doses respectively. At higher doses (40 mg/kg for 3 months and 25 mg/kg for 12 months), lipidosis was observed in several tissues of rats (lungs, mesenteric lymph nodes, epididymides, retinal tissues - the latter by electron microscopy only). As paroxetine is a lipophilic amine with both hydrophobic and hydrophilic moieties, it may accumulate in lysosomes leading to an impairment of lipid catabolism and, hence, the accumulation of lipids within the lysosomes. It should be noted that the slight degree of lipidosis seen in the rat was restricted to doses and plasma levels much higher than those observed in man. In a clinical study investigating lamellated inclusion bodies in peripheral white blood cells during long term therapy, no difference between placebo and paroxetine could be detected.

Carcinogenicity

No carcinogenic potential was detected in rat (dose levels of 1, 5 and 20 mg/kg/day) and mouse (dose levels of 1, 5 and 25 mg/kg/day) life-span studies. A non dose-related increase in malignant liver cell tumours occurred in male mice at 1 and 5 mg/kg/day which was statistically significant at 5 mg/kg/day. There was no increase at 25 mg/kg/day or in female mice and the incidence was within the historical control range.

Reproduction and Impairment of Fertility Studies

5-Hydroxytryptamine and compounds modulating this amine are known to affect reproductive function in animals and at high dose levels cause marked overt toxicity. Paroxetine at 15 and 50 mg/kg (hydrochloride salt) has been shown to impair reproductive function in rats. In male rats, chronic administration of a 50 mg/kg dose has been associated with granulomatous reactions in the epididymides accompanied by atrophy and degeneration of the seminiferous tubules. There were no biologically significant effects on fertility of female rats but corpora lutea count was slightly reduced and preimplantation loss slightly increased at 50 mg/kg in association with marked maternal toxicity.

Teralotogy Studies

Reproduction studies were performed in rats and rabbits at doses up to 42 and 5 times the maximum recommended daily human dose (60 mg) on a mg/kg basis. These are 8.3 (rat) and 1.7 (rabbit) times the maximum recommended human dose on a mg/m2 basis. These studies have revealed no evidence of teratogenic effects or of selective toxicity to the embryo.

Immunotoxicity Studies

Specific studies have demonstrated that paroxetine is unlikely to possess the potential for immunotoxicity. Serum samples were obtained from depressed patients who had received 30 mg of paroxetine daily for between six and twelve months, from groups of rats on a repeat dose toxicity study in which daily doses of 1, 5 and 25 mg/kg of paroxetine were administered for 52 weeks, from guinea pigs epicutaneously exposed (topically under an occlusive patch) to paroxetine and from New Zealand White (NZW) rabbits parenterally (i.m. and s.c.) injected with paroxetine in Freund's adjuvant. In addition as a positive control, sera were obtained from NZW rabbits which had been immunized by i.m. and s.c. injections of Freund's adjuvant emulsions containing paroxetine chemically conjugated to bovine gamma globulin (BGG). Serum antibody levels were assessed by enzyme- or radio-immunoassays (ELISA or RIA). No anti-paroxetine antibody activity was detected in serum samples from patients, from rats in the toxicity study, from guinea pigs epicutaneously exposed to paroxetine, or from rabbits parenterally injected with paroxetine. Serum anti-paroxetine antibody was detected in rabbits immunized with Freund's adjuvant emulsions containing paroxetine coupled with BGG, verifying that the RIA system employed was capable of detecting antibodies directed against paroxetine. Paroxetine also did not induce contact sensitivity reactions in guinea pigs following epicutaneous exposure.

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6. Carillo JA, Ramos Si, Herraiz AG, Llerena A, Agundez JA, Berecz R et al.

Pharmacokinetic interaction of fluvoxamine and thiorodazine in schizophrenic patients. J Clin Psychopharmacol 1999; 19(6): 494-499. Chambers CDE, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New Engl J of Med 2006 Feb 9; 354(6): 579-587. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. New Engl J Med 1996; 1010-5. Claghorn JL. The safety and efficacy of paroxetine compared with placebo in a double- blind trial of depressed outpatients. J. Clin. Psychiatry 1992; 53 Suppl: 33-35. Claghorn JL. Paroxetine: Long Term Efficacy and Tolerability. Proc. 5th World Congr Biol Psychiatr Florence 1991: 12-13. Cohn JB, Wilcox CS. Paroxetine in major depression: a double-blind trial with imipramine and placebo. J. Clin Psychiatry 1992; 53 Suppl. : 52-56. Davidson JR. Biological therapies for posttraumatic stress disorder: an overview. J Clin Psychiatry, 1997; 58 Suppl. 9:29-32. Den Boer JA, Westenberg HG, Kamerbeek, WD, Verhoeven WM, Kahn RS. Effect of serotonin uptake inhibition in anxiety disorders; a double-blind comparison of clomipramine and fluvoxamine. Int Clin Psychopharmacology 1987; 2(1): 21-32. Dewar KM, Reader TA, Grondin L, Descarries L. [3H]-paroxetine binding and serotonin content of rat and rabbit cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum and midbrain raphe nuclei region. Synapse 1991; 9(1): 14-26. DuMouchel W. Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting. Am Statistician, 1999; 53: 177-202. DuMouchel W, Pregibon D. Empirical Bayes screening for multi-item associations. Tproc Kdd 2001, 67-76. Dunbar GC, Cohn JB, Fabre LF, Feighner JP, Fieve RR, Mendels J et al. A comparison of paroxetine, imipramine and placebo in depressed out-patients. Br. J. Psychiatry 1991: 159: 394-398. Dunbar GC, Mewett S. Evaluation of Suicidal Thoughts and Acts with Paroxetine. Proc. 5th World Congr. Biol. Psychiatr Florence 1991: 36-37. Dunbar GC, Stoker MJ. Paroxetine in the Treatment of Melancholic and Severely Depressed Hospitalised Patients. Eur Neuropsychopharmacol; Abstracts of the IVth Congress of the European College of Neuropsychopharmacology, Monaco 6-9 October 1991; 1(3): Dunbar GC. Paroxetine - An Effective Antidepressant with Impressive Safety Profile. J. Psychopharmacology 1990; 4 (4): 257. Dunner DL, Cohn JB, Walshe T, III, Cohn CK, Feighner JP, Fieve RR et al., Two combined, multicentre double-blind studies of paroxetine and doxepin in geriatric patients with major depression. J. Clin Psychiatry 1992; 53 (Suppl. ): 57-60. Dunner DL, Dunbar GC. Optimal dose regimen for paroxetine. J. Clin. Psychiatry 1992; 53 Suppl: 21-26. Eric L, Petrovic D, Loga S, Kobal M, Jakovljevic M, Mewett S. A Prospective, Double- Blind, Comparative, Multicentre Study of Paroxetine and Placebo in Preventing Recurrent Major Depressive Episodes. Proc. 5th World Congr. Biol. Psychiatr. Florence 1991; 10-11. Fabre LF, A 6-week, double-blind trial of paroxetine, imipramine and placebo in depressed outpatients. J. Clin. Psychiatry 1992; 53 (Suppl): 40-43. Feighner JP, Boyer WF. Paroxetine in the treatment of depression: a comparison with imipramine and placebo. J. Clin. Psychiatry 1992; 53 (Suppl. ): 44-47. Gorman JM, Liebowitz MR, Fyer AJ, Goetz D, Campeas RB, Fyer MR et al. An open trial of fluoxetine in the treatment of panic attacks. Journal of Clinical Psychopharmacolo 1987; 7(5): 329-332. Gould RA, Otto MW, Pollack MH, Yap L. Cognitive behavioral and pharmacological treatment of generalized anxiety disorder: A preliminary meta-analysis. Behavior Therapy, 1997; 28(2): 285-305. Greenough A, Khetriwal B. Pulmonary hypertension in the newborn. Paediatr Respir Rev 2005; 111-116. Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH. Concentration- related pharmacodynamic effects of thioridazine and its metabolites in humans. Clin Pharmacol Ther 1996; 60(5): 543-553. Hindmarch I, Harrison C. The effects of paroxetine and other antidepressants in combination with alcohol on psychomotor activity related to car driving. Acta Psychiatr Scand 1989; 350: 45. Hutchinson DR, Tong S, Moon CAL, Vince M, Clarke A. A Double Blind Study in General Practice to Compare the Efficacy and Tolerability of Paroxetine and Amitriptyline in Depressed Elderly Patients. Br J Clin Res 1991; 2: 43-57. Johnson AM. An overview of the animal pharmacology of paroxetine. Acta Psychiatr Scand 1989; 350: 14-20. Kallen B. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch of Pediatr & Adolesc Med 2004; 312-316. Kennet GA, Lightowler S, Stevens NC, Blackburn TP. Obessive-Compulsive Disorder: MCCP-induced mouth movements, a model of OCD. 19th CINP Congress, Washington DC, US 1919; 10: 174-178. Kennet GA, Lightowler S, Murphy O, De B, V, Stevens NC, Tulloch IF et al. Chronic Treatment with Paroxetine and Fluoxetine, But Not Desipramine, Desensitizes 5-HT2C Receptor Function. Br. J. Pharmacol 1994; 112(Proc Suppl): 643. Kerr JS, Sherwood N, Hindmarch I. The comparative psychopharmacology of the 5-HT Reuptake Inhibitors. Hum. Psychopharmacolo 1991; 6(4): 313-317. Kessler RC McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S et al. Lifetime and 12-Month prevalence of DSM-III-R Psychiatric disorders in the United States. Results form the National Comorbidity Survey. Arch Gen Psychiatry, 1994; 51(1): 8-19. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. 1995. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995; 52(12): 1048- 1060. Kiev A. A double-blind, placebo-controlled study of paroxetine in depressed outpatients. J. Clin. Psychiatry 1992; 53 Suppl: 27-29. Kim EJ & Y u BH. Increased cholesterol levels after paroxetine treatment in patients with panic disorder. J Clin Pychopharmacolo, 2005; 597-599. Kuhs H, Rudolf GA. Cardiovascular effects of paroxetine. Psychopharmacology (Berl) 1990; 102(3): 379-382. Lara N, Baker GB, Archer S, Le-Melledo JM. Increased cholesterol levels during paroxetine administration in healthy men. J Clin Psychiatry, 2003 Dec; 1455-1459. Mancini C, Van Ameringen MV. Paroxetine in social phobia. J Clin Psychiatry 1996; 57 (11): 519-522. Marshall RD, Beebe KL, Oldham M, Oldham M, Zaninelli R Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 2001; 158(12): 1982-1988. Mason I. Paroxetine Hailed for Care Advance on Older Therapies. Hosp. Doctor 1991 (18 April): 34. Mertens C, Pintens H. A double-blind, multicentre study of paroxetine and mianserin in depression. Acta Psychiatr. Scand.1989; 350: 140. Nelson DR, Pratt GD, Palmer KR, Johnson AM, Bowery NG Effect of paroxetine, a selective 5-hydroxytryptamine uptake inhibitor, on beta-adrenoceptors in rat brain: autoradiographic and functional studies. Neuropharmacology 1991: 30 (6): 607-616. Oehrberg S, Christiansen PE, Behnke K, Borup AL, Severin B, Soegaard J et al. Paroxetine in the treatment of panic disorder-A randomized double-blind placebo controlled study. Br J Psychiatry 1995; 167(3): 374-379. Pollack MH, Zaninelli R, Goddard A, McCafferty JP, Bellew KM, Burnham D.B et al. Paroxetine in the treatment of generalized anxiety disorder: results of a placebo- controlled, flexible-dosage trial. J Clin Psychiatry, 2001; 62(5): 350-357. Rasmussen JGC, Johnson AM. Incidence of Seizures During Treatment with Antidepressants, Including the New Selective Serotonin Re-Uptake Inhibitor, Paroxetine. Proc. 5th World Congr. Biol. Psychiatr. Florence 1991: 40-41. Rickels K, Amsterdam J, Clary C, Fox I, Schweizer E, Weise C. The efficacy and safety of paroxetine compared with placebo in outpatients with major depression. J. Clin. Psychiatry 1992; 53 Suppl: 30-32. Ringold AL. Paroxetine Efficacy in social phobia. J Clin Psychiatry 1994; 55 (8): 363- 364. Rocca P, Fonzo V, Scotta M, Zanalda E, Ravizza L. Paroxetine efficacy in the treatment of generalized anxiety disorder. Acta Psychiatr Scand 1997; 95(5): 444-450. Ross R. Atherosclerosis. In: Bennet & Plum, editors. Cecil Textbook of Medicine. 20th ed. 1996. p. 292-3. Shrivastava RK, Shrivastava,Overweg N, Blumhardt CL. A double-blind comparison of paroxetine, imipramine and placebo in major depression. J. Clin. Psychiatry 1992: 53 Suppl: 48-51. Smith WT, Glaudin V. A placebo-controlled trial of paroxetine in the treatment of major depression. J. Clin. Psychiatry 1992; 53 Suppl: 36-39. Solomon SD, Davison JR. Trauma: prevalence, impairment, service use, and cost. J Clin Psychiatry, 1997; 58: Supp. 9: 5-11. Stein MB, Chartier MJ, Hazen Al, Kroft CD, Chale RA, Cote D et al. Paroxetine in the treatment of generalized social phobia: open-label treatment and double-blind placebo- controlled discontinuation. J Clin Psychopharmacol 1996; 16(3): 218-222. Thomas DR, Nelson DR, Johnson AM. Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor. Psychopharmacology (Berl). 1987; 93(2): 193-200. Tucker P, Zaninelli R, Yehuda R, Ruggiero L, Dillingham K, Pitts CD. Paroxetine in the treatment of chronic posttraumatic stress disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 2001; 62(11): 860-868. Tulloch IF, Johnson AM. The pharmacologic profile of paroxetine, a new selective serotonin reuptake inhibitor. J. Clin. Psychiatry 1992; 53 Suppl: 7-12. Von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M, Hedberg A et al. Plasma levels of thioridazine and metabolites are influenced b the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1991; 49(3): 234-240. Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000 Jan; 14-20. Wittchen H.U, Zhao S, Kessler RC, Eaton WW. DSM-III-R generalized anxiety disorder in the National Comorbidity Survey. Arch Gen Psychiatry, 1994; 51(5): 355-364. Product Monograph of PAXIL, GlaxoSmithKline Inc., dated October 24, 2007.

PART III: CONSUMER INFORMATION

ratio-PAROXETINE paroxetine hydrochloride tablets

This leaflet is part III of a three-part "Product Monograph" published when ratio-PAROXETINE was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about ratio- PAROXETINE. Contact your doctor or pharmacist if you have any questions about the drug.

Please read this information before you start to take your medication, even if you have taken this drug before. Keep this information with your medicine in case need to read it again.

ABOUT THIS MEDICATION

What the medication is used for:

ratio-PAROXETINE

has been prescribed to you by your doctor to relieve your symptoms of:

C

depression, (feeling sad, a change in appetite or weight,

difficulty concentrating or sleeping, feeling tired, headaches, unexplained aches and pain)

C

panic attacks

C

social phobia (social anxiety disorder) - avoidance and/or fear of social situations,

C

generalized anxiety or nervousness

C

obsessive compulsive disorder (recurrent and intrusive thought, feeling, idea or sensation; recurrent pattern of behavior, or unwanted thoughts or actions), or

C

posttraumatic stress disorder (anxiety following a traumatic

event, for example a car crash, physical assault, natural disaster such as an earthquake).

What it does:

ratio-PAROXETINE belongs to the family of medicines called selective serotonin reuptake inhibitors. ratio-PAROXETINE is thought to work by increasing the levels of a chemical in the brain called serotonin (5-hydroxytryptamine).

When it should not be used:

Do not use ratio-PAROXETINE if you are:

C

allergic to it or any of the components of its formulation (see list of components at the end of this section).

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currently taking or have recently taken monoamine oxidase (MAO) inhibitor antidepressants (e.g. phenelzine sulphate, moclobemide) or linezolid, a MAO inhibitor antibiotic

C

currently taking or have recently taken thioridazine or pimozide.

What the medicinal ingredient is:

Paroxetine hydrochloride

What the nonmedicinal ingredients are:

Non-medicinal ingredients include: dibasic calcium phosphate

dihydrate USP, hydroxypropyl methylcellulose, hypromellose, magnesium stearate NF, polyethylene glycol, polysorbate 80, sodium starch glycolate NF, titanium dioxide, and one or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.

There is no ethanol, gluten, lactose, sulfite, or tartrazine in ratio- PAROXETINE.

What dosage forms it comes in:

ratio-PAROXETINE

is available as a 10 mg yellow tablet, 20 mg pink tablets, and a 30 mg blue tablet.

WARNINGS AND PRECAUTIONS

During treatment with these types of medications it is important that you and your doctor have good ongoing communication about how you are feeling.

ratio-PAROXETINE

is not for use in children under 18 years of age.

New or Worsened Emotional or Behavioral Problems Particularly in the first few weeks or when doses are adjusted, a small number of patients taking drugs of this type may feel worse instead of better; for example, they may experience unusual feelings of agitation, hostility or anxiety, or have impulsive or disturbing thoughts such as thoughts of self-harm or harm to others. Should this happen to you, or to those in your care if you are a caregiver or guardian, consult your doctor immediately. Close observation by a doctor is necessary in this situation. Do not discontinue your medication on your own.

BEFORE you use ratio-PAROXETINE tell your doctor:

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all your medical conditions, including a history of seizures, liver or kidney disease, heart problems or history of any abnormal bleeding;

C

any medications (prescription or non prescription) which you are taking or have recently taken, especially monoamine oxidase inhibitor antidepressants (e.g. phenelzine sulphate, moclobemide) or any other antidepressants, thioridazine, pimozide, drugs used to prevent fits (anticonvulsants), drugs for Parkinson's disease, or drugs containing tryptophan;

C

if you have ever had any allergic reaction to medications, food, etc.

C

any natural or herbal products you are taking (e.g. St. John's Wort);

C

if you are pregnant or thinking about becoming pregnant, or if you are breast-feeding;

C

your habits of alcohol and/or street drug consumption.

C

if you drive a vehicle or perform hazardous tasks during your work.

Effects on Pregnancy and Newborns

As stated above, ask your doctor or pharmacist for advice before taking any medicine including ratio-PAROXETINE. If you are already taking/using ratio-PAROXETINE and have just found out that you are pregnant, you should talk to your doctor immediately. You should also talk to your doctor if you are planning to become pregnant.

Taking ratio-PAROXETINE in early stages of pregnancy:

Some studies have suggested an increase risk of birth defects particularly heart defects, in babies whose mothers received paroxetine in the first few months of pregnancy. These studies found that about 2 in 100 babies (2%) whose mothers received paroxetine in early pregnancy had a heart defect, compared with the normal rate of 1 in 100 babies (1%) seen in the general population. Also, in cases where paroxetine has been used, there have been reports of premature births although it is not known if these premature births are due to the use of paroxetine.

Taking ratio-PAROXETINE in later stages of pregnancy: Possible complication at birth (from taking any newer

antidepressant, including ratio-PAROXETINE):

Post-marketing reports indicate that some newborns whose mothers took an SSRI (Selective Serotonin Reuptake Inhibitor) or other newer anti-depressant, during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support and tube feeding. Reported symptoms included feeding and/or breathing difficulties, seizures, tense or overly relaxed muscles, jitteriness and constant crying.

In most cases, the newer anti-depressant was taken during the third trimester of pregnancy. These symptoms are consistent with either a direct adverse effect of the anti-depressant on the baby, or possibly a discontinuation syndrome caused by sudden withdrawal from the drug. These symptoms normally resolve over time. However, if your baby experiences any of these symptoms, contact your doctor as soon as you can.

Persistent Pulmonary Hypertension (PPHN) and newer antidepressants, including ratio-PAROXETINE:

Preliminary information suggests that use of SSRIs during the

second half of pregnancy may be associated with an increased rate of a serious lung condition (PPHN) that causes breathing difficulties in newborns soon after birth. According to the study, babies born with this condition were 6 times more likely than healthy babies to have been exposed to SSRIs. In the general population, PPHN is known to occur at a rate of about 1-2 per 1000 newborns.

If you are pregnant and taking an SSRI, or other newer

anti-depressant, you should discuss the risks and benefits of the various treatment options with your doctor. It is very important that you do NOT stop taking these medications without first consulting your doctor. See SIDE EFFECTS AND WHAT TO DO ABOUT THEM section for more information.

INTERACTIONS WITH THIS MEDICATION

Do not use ratio-PAROXETINE if you are taking or have recently taken monoamine oxidase inhibitors, thioridazine, or pimozide (Orap7).

You should tell your doctor if you are taking or have recently taken any medications (prescription, non-prescription or natural/herbal), especially:

C

other antidepressants, such as SSRIs and certain tricyclics

C other drugs that affect serotonin such as, lithium, linezolid, tramadol, tryptophan, St. John=s Wort, triptans used to treat migraines

C

certain medicines used to treat patients with irregular heart beats (arrhythmias)

C

certain medicines used to treat schizophrenia

C

certain medicines used to treat bipolar depression, such as lithium

C

a combination of fosamprenavir and ritonavir, used to treat Human Immunodeficiency Virus (HIV) infection

C procyclidine, which is used to treat Parkinson=s Disease or other movement disorders

C

metoprolol, which is used to treat high blood pressure and angina

C

certain medicines which affect blood clotting and increase bleeding, such as oral anti-coagulants (e.g. warfarin), aspirin and other non-steroidal anti-inflammatory drugs (e.g. ibuprofen)

C

certain medicines used to treat epilepsy

C

in general, drinking alcoholic beverages should be kept to a minimum or avoided completely while taking

ratio- PAROXETINE.

PROPER USE OF THIS MEDICATION

Usual dose:

C It is very important that you take ratio-PAROXETINE exactly as your doctor has instructed. Generally most people take between 20 mg to 40 mg of ratio-PAROXETINE per day for depression, obsessive-compulsive disorder, panic disorder, social phobia (social anxiety disorder), generalized anxiety disorder and posttraumatic stress disorder; although your doctor may start you at 10 mg per day for panic disorder.

C

Take your tablets in the morning, preferably with food. You should swallow the tablets whole with water. Do not chew them.

C

You should continue to take your medicine even if you do not feel better, as it may take a number of weeks for your medicine to work.

C

Keep taking your tablets, as instructed, until the doctor tells you to stop.

C

Talk to your doctor before you stop taking your medication on your own.

Remember: This medicine has been prescribed only for you. Do not give it to anybody else, as they may experience undesirable effects, which may be serious.

Missed Dose:

If you forget to take your tablet in the morning, take it as soon as you remember. Take your next dose at the normal time the next

morning, then carry on as before. Do not try to make up for a missed dose by taking a double dose the next time.

Overdose:

If you have taken a large number of tablets all at once, contact your doctor or the nearest hospital emergency department immediately, even though you may not feel sick. Show the doctor your pack of tablets.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medications, ratio-PAROXETINE can cause some side effects. You may not experience any of them. For most patients these side effects are likely to be minor and temporary. However, some may be serious. Some of these side effects may be dose related. Consult your doctor if you experience these or other side effects, as the dose may have to be adjusted.

If you experience an allergic reaction (including skin rash, hives, swelling, trouble breathing) or any severe or unusual side effects, stop taking the drug and contact your doctor immediately.

The most common side effects of paroxetine are:

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nausea

C dry mouth C drowsiness C weakness C dizziness

C

sweating

C

nervousness

C

sleep disturbances

C

sexual problems

C

Although psychiatric disorders are often associated with decreases in sexual desire, performance and satisfaction, treatment with this medication may lead to further decreases.

Other effects may include loss of appetite, constipation, diarrhea, and headache.

ratio-PAROXETINE

does not usually affect people's normal activities. However, some people feel sleepy while taking it, in which case they should not drive or operate machinery.

ratio-PAROXETINE

may raise cholesterol levels in some patients.

New or Worsened Emotional or Behavioral Problems

A small number of patients taking a drug of this type may feel worse instead of better; for example, they may experience new or worsened feelings of agitation, hostility or anxiety, or thoughts about suicide. Your doctor should be informed of such changes immediately. Close observation by a doctor is necessary in this situation. Do not discontinue your medication on your own. See also the WARNINGS AND PRECAUTIONS section.

Discontinuation Symptoms

Contact your doctor before stopping or reducing your dosage of

ratio-PAROXETINE

. Symptoms such as dizziness,

lightheadedness, nausea, vomiting, agitation/restlessness, anxiety, sweating, headache, sleep disturbance, electric shock sensations, tinnitus (buzzing, hissing, whistling, ringing or other persistent noise in the ears) and other symptoms have been reported after stopping the treatment, reducing the dosage of

ratio-PAROXETINE, or when a dose is missed. These symptoms usually disappear without needing treatment. Tell your doctor immediately if you have these or any other symptoms. Your doctor may adjust the dosage of ratio-PAROXETINE to alleviate the symptoms. See WARNINGS AND PRECAUTIONS section for more information.

Effects on Newborns

Some newborns whose mothers took an SSRI (Selective Serotonin Reuptake Inhibitor) or other newer anti-depressant, such as paroxetine, during pregnancy have shown such symptoms as breathing and feeding difficulties, jitteriness and constant crying. If your baby experiences any of these symptoms, contact your doctor as soon as you can. See WARNINGS AND PRECAUTIONS section for more information.

* If you think you have these side effects, it is important that you

seek medical advice from your doctor straight away.

This is not a complete list of side effects. For any unexpected effects while taking ratio-PAROXETINE, contact your doctor or pharmacist.

HOW TO STORE IT

• Keep all medicines out of the reach of children.

• Store at room temperature (15-30degC) in a dry place.

• Keep container tightly closed.

• If your doctor tells you to stop taking ratio-PAROXETINE, please return any left over medicine to your pharmacist.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789

By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney=s Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

You may need to read this package insert again. Please do not throw it away until you have finished your medicine. This

document plus the full product monograph, prepared for health professionals can be found at:

ratiopharm inc.

17 800, Lapointe, Mirabel Quebec, Canada, J7J 1P3 1-800-337-2584

Last revised: February 26, 2008